Determination of the 90% effective dose of remimazolam for anesthesia induction in children undergoing ophthalmic procedures: A biased-coin design up-and-down sequential trial

Determination of the 90% effective dose of remimazolam for anesthesia induction in children undergoing ophthalmic procedures: A biased-coin design up-and-down sequential trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Determination of the 90% effective dose of remimazolam for anesthesia induction in children undergoing ophthalmic procedures: A biased-coin design up-and-down sequential trial Hongyuan Ren, Ruru Guo, Wei Liu, Fei Gao, Yuechun Lu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5520496/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Remimazolam has been used in clinical practice of general anesthesia and sedation for more than five years, and the first report on pediatric anesthesia was published in 2024. However, the dosage regimen for children was still unclear. The objective of our trial was to determine the 90% effective dose (ED 90 ) of remimazolam for pediatric anesthesia induction. Methods Our trial enrolled 45 pediatric patients undergoing ophthalmic procedures from June 2024 to September 2024. The initial induction dose was 0.2mg/kg and the sedation depth was assessed by means of the Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scale. The basic rule of our dose-response trial was that the dose for each patient depended on the response of the previous patient, the dose increased by 0.05mg/kg if the previous patient got a MOAA/S score greater than 1, otherwise the current dose was maintained or reduced by 0.05mg/kg at a rate of 9:1 randomly. The anesthesiologist, who assessed sedation in three minutes, was blind to the dose allocation. Subsequently, the ED 90 of remimazolam for pediatric anesthesia induction was calculated. Additionally, the basic vital signs and adverse events during the induction were recorded. Results 45 participants were enrolled, among which 2 were excluded due to parental refusal to participate and 43 completed the trial, 35 participants achieved positive outcomes, while 8 participants had negative outcomes. The ED 90 of intravenous remimazolam for anesthesia induction was 0.29mg/kg (95% CI, 0.26-0.31mg/kg). The mean induction time was 125.37 ± 33.34 seconds (mean ± SD). Conclusion The ED 90 of intravenous remimazolam for anesthesia induction in children was 0.29mg/kg (95% CI, 0.26-0.31mg/kg). The dose is safe and efficient for anesthesia induction in pediatric participants. Trial registration: The study was registered in Chinese Clinical Trial at chictr.org.cn, and the principal investigator was Hongyuan Ren. Registration date: May 24 th 2024, First participant enrolled date: June 1 th 2024, Number: ChiCTR2400084790 URL:https://www.chictr.org.cn/showproj.html?proj=228251&u_atoken=8044a6d97e7d2997c5f6ab4b33f5cf20&u_asig=1a0c380817295931459096250e00e5 remimazolam pediatric patient ED90 MOAA/S anesthesia induction Figures Figure 1 Figure 2 Figure 3 Figure 4 Background The safety and efficiency of remimazolam have been proven in adult anesthesia both induction and maintance [ 1 , 2 ] . In this year, several studies have shown that the remimazolam can be used in pediatric patients in general anesthesia [ 3 ] and sedation [ 4 ] . As a new brilliant sedative, its advantages has been accepted worldwide, such as rapid onset and elimination [ 5 ] , no cumulative action [ 6 ] , hemodynamic stability [ 7 ] ,and a specific antagonist [ 8 ] . It provides us a painless injection and a lower rate of postoperative nausea and vomiting (PONV) compared to propofol [ 9 ] . Furthermore, remimazolam performed a short context-sensitive half-time, a high clearance and similar pharmacokinetic properties with adults under a normalized weight [ 10 ] , suggesting that it could be another excellent choice for pediatric anesthesia. Compared with adults, pediatric patients exhibit significant physiological differences, such as lower oxygen reserve, poor tolerance of hypoxia, a much larger sedative apparent volume of drug distribution which need more sedatives for getting a proper anesthesia depth [ 11 ] , especially during anesthesia induction. Therefore to determine the ED 90 for anesthesia induction was at a high priority and an optimal dosage regimen for pediatric anesthesia could offer to anesthesiologists as well. Methods Ethics This study was approved by Tianjin Medical University Eye Hospital Institutional Review Board (IRB), Number :2023KY-42. All participants’ parents signed informed consent before inclusion. Study design Our dose-respond trial carried out a biased coin design up-and‐down design(BCUD) sequential method, and the flowchart was in accordance with the CONSORT reporting guidelines [12] . Data from 45 pediatric patients who underwent strabismus, blepharoptosis, or entropion surgeries at the Tianjin Medical University Eye Hospital, Tianjin, China, from June 1st to September 30th, 2024 were included in this analysis. Our trial was carried out in accordance with the principles of the Declaration of Helsinki. Participants The participants who were enrolled with the age 2–12 years, 86–173 cm height, body mass index of 12–28 kg/m 2 , and ASA physical status 1–2. Study staff screened, approached, and recruited participants before evaluating enrollment eligibility, obtaining informed consent, and enrolling the participants. We excluded the participants with a sore throat, an upper respiratory tract infection, potential difficult airway, high risk of pulmonary aspiration, or pharyngeal pathology. Study method Based on the previous reports and our experience, the initial dose was set at 0.2 mg/kg. The dose of the subsequent patient was according to the responses of the previous one by using the BCUD method. We defined the positive was sedation success: in three minutes, otherwise was negative. The dose increased by 0.05 mg/kg in the subsequent participant for negative, and the dose maintained or decreased randomly by 0.05 mg/kg at a 9:1 ratio for the positive conversely. Sedation was assessed by using the Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scale, with the following criteria (Table 1): sedation success was defined as an MOAA/S score ≤ 1 at 3 minutes after a bolus dose administration, and sedation failure as an MOAA/S score > 1 at 3 minutes after a bolus dose administration. Randomization and Blinding Identical syringes with different dose of remimazolam were prepared by a nurse. Each syringe was labeled with a unique number (0–9), and a confidential “number-dose correspondence table” (only accessible to this nurse) was used to ensure blinding. According to BCUD method, an assistant prepared the specified syring for each participant by using a computer-generated random number list before the participant and anesthesiologist arrived in the operating room. The anesthesiologist, who was blinded to the dose scheme, accessed the sedated situation of patients by using the MOAA/S score. The patients and their parents also blinded to the dosage regimen throughout the trial. There were no other anesthetics provided during this period. Statistical Analysis More than five crossover pairs were needed for statistical analysis of the Dixon’s sequential method [13] , as a result we ended the enrollment at the eighth observation of failure–success crossover pairs. We calculated the ED 90 of remimazolam by using isotonic regression, and the bootstrapping method was applied for the 95% confidence interval (CI) [13] . We used the Pooled Adjacent Violators Algorithm (PAVA) [14] to estimate the adjusting success rate. The statistical software used was R studio for Windows version 4.4.1 and SPSS for Windows version 24.0 (SPSS Inc., Chicago, Illinois). Sample size Previous studies suggested that enrolling at least 20–40 participants will provide a stable estimation of the target dose for the most realistic scenarios [14] . We stopped the enrollment when 43 patients had completed the study. Anesthesia protocol Anesthesia protocol The anesthesiologist did the routine pre-anesthesia visit and collected the demographic data of the patients before the procedure day. The informed consents were provided to the parents after being advised the study purpose, come with the risks and benefits. The fasting scheme was in accordance with an international multidisciplinary consensus about fasting before procedure [15] . No premedication was provided. Intravenous access was secured to all patients who were accompanied by a parent in the anesthesia preparation room. Standard monitoring including the noninvasive blood pressure (NIBP), electrocardiography (ECG), peripheral oxygen saturation(SPO 2 ) and bispectral index(BIS) were conducted after the patients entered the operating theater and recorded during the induction. Adverse events Ephedrine (0.1mg/kg) was administered by more than 20% drop from the baseline of the NIBP, and atropine (0.01 mg/kg) was administered at the situation of the HR < 45–55 per min. The number of inotropes/vasopressors given during the induction was recorded Results In total, from June 1st to September 27th, 2024, 45 patients were enrolled to our trial, 2 were excluded for the parents refused to participate and a total of 43 patients successfully completed the study (Fig. 1, Flowchart). The demographic information of the patients is shown in Table 2. Primary outcome The ED 90 of intravenous injection remimazolam for anesthesia induction was 0.29mg/kg (95%CI, 0.26-0.31mg/kg). Figure 2 showed the positive and negative results of the 43 consecutive patients. The dose ranged from 0.2mg/kg to 0.35mg/kg. Table 3 showed the observed and PAVA adjusted rate for each dose level. Secondary outcomes The basic life signs were stable and the BIS dropped gradually during the induction. ( see Fig. 3 and Fig. 4) No adverse events were observed during induction. NIBP, noninvasive blood pressure, SBP, systolic blood pressure, DBP, diastolic blood pressure, MAP, mean arterial pressure HR, heart rate, BIS, bispectral index score, RR, respiratory rate Discussion The main objective of our trial was to determine the ED 90 of intravenous administration of remimazolam to achieve proper sedation during the general anesthesia induction in pediatric patients. In our trial, we found that the ED 90 of intravenous remimazolam was 0.29mg/kg, the 95% confidence index was 0.26mg/kg to 0.31mg/kg, and the average success time was 125.37 ± 34.33 seconds. The initial dose was determined based on our experiences and previous studies [ 16 , 17 , 18 ] . The BCUD method has some advantages, such as determining the ED 90 of a certain medicine, first, an ideal target effect dose with a great clinical significance can be identify by researchers, such as 90% [ 19 ] , which, second, the random method would lead a suboptimal dose to some patients rather than a high dose, which may result in a deeper sedation and even more adverse events. And a loading dose of remimazolam for adult induction was also calculated in this way [ 20 ] . Anesthesia and sedation practice in pediatrics has always been considered as a complex issue to various-field anesthesiologists, which mainly due to a more dramatic stress response to procedures in the pediatric population than in adults [ 21 ] . Moreover, invasive procedure and surgery may bring a stressful and traumatic experience to pediatric participants [ 22 ] , and cause a long-term psychological problems [ 23 , 24 ] . Hence, the comfortable medical services (optimized perioperative medication, decreased adverse events, and early recovery) in pediatric anesthesia had become a goal in the past decades. In our study, we found that the HR, NIBP, and RR were stable during the induction and the BIS showed a stable decrease in sedation depth, which presented a smooth and steady induction. Remimazolam, a novel ultrashort-acting benzodiazepine [ 25 ] , presents its clinical features of highly affinity with GABA receptors and revealed some characteristics from its parent compounds, midazolam and remifentanil [ 26 ] . With the outstanding pharmacological features such as high clearance rate, low distribution volumes, short half-times, rapid onset and recovery [ 27 , 28 ] , remimazolam presents in anesthesia with low hemodynamic fluctuations, minimal respiratory depression, and the rapid reversal by using flumazenil [ 29 , 30 ] . All the features of remimazolam, especially no injection pain, made it have the capable to be a perfect choice for pediatric anesthesia induction [ 3 , 9 ] . However, remimazolam also caused some adverse events, such as respiratory depress after high-dose injection [ 31 ] , cannot get a proper sedation which need a rescue titration or re-sedation [ 32 , 33 ] and anaphylaxis [ 34 , 35 ] . Hence, our study provided an accuracy dosage regimen, which may lead a safe and efficient anesthesia induction in pediatric patients. There were several limitations to the study. First, participants in our study with ASA physical status 1–2, lack of estimation about the participant with a more than 2 status. But our outcome would be useful to develop further discussion on whether these results can be generalized to a broader pediatric population. Second, the sample size was based on previous studies and without certain kind of calculation, so it may be insufficient in some cases. Third, such as the any previous experiences of sedation or anesthesia, real fasting time, and the sleep quality of the night before might have influence on the outcomes. Forth, the patient in our trial were aged 2–12 years, the other age intervals of children were not generalized in our trial. Last, we did not calculate the 95% effective dose, which may be more clinically relevant, and sample size were insufficient, it might be better to consider this study as a pilot study Conclusions The 90% effective dose of remimazolam for anesthesia induction in pediatric patients was 0.29mg/kg (95% CI, 0.26-0.31mg/kg). The dose is safe and efficient for anesthesia induction in pediatric participants. Abbreviations ASA Anesthesiology Society of American ED effective dose MOAA/S Modified Observer’s Assessment of Alertness and Sedation CI confidence interval PONV postoperative nausea and vomiting BCUD biased coin design up-and‐down PAVA Pooled Adjacent Violators Algorithm NIBP noninvasive blood pressure ECG electrocardiography SPO 2 peripheral oxygen saturation BIS bispectral index SBP systolic blood pressure DBP diastolic blood pressure MAP mean arterial pressure HR heart rate RR respiratory rate Declarations Ethics approval and consent to participate This research followed the tenets of the Declaration of Helsinki, written informed consent was obtained from all the subjects after explanation of the nature and possible consequences of the study. This study was approved by the ethics committee of Tianjin Medical University Eye Hospital. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests Funding This work was supported by Tianjin Key Medical Discipline ( Specialty ) Construction Project(TJYXZDXK-037A)The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Author Contribution Hongyuan Ren: Conceptualization, Methodology, Writing- Original draft preparation.Ruru Guo: Visualization, Investigation, Wei Liu: Software, Validation.Fei Gao: Software, Data curation,Yuechun Lu: Supervision, Writing- Reviewing and Editing, Acknowledgement We feel great thanks for your professional review work on our article Availability of data and material The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References PAMBIANCO D J, BORKETT K M RIFFDS, et al. 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Cite Share Download PDF Status: Under Review Version 1 posted Editor assigned by journal 14 Oct, 2025 Reviews received at journal 30 Sep, 2025 Reviewers agreed at journal 16 Sep, 2025 Reviewers invited by journal 10 Sep, 2025 Submission checks completed at journal 02 Sep, 2025 First submitted to journal 27 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5520496","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":529375292,"identity":"4dc02311-6390-42e5-81c1-6113fb6c24a7","order_by":0,"name":"Hongyuan Ren","email":"","orcid":"","institution":"Tianjin Medical University Eye Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongyuan","middleName":"","lastName":"Ren","suffix":""},{"id":529375293,"identity":"ef4658df-7e7e-4d34-8807-51bcf237fc94","order_by":1,"name":"Ruru Guo","email":"","orcid":"","institution":"Tianjin Medical University Eye 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4","display":"","copyAsset":false,"role":"figure","size":47994,"visible":true,"origin":"","legend":"\u003cp\u003ethe variation of HR, BIS and RR\u003c/p\u003e\n\u003cp\u003eHR, heart rate, BIS, bispectral index score, RR, respiratory rate\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5520496/v1/02d682aaf4065b3cc94578f1.jpeg"},{"id":104408886,"identity":"31c21162-b48d-4254-af89-5fb78525f345","added_by":"auto","created_at":"2026-03-11 12:43:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":857535,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5520496/v1/6fb49187-523f-4314-b72f-157a25bb579d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eDetermination of the 90% effective dose of remimazolam for anesthesia induction in children undergoing ophthalmic procedures: A biased-coin design up-and-down sequential trial\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThe safety and efficiency of remimazolam have been proven in adult anesthesia both induction and maintance\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. In this year, several studies have shown that the remimazolam can be used in pediatric patients in general anesthesia\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e and sedation\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. As a new brilliant sedative, its advantages has been accepted worldwide, such as rapid onset and elimination\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, no cumulative action\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, hemodynamic stability\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e,and a specific antagonist\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. It provides us a painless injection and a lower rate of postoperative nausea and vomiting (PONV) compared to propofol \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Furthermore, remimazolam performed a short context-sensitive half-time, a high clearance and similar pharmacokinetic properties with adults under a normalized weight\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, suggesting that it could be another excellent choice for pediatric anesthesia. Compared with adults, pediatric patients exhibit significant physiological differences, such as lower oxygen reserve, poor tolerance of hypoxia, a much larger sedative apparent volume of drug distribution which need more sedatives for getting a proper anesthesia depth\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e, especially during anesthesia induction. Therefore to determine the ED\u003csub\u003e90\u003c/sub\u003e for anesthesia induction was at a high priority and an optimal dosage regimen for pediatric anesthesia could offer to anesthesiologists as well.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003eEthics\u003c/h2\u003e\n \u003cp\u003eThis study was approved by Tianjin Medical University Eye Hospital Institutional Review Board (IRB), Number :2023KY-42.\u003c/p\u003e\n \u003cp\u003eAll participants\u0026rsquo; parents signed informed consent before inclusion.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eOur dose-respond trial carried out a biased coin design up-and‐down design(BCUD) sequential method, and the flowchart was in accordance with the CONSORT reporting guidelines\u003csup\u003e[12]\u003c/sup\u003e. Data from 45 pediatric patients who underwent strabismus, blepharoptosis, or entropion surgeries at the Tianjin Medical University Eye Hospital, Tianjin, China, from June 1st to September 30th, 2024 were included in this analysis. Our trial was carried out in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eThe participants who were enrolled with the age 2\u0026ndash;12 years, 86\u0026ndash;173 cm height, body mass index of 12\u0026ndash;28 kg/m\u003csup\u003e2\u003c/sup\u003e, and ASA physical status 1\u0026ndash;2. Study staff screened, approached, and recruited participants before evaluating enrollment eligibility, obtaining informed consent, and enrolling the participants. We excluded the participants with a sore throat, an upper respiratory tract infection, potential difficult airway, high risk of pulmonary aspiration, or pharyngeal pathology.\u003c/p\u003e\n\u003ch3\u003eStudy method\u003c/h3\u003e\n\u003cp\u003eBased on the previous reports and our experience, the initial dose was set at 0.2 mg/kg. The dose of the subsequent patient was according to the responses of the previous one by using the BCUD method. We defined the positive was sedation success: in three minutes, otherwise was negative. The dose increased by 0.05 mg/kg in the subsequent participant for negative, and the dose maintained or decreased randomly by 0.05 mg/kg at a 9:1 ratio for the positive conversely.\u003c/p\u003e\n\u003cp\u003eSedation was assessed by using the Modified Observer\u0026rsquo;s Assessment of Alertness and Sedation (MOAA/S) scale, with the following criteria (Table\u0026nbsp;1): sedation success was defined as an MOAA/S score\u0026thinsp;\u0026le;\u0026thinsp;1 at 3 minutes after a bolus dose administration, and sedation failure as an MOAA/S score\u0026thinsp;\u0026gt;\u0026thinsp;1 at 3 minutes after a bolus dose administration.\u003c/p\u003e\n\u003cdiv\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1772822087.png\"\u003e\u003c/div\u003e\n\u003ch3\u003eRandomization and Blinding\u003c/h3\u003e\n\u003cp\u003eIdentical syringes with different dose of remimazolam were prepared by a nurse. Each syringe was labeled with a unique number (0\u0026ndash;9), and a confidential \u0026ldquo;number-dose correspondence table\u0026rdquo; (only accessible to this nurse) was used to ensure blinding. According to BCUD method, an assistant prepared the specified syring for each participant by using a computer-generated random number list before the participant and anesthesiologist arrived in the operating room. The anesthesiologist, who was blinded to the dose scheme, accessed the sedated situation of patients by using the MOAA/S score. The patients and their parents also blinded to the dosage regimen throughout the trial. There were no other anesthetics provided during this period.\u003c/p\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n \u003cp\u003eMore than five crossover pairs were needed for statistical analysis of the Dixon\u0026rsquo;s sequential method \u003csup\u003e[13]\u003c/sup\u003e, as a result we ended the enrollment at the eighth observation of failure\u0026ndash;success crossover pairs. We calculated the ED\u003csub\u003e90\u003c/sub\u003e of remimazolam by using isotonic regression, and the bootstrapping method was applied for the 95% confidence interval (CI)\u003csup\u003e[13]\u003c/sup\u003e. We used the Pooled Adjacent Violators Algorithm (PAVA) \u003csup\u003e[14]\u003c/sup\u003e to estimate the adjusting success rate. The statistical software used was R studio for Windows version 4.4.1 and SPSS for Windows version 24.0 (SPSS Inc., Chicago, Illinois).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eSample size\u003c/h3\u003e\n\u003cp\u003ePrevious studies suggested that enrolling at least 20\u0026ndash;40 participants will provide a stable estimation of the target dose for the most realistic scenarios\u003csup\u003e[14]\u003c/sup\u003e. We stopped the enrollment when 43 patients had completed the study.\u003c/p\u003e\n\u003ch3\u003eAnesthesia protocol\u003c/h3\u003e\n\u003cdiv\u003eAnesthesia protocol\u003c/div\u003e\n\u003cp\u003eThe anesthesiologist did the routine pre-anesthesia visit and collected the demographic data of the patients before the procedure day. The informed consents were provided to the parents after being advised the study purpose, come with the risks and benefits.\u003c/p\u003e\n\u003cp\u003eThe fasting scheme was in accordance with an international multidisciplinary consensus about fasting before procedure\u003csup\u003e[15]\u003c/sup\u003e. No premedication was provided. Intravenous access was secured to all patients who were accompanied by a parent in the anesthesia preparation room. Standard monitoring including the noninvasive blood pressure (NIBP), electrocardiography (ECG), peripheral oxygen saturation(SPO\u003csub\u003e2\u003c/sub\u003e) and bispectral index(BIS) were conducted after the patients entered the operating theater and recorded during the induction.\u003c/p\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003eAdverse events\u003c/h2\u003e\n \u003cp\u003eEphedrine (0.1mg/kg) was administered by more than 20% drop from the baseline of the NIBP, and atropine (0.01 mg/kg) was administered at the situation of the HR\u0026thinsp;\u0026lt;\u0026thinsp;45\u0026ndash;55 per min. The number of inotropes/vasopressors given during the induction was recorded\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\"\u003e\n \u003cp\u003eIn total, from June 1st to September 27th, 2024, 45 patients were enrolled to our trial, 2 were excluded for the parents refused to participate and a total of 43 patients successfully completed the study (Fig. 1, Flowchart). The demographic information of the patients is shown in Table 2.\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1772822166.png\"\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003ePrimary outcome\u003c/h2\u003e\n \u003cp\u003eThe ED\u003csub\u003e90\u003c/sub\u003e of intravenous injection remimazolam for anesthesia induction was 0.29mg/kg (95%CI, 0.26-0.31mg/kg). Figure 2 showed the positive and negative results of the 43 consecutive patients. The dose ranged from 0.2mg/kg to 0.35mg/kg. Table 3 showed the observed and PAVA adjusted rate for each dose level.\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1772822224.png\"\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003eSecondary outcomes\u003c/h2\u003e\n \u003cp\u003eThe basic life signs were stable and the BIS dropped gradually during the induction. ( see Fig.\u0026nbsp;3 and Fig.\u0026nbsp;4)\u003c/p\u003e\n \u003cp\u003eNo adverse events were observed during induction.\u003c/p\u003e\n \u003cp\u003eNIBP, noninvasive blood pressure, SBP, systolic blood pressure, DBP, diastolic blood pressure, MAP, mean arterial pressure\u003c/p\u003e\n \u003cp\u003eHR, heart rate, BIS, bispectral index score, RR, respiratory rate\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe main objective of our trial was to determine the ED\u003csub\u003e90\u003c/sub\u003e of intravenous administration of remimazolam to achieve proper sedation during the general anesthesia induction in pediatric patients.\u003c/p\u003e\u003cp\u003eIn our trial, we found that the ED\u003csub\u003e90\u003c/sub\u003e of intravenous remimazolam was 0.29mg/kg, the 95% confidence index was 0.26mg/kg to 0.31mg/kg, and the average success time was 125.37\u0026thinsp;\u0026plusmn;\u0026thinsp;34.33 seconds. The initial dose was determined based on our experiences and previous studies\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. The BCUD method has some advantages, such as determining the ED\u003csub\u003e90\u003c/sub\u003e of a certain medicine, first, an ideal target effect dose with a great clinical significance can be identify by researchers, such as 90%\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, which, second, the random method would lead a suboptimal dose to some patients rather than a high dose, which may result in a deeper sedation and even more adverse events. And a loading dose of remimazolam for adult induction was also calculated in this way\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAnesthesia and sedation practice in pediatrics has always been considered as a complex issue to various-field anesthesiologists, which mainly due to a more dramatic stress response to procedures in the pediatric population than in adults\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Moreover, invasive procedure and surgery may bring a stressful and traumatic experience to pediatric participants\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e, and cause a long-term psychological problems\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Hence, the comfortable medical services (optimized perioperative medication, decreased adverse events, and early recovery) in pediatric anesthesia had become a goal in the past decades. In our study, we found that the HR, NIBP, and RR were stable during the induction and the BIS showed a stable decrease in sedation depth, which presented a smooth and steady induction.\u003c/p\u003e\u003cp\u003eRemimazolam, a novel ultrashort-acting benzodiazepine\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e, presents its clinical features of highly affinity with GABA receptors and revealed some characteristics from its parent compounds, midazolam and remifentanil\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. With the outstanding pharmacological features such as high clearance rate, low distribution volumes, short half-times, rapid onset and recovery\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e, remimazolam presents in anesthesia with low hemodynamic fluctuations, minimal respiratory depression, and the rapid reversal by using flumazenil\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. All the features of remimazolam, especially no injection pain, made it have the capable to be a perfect choice for pediatric anesthesia induction\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. However, remimazolam also caused some adverse events, such as respiratory depress after high-dose injection\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e, cannot get a proper sedation which need a rescue titration or re-sedation\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e and anaphylaxis\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. Hence, our study provided an accuracy dosage regimen, which may lead a safe and efficient anesthesia induction in pediatric patients.\u003c/p\u003e\u003cp\u003eThere were several limitations to the study. First, participants in our study with ASA physical status 1\u0026ndash;2, lack of estimation about the participant with a more than 2 status. But our outcome would be useful to develop further discussion on whether these results can be generalized to a broader pediatric population. Second, the sample size was based on previous studies and without certain kind of calculation, so it may be insufficient in some cases. Third, such as the any previous experiences of sedation or anesthesia, real fasting time, and the sleep quality of the night before might have influence on the outcomes. Forth, the patient in our trial were aged 2\u0026ndash;12 years, the other age intervals of children were not generalized in our trial. Last, we did not calculate the 95% effective dose, which may be more clinically relevant, and sample size were insufficient, it might be better to consider this study as a pilot study\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe 90% effective dose of remimazolam for anesthesia induction in pediatric patients was 0.29mg/kg (95% CI, 0.26-0.31mg/kg). The dose is safe and efficient for anesthesia induction in pediatric participants.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eASA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAnesthesiology Society of American\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eED\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eeffective dose\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMOAA/S\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eModified Observer\u0026rsquo;s Assessment of Alertness and Sedation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003econfidence interval\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePONV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003epostoperative nausea and vomiting\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBCUD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebiased coin design up-and‐down\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePAVA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePooled Adjacent Violators Algorithm\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNIBP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003enoninvasive blood pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eECG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eelectrocardiography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSPO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eperipheral oxygen saturation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBIS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebispectral index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSBP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003esystolic blood pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDBP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ediastolic blood pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMAP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emean arterial pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eheart rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erespiratory rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003eThis research followed the tenets of the Declaration of Helsinki, written informed consent was obtained from all the subjects after explanation of the nature and possible consequences of the study. This study was approved by the ethics committee of Tianjin Medical University Eye Hospital.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis work was supported by Tianjin Key Medical Discipline ( Specialty ) Construction Project(TJYXZDXK-037A)The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eHongyuan Ren: Conceptualization, Methodology, Writing- Original draft preparation.Ruru Guo: Visualization, Investigation, Wei Liu: Software, Validation.Fei Gao: Software, Data curation,Yuechun Lu: Supervision, Writing- Reviewing and Editing,\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe feel great thanks for your professional review work on our article\u003c/p\u003e\u003ch2\u003eAvailability of data and material\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePAMBIANCO D J, BORKETT K M RIFFDS, et al. A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy [J]. Gastrointest Endosc. 2016;83(5):984\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDOI M, MORITA K, TAKEDA J, et al. Efficacy and safety of remimazolam versus propofol for general anesthesia: a multicenter, single-blind, randomized, parallel-group, phase IIb/III trial [J]. J Anesth. 2020;34(4):543\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBAI C, XU M, GUO Y et al. Clinical Application and Research Progress of Remimazolam for Pediatric Patients [J]. Drug design, development and therapy, 2024, 18(1221-9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHIRANO T, KIMOTO Y, KURATANI N et al. Remimazolam for Pediatric Procedural Sedation: Results of an Institutional Pilot Program [J]. J Clin Med, 2023, 12(18).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePATON D J D O. T. Remimazolam: a short-acting benzodiazepine for procedural sedation [J]. 2021, 57(5): 337\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSTOHR T, COLIN P J, OSSIG J, et al. Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment [J]. Br J Anaesth. 2021;127(3):415\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTAN Y, OUYANG W, TANG Y, et al. Effect of remimazolam tosilate on early cognitive function in elderly patients undergoing upper gastrointestinal endoscopy [J]. J Gastroenterol Hepatol. 2022;37(3):576\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWESOLOWSKI A M, ZACCAGNINO M P MALAPERORJ, et al. Remimazolam: Pharmacologic Considerations and Clinical Role in Anesthesiology [J]. Pharmacotherapy. 2016;36(9):1021\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGOLDWATER D R ANTONIKLJ, KILPATRICK G J, et al. 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Dose finding using the biased coin up-and-down design and isotonic regression [J]. Biometrics, 2002, 58(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNATHAN L P, MARIO PS. Advances in and limitations of up-and-down methodology: a pr\u0026eacute;cis of clinical use, study design, and dose estimation in anesthesia research [J]. Anesthesiology, 2007, 107(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGREEN S, LEROY P, ROBACK M, et al. An international multidisciplinary consensus statement on fasting before procedural sedation in adults and children [J]. Anaesthesia. 2020;75(3):374\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSHIOJI N, EVERETT T, SUZUKI Y, et al. Pediatric sedation using dexmedetomidine and remimazolam for magnetic resonance imaging [J]. J Anesth. 2022;36(1):1\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYOSHITAKA K, TATSUYA H, NORIFUMI K et al. Remimazolam as an Adjunct to General Anesthesia in Children: Adverse Events and Outcomes in a Large Cohort of 418 Cases [J]. J Clin Med, 2023, 12(12).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang X, Lin C, Chen S, et al. Remimazolam for the prevention of emergence delirium in children following tonsillectomy and adenoidectomy under sevoflurane anaesthesia: a randomized controlled study. Drug Des Devel Ther. 2022;16:3413\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/DDDT.S381611\u003c/span\u003e\u003cspan address=\"10.2147/DDDT.S381611\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRONALD B G, DOLORES M, MALACHY O C et al. Up-down determination of the 90% effective dose of phenylephrine for the treatment of spinal anesthesia-induced hypotension in parturients undergoing cesarean delivery [J]. Anesth Analg, 2009, 110(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLu Z, Zhou N, Li Y, Yang L, Hao W. Up-down determination of the 90% effective dose (ED90) of remimazolam besylate for anesthesia induction. Ann Palliat Med. 2022;11(2):568\u0026ndash;73. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.21037/apm-22-89\u003c/span\u003e\u003cspan address=\"10.21037/apm-22-89\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFANG Y, WANG C, GAO Y et al. The safety and efficacy of remimazolam tosylate for induction and maintenance of general anesthesia in pediatric patients undergoing elective surgery: Study protocol for a multicenter, randomized, single-blind, positive-controlled clinical trial [J]. Frontiers in pharmacology, 2023, 14(1090608.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKARA MC, LUIS I R, JACQUELINE T et al. General anesthesia in the pediatric population [J]. Curr Opin Ophthalmol, 2014, 25(5).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eF A. Preoperative anxiety in children. Predictors and outcome [J]. Arch Pediatr Adolesc Med, 1997, 151(6).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZ N K, L C M, T Z O C et al. Preoperative anxiety in children. Predictors and outcomes [J]. Arch Pediatr Adolesc Med, 1996, 150(12).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCHITILIAN H V, ECKENHOFF R G, RAINES DE. Anesthetic drug development: Novel drugs and new approaches [J]. Surg Neurol Int. 2013;4(Suppl 1):S2\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZHOU Y, HU P. Metabolite characterization of a novel sedative drug, remimazolam in human plasma and urine using ultra high-performance liquid chromatography coupled with synapt high-definition mass spectrometry [J]. J Pharm Biomed Anal. 2017;137:78\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSHENG X Y, LIANG Y, YANG X Y, et al. Safety, pharmacokinetic and pharmacodynamic properties of single ascending dose and continuous infusion of remimazolam besylate in healthy Chinese volunteers [J]. Eur J Clin Pharmacol. 2020;76(3):383\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSNEYD JR, GAMBUS P L, RIGBY-JONES A, E. Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review [J]. Br J Anaesth. 2021;127(1):41\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSNEYD J R, RIGBY-JONES A, E. Remimazolam for anaesthesia or sedation [J]. Curr Opin Anaesthesiol. 2020;33(4):506\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKEAM SJ, Remimazolam. First Approval [J]. Drugs. 2020;80(6):625\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKIM KM. Remimazolam: pharmacological characteristics and clinical applications in anesthesiology [J]. Anesth Pain Med (Seoul). 2022;17(1):1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMIYANISHI M, YAGURAMAKI T, MAEHARA Y, et al. Three cases of difficulty in achieving definitive loss of consciousness with remimazolam [J]. JA Clin Rep. 2022;8(1):4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGODAI K. What are mechanisms of re-sedation caused by remimazolam? [J]. J Anesth. 2021;35(3):466.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTSURUMI K, TAKAHASHI S, HIRAMOTO Y, et al. Remimazolam anaphylaxis during anesthesia induction [J]. J Anesth. 2021;35(4):571\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUCHIDA S, TAKEKAWA D, KITAYAMA M, et al. Two cases of circulatory collapse due to suspected remimazolam anaphylaxis [J]. JA Clin Rep. 2022;8(1):18.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"remimazolam, pediatric patient, ED90, MOAA/S, anesthesia induction","lastPublishedDoi":"10.21203/rs.3.rs-5520496/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5520496/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRemimazolam has been used in clinical practice of general anesthesia and sedation for more than five years, and the first report on pediatric anesthesia was published in 2024. However, the dosage regimen for children was still unclear. The objective of our trial was to determine the 90% effective dose (ED\u003csub\u003e90\u003c/sub\u003e) of remimazolam for pediatric anesthesia induction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur trial enrolled 45 pediatric patients undergoing ophthalmic procedures from June 2024 to September 2024. The initial induction dose was 0.2mg/kg and the sedation depth was assessed by means of the Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scale. The basic rule of our dose-response trial was that the dose for each patient depended on the response of the previous patient, the dose increased by 0.05mg/kg if the previous patient got a MOAA/S score greater than 1, otherwise the current dose was maintained or reduced by 0.05mg/kg at a rate of 9:1 randomly. The anesthesiologist, who assessed sedation in three minutes, was blind to the dose allocation. Subsequently, the ED\u003csub\u003e90\u003c/sub\u003e of remimazolam for pediatric anesthesia induction was calculated. Additionally, the basic vital signs and adverse events during the induction were recorded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e45 participants were enrolled, among which 2 were excluded due to parental refusal to participate and 43 completed the trial, 35 participants achieved positive outcomes, while 8 participants had negative outcomes. The ED\u003csub\u003e90\u003c/sub\u003e of intravenous remimazolam for anesthesia induction was 0.29mg/kg (95% CI, 0.26-0.31mg/kg). The mean induction time was 125.37 ± 33.34 seconds (mean ± SD).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ED\u003csub\u003e90\u003c/sub\u003e of intravenous remimazolam for anesthesia induction in children was 0.29mg/kg (95% CI, 0.26-0.31mg/kg). The dose is safe and efficient for anesthesia induction in pediatric participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was registered in Chinese Clinical Trial at chictr.org.cn, and the principal investigator was Hongyuan Ren.\u003c/p\u003e\n\u003cp\u003eRegistration date: May 24\u003csup\u003eth\u003c/sup\u003e 2024,\u003c/p\u003e\n\u003cp\u003eFirst participant enrolled date: June 1\u003csup\u003eth\u003c/sup\u003e 2024,\u003c/p\u003e\n\u003cp\u003eNumber: ChiCTR2400084790\u003c/p\u003e\n\u003cp\u003eURL:https://www.chictr.org.cn/showproj.html?proj=228251\u0026amp;u_atoken=8044a6d97e7d2997c5f6ab4b33f5cf20\u0026amp;u_asig=1a0c380817295931459096250e00e5\u003c/p\u003e","manuscriptTitle":"Determination of the 90% effective dose of remimazolam for anesthesia induction in children undergoing ophthalmic procedures: A biased-coin design up-and-down sequential trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 14:21:05","doi":"10.21203/rs.3.rs-5520496/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorAssigned","content":"","date":"2025-10-14T09:59:47+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-30T20:15:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"269034155841820209031748317502437753409","date":"2025-09-16T21:32:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-10T09:40:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-02T10:17:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-08-27T08:42:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e167ee40-0647-4ba2-b666-430c5d648589","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-08T14:21:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 14:21:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5520496","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5520496","identity":"rs-5520496","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}