Non-inferiority trial of remimazolam versus propofol for fast-track anesthesia in children undergoing percutaneous closure of atrial septal defect

Abstract

Background and objective

Remimazolam, a new member of the benzodiazepine class, has been used as an alternative to propofol during anesthesia induction. In this study, we aimed to examine the effectiveness and safety of remimazolam compared with propofol for both the induction and maintenance of fast-track general anesthesia in children undergoing percutaneous closure of an atrial septal defect (ASD).

Methods

We carried out a single-center, prospective, randomized controlled, observer-blinded, non-inferiority trial among 101 children, of whom 57 received remimazolam and 44 received propofol. All children underwent percutaneous closure of an atrial septal defect and had an American Society of Anesthesiologists (ASA) physical status of II before surgery. The primary outcome was the time to laryngeal mask airway (LMA) removal, measured in minutes.

Results

We included all 101 patients in the final analysis. Children in the remimazolam group had a significantly shorter time to LMA removal (mean difference [MD]: ‑7.97 min; 95% CI: ‑8.91 to ‑7.02; p < 0.001) and a shorter duration of hospitalization (median 5 vs. 7 days; p < 0.001) than the propofol group. The Pediatric Anesthesia Emergence Delirium (PAED) score was also lower in the remimazolam group (median 3 vs. 6; p < 0.001), indicating a reduced occurrence of postoperative emergence delirium. Fewer children in the remimazolam group required a vasopressor (26% vs. 64%). Mean arterial pressure and heart rate each showed a significant intervention-by-time interaction (their trajectories over time differed between groups), without a significant overall between-group difference in either.

Conclusions

This study suggests that remimazolam offers advantages over propofol for fast-track anesthesia in children undergoing percutaneous ASD closure, including faster LMA removal, shorter hospitalization, and a lower incidence of postoperative emergence delirium, with a differing intraoperative mean arterial pressure trajectory and comparable overall hemodynamic stability.

Trial registration number

ChiCTR2500109737, Registration date: 24 Sep. 2025. Retrospectively registered.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12871-026-04106-1.

Background

Congenital heart disease (CHD) is one of the most common birth anomalies worldwide, with a global incidence of approximately 8 to 12 cases per 1000 live births [1, 2]. In China, CHD comprises about 26.7% of all congenital anomalies, with an estimated 150,000 to 200,000 new cases each year (Ministry of Health of the People’s Republic of China. Report on the Prevention and Treatment of Birth Defects in China, 2012). CHD is most commonly treated with surgery, which also requires general anesthesia [3]. However, general anesthesia can pose a risk of complications during surgery in children, since CHD can leave children immunosuppressed and vulnerable [4]. Over the years, considerable research has sought the ideal anesthetic drugs to minimize the risk of complications, and propofol has been one of the most commonly used drugs during CHD surgery [3, 5–8]. However, propofol has some significant adverse effects in children with CHD, such as affecting blood flow during surgery, which can ultimately lead to cyanotic heart disease [9], and depressing mitochondrial function, with potential cerebrovascular complications [10].

Remimazolam, a new short-acting benzodiazepine anesthetic with fewer adverse effects than propofol, has recently emerged [11]. Remimazolam can be characterized by rapid onset, quick recovery from the anesthesia, and better hemodynamic stability compared to propofol, and, more importantly, it can be effectively antagonized by flumazenil [12]. A recent comparison meta-analysis study of eleven articles, featuring the effect of remimazolam vs. propofol, mentioned that remimazolam had lower incidences of intra-operative hypotension and bradycardia, better heart rate, and less injection pain [11]. A recent study evaluating the comparative recovery quality after general anesthesia with remimazolam vs. propofol indicated that remimazolam had a better score on the 15-item quality of recovery (QoR‑15) scale compared to propofol [13].

While research on the efficacy and safety of remimazolam has become a trend among scientists [5, 11], studies assessing the effect of remimazolam on CHD patients were rarely done. Furthermore, most available studies of remimazolam in children have reported major bias and design flaws that may have an impact on the true effect of remimazolam in children [14]. Therefore, we sought to examine the effectiveness and safety of remimazolam in comparison to propofol for both the induction and maintenance of fast-track general anesthesia in children undergoing percutaneous closure of an atrial septal defect.

Methods

Trial design

This was a single-center, prospective, randomized controlled, observer-blinded, non-inferiority trial. The trial was carried out at Zhengzhou University Central China Fuwai Hospital, affiliated with Henan Provincial People’s Hospital, Zhengzhou, China, from January 2024 to December 2024.

Study participants

A total of 101 children (aged 2 to 8 years) scheduled for elective percutaneous closure of an atrial septal defect under fast-track general anesthesia were considered eligible (Fig. 1). All participants had an American Society of Anesthesiologists (ASA) physical status of II [15]. Potential patients were referred to the department by a medical doctor.

Fig. 1.

Population flowchart of the included study participants

During the screening phase of this trial, the patients who participated in other clinical studies within the three months prior to this trial were considered ineligible. Additionally, patients with complex cyanotic CHD, congenital anomalies other than CHD, those who had already undergone cardiac intervention or surgery, those who required re-intervention, or those with a history of allergic reactions to either remimazolam or propofol were also considered ineligible during screening.

Patients diagnosed by cardiac surgeons as unsuitable for surgical intervention under general anesthesia, who required open-heart surgery for emergency treatment, and those who had undergone surgical intervention, but the procedure was unsuccessful were deemed ineligible.

Randomization and masking

Participants were randomly allocated to the remimazolam or propofol group using a computer-generated random-number sequence. Allocation was concealed with sequentially numbered, sealed opaque envelopes managed by a nurse not otherwise involved in the study and opened only after the patient arrived in the operating room. Because remimazolam and propofol differ in appearance and concentration, the attending anesthesiologist could not be blinded; the trial was therefore observer-blinded, with patients, their parents, and all outcome assessors masked to group allocation. To limit performance and detection bias, study drugs were prepared and administered by an anesthesiologist who took no part in outcome assessment.

Study intervention

Patients in the remimazolam group received 0.1 mg kg‑1 for induction and 0.3–0.7 mg kg‑1 h‑1 for maintenance. The propofol group received 1.0–1.5 mg kg‑1 for induction and 4–10 mg kg‑1 h‑1 for maintenance. Both groups had the same anesthesia protocol for all aspects. All procedures were performed under general anesthesia with a laryngeal mask airway (LMA) in every child. In both groups, anesthesia was induced with sufentanil and the neuromuscular blocking agent rocuronium, and remifentanil was infused for intraoperative analgesia during maintenance. Depth of anesthesia was guided by the Bispectral Index (BIS), with infusion rates titrated to a target BIS of 40 to 60 uniformly in both groups; transient decreases in BIS below 40 occurred in 2 of 57 patients in the remimazolam group (lasting 7 and 8 min) and in 4 of 44 patients in the propofol group (lasting 7 to 10 min), and in each instance the maintenance infusion rate was reduced (remimazolam from 0.7 to 0.4 mg kg‑1 h‑1; propofol from 10 to 4–5 mg kg‑1 h‑1) until BIS returned to the target range; no patient recorded a BIS value above 60. At the end of surgery, flumazenil 0.1 mg was administered to one remimazolam-group patient because of delayed emergence with prolonged laryngeal-mask tolerance, and no propofol-group patient received flumazenil.

Outcomes

The primary outcome was the time to LMA removal, measured in minutes. It was defined as the interval from discontinuation of the maintenance anesthetic at the end of the procedure to removal of the LMA, with removal performed once the patient demonstrated adequate spontaneous ventilation and protective airway reflexes [16]. Secondary outcomes were the time to loss of consciousness (recorded in seconds), the Pediatric Anesthesia Emergence Delirium (PAED) score, the duration of hospitalization (days), and mean arterial pressure (MAP) and heart rate (HR) at predefined time points. The name and dose of any vasopressor administered during surgery were also recorded.

Clinical assessment and data

All the anesthesiologists and outcome assessors were trained by a single surgeon (Pengyu Qin) to record all the parameters during surgery and anesthesia procedures. Later, their data-collection techniques were standardized using established protocols. Before initiating the final study, a pilot study among 10% of the study participants was conducted to assess the standardized clinical parameter-measuring techniques among the healthcare providers. Study participants included in the pilot study were not included in the final study.

Initially, the age, sex, and weight of all patients were measured and recorded, and relevant clinical histories were obtained from their parents. All vital signs were monitored after the patient entered the operating room. The MAP and HR were recorded at seven time points: (T0) before induction, (T1) before LMA insertion, (T2) immediately after LMA insertion, (T3) at the start of surgery, (T4) at the end of surgery, (T5) immediately after LMA removal, and (T6) five minutes after LMA removal.

Vasopressor agents were utilized, if necessary, to maintain the blood pressure within the normal limit during the surgical procedure.

Patients were shifted to the post-operative room after LMA removal with all the post-anesthesia care unit (PACU) facilities. The level of delirium was assessed using the 5-item PAED scale 15 min after LMA removal.

Statistical analysis

All the statistical analyses of this study were conducted using R software version 4.4, and several packages were used to run all the descriptive and analytic tests [17]. For the descriptive table, the continuous variables were presented with their mean and standard deviation (SD), and the categorical variables were mentioned as frequencies and percentages. All the primary and secondary outcomes of this study were analyzed utilizing either the independent t-test when the data appeared to be normal or the Mann-Whitney U test when the data were not normal. The normality of the data was assessed using the Shapiro-Wilk test and histogram figures for all the continuous variables regardless of whether they were outcome or independent variables. The primary outcome of this study was analyzed using the independent t-test since the data structure was found to be normal. The homogeneity of variance was evaluated using Levene’s test. For continuous secondary outcomes or independent variables, we used relevant parametric or non-parametric statistical tests based on the data normality. When the data were normal, we conducted t-tests, and when they were not normal, we conducted Mann-Whitney U tests. For categorical variables, we used chi-square tests or Fisher’s exact tests, depending on the number of cases in each of the cells. For the repeated-measures variables (MAP and HR), we performed a two-way repeated-measures analysis of variance (ANOVA) to assess the effects of time, intervention, and their interaction. If the assumption of sphericity was violated, the Greenhouse-Geisser correction was applied, and post-hoc pairwise comparisons were conducted using the Bonferroni correction. Effect sizes were reported as mean differences (MD) or risk ratios (RR) with their corresponding 95% confidence intervals (CIs). For non-parametric data, the Hodges-Lehmann estimator was used to estimate the median difference and its 95% CI. Data were visualized using ggplot2, with line plots and error bars used to display changes in continuous variables over time and boxplots or bar charts used for categorical comparisons. All analyses were performed in accordance with the CONSORT guidelines for randomized controlled trials (supplementary file 1), and all statistical tests were two-tailed, with p-values < 0.05 considered statistically significant. The sample size was determined a priori for the primary outcome, time to LMA removal, under a non-inferiority framework. Assuming an emergence-time standard deviation of approximately 3 min based on prior pediatric studies of remimazolam and propofol, a non-inferiority margin of 2 min, a one-sided alpha of 0.025, and 90% power, 48 patients per group were required; allowing for approximately 10% attrition, the target was 53 per group. A total of 101 children (57 remimazolam, 44 propofol) were enrolled and analyzed.

Results

Demographic and clinical characteristics

The demographic and general clinical characteristics of the 101 study participants are presented in Table 1. Participants were treated in two groups: the first received remimazolam (n = 57) and the second received propofol (n = 44). The mean (SD) age was 5.4 (1.6) years in the remimazolam group and 6.3 (1.6) years in the propofol group. Males made up 47.4% of the remimazolam group and 38.6% of the propofol group. All patients in both groups were classified as ASA II and underwent the same procedure, percutaneous closure of the atrial septal defect. Vasopressor use differed between the groups: approximately one-quarter of the remimazolam group (15/57, 26.3%) received a vasopressor, most commonly methoxamine 0.5 mg, whereas approximately two-thirds of the propofol group (28/44, 63.6%) received methoxamine 1 mg. No adverse reactions were reported in either group. The mean (SD) time to LMA removal was 2.4 (0.6) minutes in the remimazolam group and 10.4 (3.2) minutes in the propofol group, and the mean (SD) duration of hospitalization was 4.9 (1.5) days and 7.8 (2.7) days, respectively. Mean (SD) body weight was similar between groups (remimazolam 19.4 (5.7) kg; propofol 20.9 (5.3) kg). Mean (SD) height was 111.6 (12.9) cm in the remimazolam group and 117.2 (13.0) cm in the propofol group (mean difference 5.55 cm, 95% CI 0.40 to 10.70; p = 0.035). No sedation failures occurred in either group; all patients achieved and maintained adequate general anesthesia with the assigned hypnotic agent, and none required conversion to an alternative agent.

Table 1.

Demographic characteristics of the study patients

Characteristics	Remimazolam (n = 57)	Propofol (n = 44)
Age in years (mean ± SD)	5.4 ± 1.6	6.3 ± 1.6
Sex, Male (n, %)	27 (47.4)	17 (38.6)
Weight in kg (mean ± SD)	19.4 ± 5.7	20.9 ± 5.3
Height in cm (mean ± SD)	111.6 ± 12.9	117.2 ± 13.0
ASA Grade II (n, %)	57 (100)	44 (100)
Surgery name: Percutaneous closure of atrial septal defect (n, %)	57 (100)	44 (100)

Primary outcome

Figure 2 presents a forest plot depicting the effect estimate, i.e., the mean difference of time to LMA removal after anesthesia between the remimazolam and propofol groups of study participants. The mean difference in time to LMA removal after anesthesia was estimated to be ‑7.97 min, with the 95% confidence interval (CI) ranging from ‑8.91 to ‑7.02 min. The findings of this primary outcome indicate that patients in the remimazolam group had a shorter time to LMA removal compared to propofol, suggesting that remimazolam may facilitate quicker recovery from anesthesia.

Fig. 2.

Forest plot of the mean difference between two intervention groups in time to LMA removal (in minutes)

Secondary outcomes and other independent variables

In Table 2, we presented the effect estimates of secondary outcomes and other independent variables, i.e., age, sex, and weight, comparing the two intervention groups of this study.

Table 2.

Effect estimates of independent variables and secondary outcomes included in this research

Variables	Unit of measurement	Remimazolam (n = 57)	Propofol (n = 44)	Mean differencea/ Risk ratiob (95% CI)	p-value
Age, Median (Q1, Q3)	Years	6 (4, 6)	6 (5, 8)	1c (0, 2)	< 0.01d
Sex, Male	NA	27 (47.4%)	17 (38.6%)	1.23b (0.77, 1.95)	0.5
Weight, Mean ± SD	Kilogram	19.4 ± 5.7	20.9 ± 5.3	1.45a (-0.8, 3.7)	0.193
Height, Mean ± SD	Centimeter	111.6 ± 12.9	117.2 ± 13.0	5.55a (0.40, 10.70)	0.035
Hospitalization days, Median (Q1, Q3)	Days	5 (4, 6)	7 (6, 9)	3c (2, 3)	< 0.001d
Time of loss of consciousness, Median (Q1, Q3)	Seconds	60 (55, 65)	28 (25, 30.5)	30c (28, 33)	< 0.001d
PAED score, Median (Q1, Q3)	PAED score	3 (2, 3)	6 (5, 6)	-3c (-3.0, -2.0)	< 0.001d

^aMean difference between the two groups with 95% confidence interval, calculated for the normally distributed continuous variables (weightand height) using the independent-samples t-test

^bRisk ratio with 95% confidence interval for the categorical variable (sex), calculated as the proportion in the Remimazolam group relativeto the Propofol group; the corresponding p-value is derived from thechi-square test

^cHodges-Lehmann Estimate, since the data did not pass the normality test, the mean difference is not applicable for the Mann-Whitney U test

^dp-value is considered from the Mann-Whitney U test

Among the secondary outcomes, the duration of hospitalization differed significantly between the groups: children who received remimazolam stayed fewer days than those who received propofol (median difference 3.0 days; 95% CI 2.0 to 3.0; p < 0.001). Loss of consciousness during induction occurred later in the remimazolam group than in the propofol group (median 60 vs. 28 s; median difference 30 s; 95% CI 28 to 33; p < 0.001), consistent with the slower onset expected for remimazolam. The PAED score was significantly lower (lower is better) in the remimazolam group than in the propofol group (median difference ‑3.0; 95% CI ‑3.0 to ‑2.0; p < 0.001), indicating less postoperative emergence delirium.

Among the other independent variables, the intervention groups had significant differences in age (median difference 1.0, 95% CI 0 to 2; p < 0.01). The sex and weight of these two independent variables did not show any significant difference for the intervention groups.

Table 3 presents the two-way repeated-measures ANOVA results for MAP and HR. For MAP, the main effect of intervention was not statistically significant (F = 1.55, p = 0.22), whereas the intervention-by-time interaction was significant (F = 28.28, p < 0.001), indicating that the MAP trajectory over time differed between the groups. For HR, the main effect of intervention was not statistically significant (F = 2.19, p = 0.14), whereas the intervention-by-time interaction was significant (F = 6.08, p < 0.001), indicating that the HR trajectory over time also differed between the groups.

Table 3.

ANOVA table for mean arterial pressure (MAP) and heart rate (HR)

Variables	Sum of squares	Mean square	F	p-value
Mean Arterial Pressure
Intervention	328	327.5	1.55	0.22
Time	16,321	2720.1	667.44	< 0.001
Intervention and time	691	115.2	28.28	< 0.001
Heart rate
Intervention	2022	2022.0	2.19	0.14
Time	27,945	4657.5	346.87	< 0.001
Intervention and time	490	81.7	6.08	< 0.001

Figure 3 illustrates the MAP trends at seven time points (T0-T6) during anesthesia as the intention-to-treat analysis approach, comparing the two intervention groups. From the figure, we can say that the MAP values fluctuated somewhat over time for both remimazolam and propofol. The MAP trajectories over time differed between the groups (significant intervention-by-time interaction), without a significant overall between-group difference in MAP.

Fig. 3.

The mean arterial pressure (MAP) during anesthesia with the intention to treat the population. The timepoints for recording the MAP are, before induction (T0), before LMA insertion (T1), immediately after LMA insertion (T2), at the start of surgery (T3), at the end of surgery (T4), immediately after LMA removal (T5), and 5 minutes after LMA removal (T6)

Figure 4 depicts the HR trends at seven time points (T0-T6) during anesthesia under the intention-to-treat approach. HR varied over time in both groups and was modestly higher in the remimazolam group than in the propofol group at most intraoperative time points, consistent with the significant intervention-by-time interaction; both groups nonetheless remained within a clinically acceptable range throughout.

Fig. 4.

The heart rate (HR) during anesthesia with the intention to treat the population. The timepoints for recording the HR are, before induction (T0), before LMA insertion (T1), immediately after LMA insertion (T2), at the start of surgery (T3), at the end of surgery (T4), immediately after LMA removal (T5), and 5 minutes after LMA removal (T6)

Discussion

The findings of this study provide evidence for using remimazolam as an alternative to conventional anesthetic agents such as propofol in children undergoing percutaneous closure of an atrial septal defect. We found significant differences in time to LMA removal, hospitalization duration, and postoperative recovery between the two agents, and differing intraoperative mean arterial pressure and heart-rate trajectories over time (significant intervention-by-time interactions), without a significant overall between-group difference in either.

The most notable finding of this trial was the short time to LMA removal for the remimazolam group of patients. A recent systematic review and meta-analysis of 14 RCTs comparing the same agents for tracheal intubation reported results consistent with ours [18]. Although a few studies reported no or only minimal differences [19], the findings of a systematic review and meta-analysis (SRMA) lie at the very top of the evidence hierarchy in terms of the strength and quality of particular findings [20]. The findings of our research were clinically significant, as they indicate that remimazolam may improve postoperative recovery for CHD patients, which will eventually reduce the treatment cost and, most importantly, the adverse effects among the patients.

In this study, mean arterial pressure followed a different trajectory over time in the two groups, reflected in a significant intervention-by-time interaction; a significant intervention-by-time interaction was likewise observed for heart rate, although the main effect of group was not significant for either variable. Remimazolam has been associated with hemodynamic stability in several adult populations [12, 21, 22]. Chen et al. reported that in 90 children undergoing fiberoptic bronchoscopy, remimazolam provided better hemodynamic stability than low-dose propofol, at a dose similar to that used in our propofol group [23]. Maintaining stable hemodynamics is important for patient safety, particularly in children [24]. Overall, our ANOVA results indicate that the mean arterial pressure and heart-rate trajectories over time differed between the agents (significant intervention-by-time interactions), without a significant overall between-group difference in either variable.

In our study, the remimazolam group showed better performance in terms of patients’ postoperative emergence delirium score. We found lower PAED scores in the remimazolam group compared with the propofol group, indicating a reduced incidence of postoperative emergence delirium for the remimazolam group [25, 26]. Postoperative emergence delirium is responsible for many complications and may even cause death [25, 26]. Therefore, an anesthetic agent that reduces postoperative emergence delirium is advantageous. Other studies also found results similar to ours [25, 26].

We also found differences in the use of vasopressors between the two groups of intervention. A higher proportion of patients in the propofol group required vasopressors, compared with the remimazolam group; similar findings have been reported in other studies [22, 25–27]. These single-center findings are hypothesis-generating and support evaluating remimazolam as an alternative to propofol in larger, multicenter trials.

A notable finding of this trial was the markedly shorter hospital stay in the remimazolam group (median 5 vs. 7 days), a difference of approximately three days. In practical terms this is more clinically meaningful than the difference in time to LMA removal. Faster emergence, a lower incidence of emergence delirium, and a reduced vasopressor requirement may together contribute to earlier readiness for discharge; however, length of stay is also influenced by institutional discharge practices and other non-anesthetic factors. This association should therefore be interpreted with caution and confirmed in larger, multicenter studies.

One of the major strengths of this study is its focus on pediatric patients with congenital cardiac diseases, a population that is often under-considered in anesthesia research. The study provides valuable evidence on the use of remimazolam in children in regular clinical practice, which contributes to the limited evidence available in this important field of research. Additionally, the randomized controlled trial study design increased the reliability and acceptability of the findings by minimizing bias as much as possible and allowing for direct comparison between these two interventions. Furthermore, the complex assessment of multiple clinical outcomes during the surgery, which included time to LMA removal, MAP, HR, and postoperative recovery, provided a clear and more complete picture of the effects of remimazolam and propofol among the children, allowing a fuller understanding of their differences in terms of benefits and drawbacks.

However, the study also had several limitations. One of the main limitations of this study was the relatively small sample size, which may limit the generalizability of the findings. Although the results were statistically significant, a larger sample size would provide stronger evidence and allow us to perform subgroup analyses. Obtaining consent or assent from patients or their parents is challenging due to the complexity of congenital heart diseases (CHDs), which also contributes to the low sample size of this study. Additionally, the study was conducted in a hospital in China, which may introduce site-specific biases and less racial heterogeneity. Multicenter and multi-race studies would help to generalize the findings from different settings and populations. The study primarily focused on quick postoperative outcomes, which might have created some biases for long-term side effects of anesthetic agents. In this study, we did not perform any long-term follow-up interviews or evaluations among the study participants. Baseline age differed significantly between groups (median difference 1 year); although all children were 2 to 8 years old, height was correspondingly lower in the remimazolam group (111.6 vs. 117.2 cm; p = 0.035), consistent with the younger age. This baseline imbalance is a potential confounder. Continuous BIS values and time-in-range could not be reported because they were not exported to the anesthesia record, and BIS is less extensively validated in young children.

Conclusions

In conclusion, this study found that remimazolam had advantages over conventional propofol in pediatric anesthesia, including shorter time to LMA removal, reduced hospitalization duration, a differing intraoperative mean arterial pressure trajectory (without a significant overall between-group difference), and a lower incidence of postoperative emergence delirium. These findings suggest that remimazolam may be a preferable option for children undergoing percutaneous closure of an atrial septal defect, where rapid recovery and stable hemodynamics are important. Future research should use larger, multicenter trials with long-term follow-up to confirm and generalize these findings, and should consider the cost-effectiveness of remimazolam compared with propofol.

Abbreviations

CHD

Congenital heart diseases

HR

Heart rate

MAP

Mean arterial pressure

PACU

Post-anesthesia care unit

PAED

Pediatric Anesthesia Emergence Delirium

RCT

Randomized controlled trial

Authors’ contributions

Conceptualization: PQ, HL, LQ. Methodology: PQ, LQ. Data collection: HJ. Data management: XS. Data analysis: HZ. Data visualization : PQ, SS. Writing – draft: PQ. Writing – review: HL, LQ. Writing – finalization: PQ.

Funding

The authors did not receive any funding to conduct this study.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to hospital data confidentiality policies but are available from the corresponding author on reasonable request. Requests for access to the anonymized raw data should be directed to Dr. Hongqi Lin (email: 1061407570@qq.com).

Declarations

Ethics approval and consent to participate

The protocol of this study was approved by the ethics review committee (ERC) of Zhengzhou University Central China Fuwai Hospital, affiliated with Henan Provincial People’s Hospital on 27-06-2024 (registration number: (2024) Ethical Approval No. 37). The written informed assent from the parents of the children was collected from all the participants during enrollment. This study was conducted in accordance with the 1964 Declaration of Helsinki and its amendments. This study was designed and reported in accordance with the CONSORT (Consolidated Standards of Reporting Trials) guidelines for randomized controlled trials.

Consent for publication

Not required.

Competing interests

The authors declare no competing interests.