Determination of the EC90 of remifentanil for blocking the adrenergic responses to intubation when administered with propofol: an up-down sequential allocation study protocol using the k-in-a-row design versus biased-coin design

Determination of the EC90 of remifentanil for blocking the adrenergic responses to intubation when administered with propofol: an up-down sequential allocation study protocol using the k-in-a-row design versus biased-coin design | 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 EC90 of remifentanil for blocking the adrenergic responses to intubation when administered with propofol: an up-down sequential allocation study protocol using the k-in-a-row design versus biased-coin design Luoyun Li, Baichun Xing, Guoping Wang, Jin Zhang, Qin Fan, Jianing Guo, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5192866/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Endotracheal intubation(EI), as a noxious stimulus, can cause significant adrenergic responses. Remifentanil and propofol have excellent controllable pharmacokinetic characteristics and are commonly used in anesthesia induction. It is vital to assess how drug effects change with increasing doses using dose-response characterisation in anesthesia induction. It has a great clinical significance for optimizing medication strategies to reduce cardiovascular response during EI that determine effect-site concentration (Ce) of remifentanil to block adrenergic responses (BAR) to EI in 90% participants (EC 90 BAR EI ) and establish a dose-response curve. However, the EC 90 BAR EI of remifentanil using the k-in-a-row design (KRD) versus biased-coin design (BCD) up-and-down methods (UDM) when administered with propofol has not been established. The present study was designed to determine and evaluate the EC 90 BAR EI of remifentanil using BCD versus KRD undergoing propofol anesthesia induction. Methods This is a prospective, randomized sequential allocation dose-finding trial to determine and evaluate the EC 90 of remifentanil required to BAR to EI using the KRD versus BCD UDMs when administered with propofol. We will recruit patients who are Implemented elective surgery for EI under general anesthesia, and randomly allocate them in a 1:1 ratio to the KRD versus BCD groups in advance. The Ce for the follow-up participants increased, decreased or remain same according to the 'negative' or 'positive' response of the previous participant, based on the dose-transition rules of the KRD versus BCD sequential UDMs. Positive response was defined as success. The primary outcomes are the rate of success and Ce of remifentanil blocking adrenergic responses to EI when administered with propofol using KRD versus BCD UDMs in 90% participants. Secondary outcomes include changes of hemodynamic indicators, sedation levels, and safety during anesthesia induction and EI. We plan to enroll 120 participants undergoing elective surgery for EI under general anesthesia and receive one of the KRD versus BCD UDMs. The EC90 and 90% confidence intervals(90%CIs) were estimated using R-Foundation centered isotonic regression (CIR) and the pooled adjacent violators algorithm(PAVA) with bootstrapp. Discussion This is the first prospective, randomized adaptive dose-finding trial to quantify and assess the EC 90 BAR EI of remifentanil using KRD versus BCD UDMs undergoing propofol anesthesia induction. The results of this study contribute to optimizing the target controlled infusion(TCI) strategy of remifentanil during EI, and analyzing the efficacy of two rule-based designs for high percentile dose-finding in anesthesiology research as the basis for rational drug administration schemes. Trial registration: Chinese Clinical Trial Registry, ChiCTR2300078275.Registered on 3rd December 2023. Effective concentration in 90% patients Block adrenergic response Endotracheal Intubation Dose-finding K-in-a-row design Biased coin design Up-and-down method Remifentanil Propofol Target controlled infusion Figures Figure 1 Figure 2 Background The noxious stimulus to EI can activate sympathetic adrenergic system, and lead to hemodynamic instability, such as hypertension and tachycardia [1] . It is crucial for maintaining an optimal target range of hemodynamic indicators during EI. It has been suggested that various pharmacological strategies control cardiovascular responses induced by these noxious stimuli [2–3] . Because of its unique pharmacokinetic and pharmacodynamic properties, remifentanil and propofol are commonly used for TCI in clinical anesthesia induction and maintenance [4,5] . Compared to fentanyl and sufentani, remifentanil can inhibit more effectively adrenergic responses to EI [4–8] . It is essential to use dose-response relationship in anesthesia induction to determine how drug action changes with increasing dose. In recent years, it is mainly focused on the dose-response relationship of the median effective dose(ED50) that remifentanil inhibit the cardiovascular responses to EI in, and using the ED50 to estimate the ED95 [9–13] . However, there has been little on dose-finding study of the EC 90 BAR EI of remifentanil using KRD versus BCD undergoing propofol anesthesia induction. The non-median target percentile dose-finding is also very popular in biomedical studies, and the EC90 or ED90-finding has become a hotspot in anesthesiology research recently [14–23] . KRD versus BCD are commonly used designs in the UDMs, mainly used for evaluation designs of non-median target percentile(hign percentile) dose-finding in anesthesiology study [14,15,24–27] . Using dose escalation study methods, the study sought to understand the EC90 of dose-response relationship of remifentanil required to control cardiovascular responses to EI with UDMs using KRD versus BCD during propofol anesthesia induction. This study aim to determine and assess the EC 90 BAR EI of remifentanil using KRD versus BCD UDMs when administered with propofol. Methods Study design, ethics, and trial registration This study is an prospective, randomized adaptive dose-finding trial to determine and assess the EC 90 BAR EI of remifentanil using KRD versus BCD UDMs when administered with propofol at a tertiary hospital. The Ethics Committee of Heping Hospital Affiliated to Changzhi Medical College approved this study. The study protocol was developed in accordance with the SPIRIT 2013 Statement [28] . This trial is registered at the Chinese Clinical Trial Registry, (ChiCTR: 2300078275). [ https://www.chictr.org.cn/searchproj.html ]. Participants Inclusion criteria Inclusion criteria are participants scheduled for elective surgeries under general endotracheal anaesthesia in an academic hospital (Heping Hospital Affiliated to Changzhi Medical College), with American Society of anaesthesiologists physical status I-II, aged 18–64 years [11] and agree to sign informed consent. Exclusion criteria Patients who deemed to have one or more of the following will be excluded: -- Patients who have allergies or contraindications to opioids, propofol and their components. -- Patients who use of other sedatives such as propofol or midazolam within 24 hours before surgery. -- Patients with severe central nervous system, respiratory or circulatory system diseases. -- Patients with difficult airway, Liver dysfunction, renal dysfunction, mental disorders, long-term use of psychotropic drugs, cognitive dysfunction, long-term use of psychotropic or sedative-hypnotic drugs, drug abuse and drinking. -- Patients with Allen test positive, Hypertension, Hemodynamic instability(systolic blood pressure [SBP] 180mmHg, diastolic blood pressure DBP > 110mmHg, peripheral blood oxygen saturation [SpO2] < 90%). -- Participants who participate in other clinical studies within recent one month. -- Patients with a history of difficult endotracheal intubation. -- Patients who are judged or suspected to be difficult endotracheal intubation, defined as a Mallampati class IV airway; retrognathia; restricted neck movements; or more than two criteria among the following(e.g,Mallampati class III airway, mouth opening less than 35mm, or thyromental distance less than 65mm). All of these parameters were estimated by an experienced anesthesiologist. Enrollment of participants and allocation Consent to participate, enrollment of participants We will require written informed consent from participants or their authorized representatives to be included in this trial. The doctors among the researchers will attempt to invite all eligible patients who meet the above criteria to participate in this trial. Each trial is conducted by a trial team. The trial team consists of three people, including one professional physician, one assistant physician, and one physician. Allocation In this study, participants will be randomly assigned. Firstly, a statistician who did not participate in this experiment created an allocation list for each trial team using a 1:1 KRD versus BCD ratio based on a computer-generated random number table before the trial began. Second, a secretary who is not involved in this trial will conceal the Ce of the allocated drugs within the lists with un-stickable tapes, and distribute the respective allocation lists to each trial team before enrollment of the first patient in the trial. Finally, when consent for trial participation is obtained from a participant, the physician will write besides the identification number of the participant's electronic health record, age, gender, primary disease and type of surgery on the list in sequential order before unsealing the tapes to avoid allocation again and confirm their allocation. Randomization and blinding This study is an adaptive dose-finding trial with KRD versus BCD sequential allocation methods.In adaptive clinical trials with KRD versus BCD UDMs, randomization is often not used in the traditional sense. Instead of randomly assigning participants to different treatment groups, the two designs adapts the treatment allocation based on the outcomes observed during the trial. The next participant's treatment assignment may depend on the response of the previous participant, creating a sequence of adaptive treatment allocations. While the two designs were not based on randomization in the conventional sense, it still aim to minimize bias and ensure the validity of the study results by adjusting the treatment allocation based on observed responses. The random walk rules for the sequential allocation of dose levels to participants in this trial were implemented using the KRD versus BCD UDMs [15,24,27,29–31] . Participants are sequentially assigned the next higher, same, or next lower dose level according to the transition rules of KRD versus BCD UDMs, which is determined by ethical considerations as well as the response of the participant's binary endpoints [14,15] . The participants and the professional physician for EI were not aware of the Ce of remifentanil. An assistant physician was responsible for the TCI of remifentanil, recording various data and calculating the Ce of remifentanil according to the previous participant's response. Participants were enrolled, and participants to interventions were assigned by Luoyun Li, Baichun Xing, Zehua Wang, Qin Fan and Chunyu Li. The random allocation sequence were generated using SPSS 27.0 by Jianing Guo and Guoping Wang. Data was analysised by Fangsheng Xu and Jin Zhang who were blinded to the interventions. Protocols of investigational drug administration The detailed administration protocols of two designs are as follows (Fig. 1 and Table 1 ). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate(HR), pulse oximetry(SpO2) and Ai were recorded 1 min before induction, 2 min and 1 min before EI, at EI and at each min for 3 min after EI. The pre-induction baseline value was defined as MAP and HR at 1 min before induction. The pre-EI baseline values was defined as the average values of MAP and HR at 1 min before EI. The changes of MAP and HR during EI (delta MAP and delta HR ) were defined as the difference between the pre-EI baseline values and the maximal value within the first 3 min following post-EI. The binary endpoint of adrenergic responses to EI was defined as the changes of hemodynamic(delta MAP, delta HR ) between the pre-EI baseline values and the maximal value within the first 3 min following post-EI, including negative responses(delta MAP versus delta HR is 20% higher than the pre-EI value) and positive responses(delta MAP or delta HR of post-EI is 20% less than or equal the pre-EI value) [11,32–34] . If the adrenergic responses to EI was negative, the binary endpoint was defined as failure; Conversely, if the adrenergic responses to EI was positive, the binary endpoint was defined as success. Based on previous study and our clinical experience [35–38] , remifentanil was administered at initial Ce 2ng/ml to the first participant in each group(Ruijie; Yichang Renfu Pharmaceutical Co., Ltd., Hubei, China), and the step change of Ce was definded as 0.5 ng/ml in the study. Remifentanil Ce of next participant were determined by the binary endpoint evaluation of the previous subject,as per the KRD versus BCD UDMs [15] . KRD group According to defined binary endpoint, participant's dose was assigned for target the EC90 with the transition rule of KRD (This study used K = 6 from literature recommend) in KRD group [15] : If a participant was negative response, -- Increase Ce of TCI remifentanil. If a participant was positive response, -- Decrease Ce of TCI remifentanil (but only after observing 6 consecutive positive responses at the same Ce of TCI remifentanil ). -- Otherwise, remain the same Ce of TCI remifentanil. BCD group According to defined binary endpoint, participant's dose was assigned for target the EC90 using the transition rule of BCD in BCD group [15] : If a participant was negative response, -- Increase the Ce of TCI remifentanil. If a participant was positive response,“toss a biased coin” (draw a random number) and then either: -- Decrease the Ce of TCI remifentanil with probability inverse to the odds of positive response at the target(with a probability of 0.1); -- Otherwise, remain the same Ce of TCI remifentanil(with a probability of 1-0.1 = 0.9) . Outcomes measures Following is the definition of different timepoints in the trial. Time 1 (T 1 ) was defined as 1 min before induction, Time 2(T 2 ) was defined as after administering remifentanil(reaching equilibrium between plasma and effect-site concentrations), Time 3 (T 3 ) was defined as after administering propofol(reaching equilibrium between plasma and effect-site concentrations), Time 4(T 4 ) was defined as 1 min before EI, Time 5(T 5 ) was defined as within the first 3 min following EI, Time 6(T 6 ) was defined as during postoperative 48 h. Following is the summary of outcomes in the trial(Table 1 ). Primary outcome --Proportion of participants who achieve the success and Ce of remifentanil blocking adrenergic responses to EI when administered with propofol in 90% participants between two groups (e.g.,T 4 ,T 5 ). Secondary outcomes Secondary outcomes of this study will include the following: --The changes of the hemodynamic parameter(HR, MAP, SBP ,DBP) and sedation level (Ai values) at different time points(e.g.,T 1 ,T 2 ,T 3 ,T 4 ,T 5 ). --The changes of MOAA/S score and Ai values during anesthesia induction. --Adverse events related to remifentanil with propofol during anesthesia induction, include great hemodynamic change, hypoxemia, muscle tremor, symptoms of chest wall rigidity, choking cough, and postoperative nausea and vomiting during postoperative 48 h. --Time and frequency of rescue medication consumption. Study conductance Preparation before general anesthesia All participants were routinely fasted of food and water without any premedication before surgery. A standard monitoring and anesthetic technique was applied to all participants in this study. Study conductance is displayed in a flow diagram(Table 1 ). After arrival at the operating room, the participants are given inhaled oxygen and conventional fluid infusion(10 ml/kg Ringer's solution before anesthesia induction) and monitors will be attached including an electrocardiograms (ECG), pulse oximetry (SpO2), heart rate (HR), invasive blood pressure (IBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and end-tidal carbon dioxide (PetCO2)(BeneVision M15 Monitor, Mindray,China), Ai for the depth of anesthesia (ConView YY-106; Pearlcare Medical Technology Company Limited, Zhejiang, China), and MOAA/S [39] . The invasive arterial blood pressure is established under local anesthesia in participants with a negative Allen test. Sedation was assessed using Ai and MOAA/S. Target sedation in the trial was defined as a Ai target between 40 to 60 (Ai is quite the same as BIS does) [39] and MOAA/S score of less than or equal to 1. Anesthesia induction Following is the order of anesthesia induction in the trial: remifentanil-propofol-rocuronium bromide (Table.1).Before anesthesia induction, preoxygenation of patients with 100% oxygen and remove nitrogen and oxygen via facial masks for 3min is applied. Drugs were administered via TCI with an infusion pump(Fresenius Kabi, France) driven by STANPUMP. Remifentanil and propofol were administered via TCI (Ce) according to the Minto model and Schnider model, respectively [40,41] . Sedation level is assessed by the professional physician every 10 seconds after propofol TCI until target sedation (Ai between 60 − 40), and bolus rocuronium (0.6mg/kg) was given within 30 seconds, and artificial ventilation was initiated. EI is performed under visual laryngoscopy after 2 minutes of bolus rocuronium. Safety, Rescue therapy and Criteria for withdrawal We define each safety issue when one or more of the following respective criteria are met during data collection. Rescue therapy is needed. -- Excessive hemodynamic changes include: systolic blood pressure 180mmHg; HR 120 bpm. -- Hypoxia is defined as SpO 2 ≤ 92% for more than 10 seconds. -- Criteria for withdrawal: If the patient experiences excessive hemodynamic changes, hypoxemia, severe muscle tremors, or persistent chest wall stiffness, we will handle it according to the emergency disposal plan, and the patient will withdraw from this study. -- The following cases will be treated with the same concentration of remifentanil. Data collection and management and monitoring Data collection Data collected from standard monitoring and assessment at different timepoint included: SpO 2 , HR, SBP, DBP, MAP, EtCO 2 , Ai, MOAA/S and remifentanil Ce. Patient demographics was collected during the medical consultation with the professional physician. Data management All of this data will be stored in electronic files. The accuracy of the input data will be confirmed by another person. Only individuals with permission from the principal investigator are allowed to access the database. We will provide each participant with a research identification number in the electronic file for anonymity. The table that display a list of the identification numbers of this study and the corresponding participant's electronic health records, respectively, will be stored in a locked cabinet in a secure area.The Research Management Committee will have access to the final trial dataset. After the trial is completed, the raw data and results will be submitted to the Research Management Committee.They will be disclosed to the public after the results are announced. Data monitoring The Data Monitoring Committee (DMC) is composed of a physician responsible for data collection and organization, a trial manager and a statistician. The DMC will hold three meetings annually throughout the entire trial process. The DMC is responsible for safeguarding the interests of trial participants, evaluating the safety of intervention measures, and monitoring the overall trial progress.Any deviation from the plan will be recorded in the report. Any modification to all major plan will be discussed and agreed upon by the researchers, and then submitted to the Certified Review Board (CRB) of the Heping Hospital Affiliated to Changzhi Medical College for approval, and will be updated in the trial registration book and communicated to relevant parties. The trial team has designed and prepared for experimental implementation, and will publish the results. The research team holds regular monthly meetings to discuss project progress. The DMC physician will record the actual number of enrolled participants, excluded cases, demographic and other baseline characteristics, incidence of complications and combination therapy, and comprehensive efficacy evaluation, analysis of compliance and safety. The DMC physician will also describe the participant's demographic characteristics, history of medical and treatment. Statistics Statistical analyses Statistical analysis was performed using SPSS software, version 27.0 (SPSS, Inc, Chicago, IL). Normally distributed continuous variables are described as mean ± standard deviation (SD), while nonnormally distributed continuous variables are described as the medians [interquartile range (IQR)].Categorical variables are described as numbers (%). The trial will use Student's t-test, analysis of variance, Mann Whitney test, or Kruskal Wallis test to compare continuous variables, and chi square test to compare categorical variables. The EC90 and 90% confidence intervals(CIs) were estimated by R-Foundation CIR and the PAVA with bootstrapping(Fig. 2 ). The PAVA algorithm is most commonly used for solving isotonic regression.Unless using larger sample sizes (n > 100), it is not recommended to report CIs at the 95% confidence level. It is recommended to use 90% or less [15] . Therefore, statistical results are presented as point estimates (90% CI) in this trial. EC90 was calculated using CIR with a bias-corrected Morris 90% confidence interval(CI) derived by bootstrapping using“dosefind” and“quickinverse” commands in the CIR R package(R’s ‘cir’ Package authored and maintained by Dr. Oron) [15] .PAVA-adjusted response rates were estimated using the weighted isotonic regression method [15,42] . This trial generates binary(positive/negative) response data. The proportion of negative responses at each dose is calculated and plotted by a dose-response plot. Targeting the EC90, from the dose-response observation pairs, isotonic regression methods are used to estimate the dose-response curve [15,42] . Sample size estimation It is suggested in previous studies that including at least 50 to 60 participants will provide stable estimates of the target dose for EC90 [15] . This trial will be recruiting 120 cases in two groups, there are 60 cases in each group. Adverse event reporting and harms Adverse events(AEs) are defined as all undesirable or nonintended diseases and signs that may have a potential causal relationship with the investigational drug. All AEs were shared with the researchers, and will be dealt with appropriately. Serious AEs related to this trial will be reported to the Heping Hospital Affiliated to Changzhi Medical College CRB within 15 days. Patient and public participation In our previous pilot trials, the project of this trial was reviewed by patients with scheduled for elective surgery. During the scheme design phase, we solicited opinions from participating medical centers on the content of ethical and safety assessments. Dissemination plan The results of this trial will be announced at anesthesia conferences (local and international). The main research results of this trial will be informed at the trial registration office. The complete research report will be published in national and/or international conferences as well as peer-reviewed journals. Discussion This is the first prospective, random sequential allocation adaptive dose-finding trial to determine and assess the EC 90 BAR EI of remifentanil using KRD versus BCD UDMs when administered with propofol. The results of this study could help to optimize anti-noxious management and remifentanil TCI strategy during EI. This study also contribute to analyzing the efficacy of two rule-based designs for high percentile dose-finding in anesthesiology research as the basis for rational drug administration schemes. Using dose escalation study methods, the study sought to understand the EC90 of dose-response relationship of remifentanil with propofol required to blunt cardiovascular responses to EI. If there is no difference between the two designs for quantify EC90, KRD and BCD will be used to evaluate and recognize dose-response relationship (high percentage dose-finding) in anesthesiology study. Trial status Patient recruitment began in Jan 2025. The trial was expected to end in Dec 2025, but we estimate that patient recruitment will be completed in Dec 2025 due to slow accrual. The current protocol is version 2.0, dated 3 Sep 2024. Abbreviations EI Endotracheal Intubation ED90 Effective Dose in 90% patients Ce Effect-site Concentration BAR Block Adrenergic Response EC90 Effective-site Concentration in 90% patients EC 90 BAR EI Effect-site Concentration to Block Adrenergic Response to Endotracheal Intubation in 90% patients UDM Up-and-Down Methods KRD K-in-a-Row Design BCD Biased-Coin Design Ai Anesthesia index MOAA/S Modified Observer Assessment of Alertness and Sedation Scale 90%CIs 90% confidence intervals CIR Centered Isotonic Regression PAVA Pooled Adjacent Violators Algorithm TCI Target Controlled Infusion SD Standard Deviation IQR Interquartile Range AEs Adverse Events CRB Certified Review Board Declarations Ethics approval and consent to participate The trial protocol has received approval from the Ethics Committee of Heping Hospital Affiliated to Changzhi Medical College(approval number: 2024 No.086)on 3rd September 2024. The protocol of this trial was registered at the Chinese Clinical Trial Registry(ChiCTR:2300078275). This trial will be implemented in accordance with the ethical principles stated in the Declaration of Helsinki. The researchers will identify eligible participants according to the inclusion criteria. Eligible participants will receive written and oral information and will be included after researcher has obtained informed written consent. These materials are available from the corresponding author on request. Confidentiality of the data of trial and the results of monitoring will be protected. Any changes to the protocol or AEs will be reported to the DMC. If any harm related to this study occurs, participants can get free treatment provided by the affiliated Heping Hospital of Changzhi Medical College, which will handle it in accordance with relevant laws and regulations. The qualification screening of surgical patients will be conducted before surgery. Researchers will provide participants with a detailed introduction to the trial, including the purpose, process, and requirements after qualification confirmation. All participants will voluntarily participate in the trial and sign an informed consent form. Protocol amendments Any significant modifications to the trial plan will be promptly reported to the Ethics Committee of Heping Hospital Affiliated to Changzhi Medical College,and updated on ChiCTR.gov. Consent or assent: ancillary studies There are no relevant plans. Confidentiality Participants will be assigned a unique identifier after registration, replacing the need for participants names in the data collection process. This unique identifier is only meaningful to the trial team and ensures the confidentiality of participants. The chief researcher will be in charge of these unique identifiers securely storing and protecting at the end of the trial according to the research guidelines. Any publications produced by the study will not include any participants personally identifiable information and will always secure the privacy of participants. The trial database will allow Li Chunyu's application to access the final trial dataset. Competing interests The authors declare no competing interests.  Dissemination policy The trial results will be prepared for submission to an international peer-reviewed journal. This process involves compiling data into a comprehensive manuscript outlining the methods, findings, and impacts of the experiment. The public can access the complete protocol through ChiCTR.gov.website (ChiCTR2300078275), but it does not involve the participants personal information. This database will allow reasonable applications of the corresponding authors to access the final experimental dataset. Acknowledgements The authors would like to sincerely thank Jintai Jia, Ping Wu and Dongzheng Gai for their support in conduction of the study, and also thank all staff members in the anesthesia department and operating room for care of the patients.  Funding Not applicable. Availability of data and material The dataset generated from the current study will be available from the corresponding author upon reasonable request. Authors ’ contributions Jin Zhang,Fangsheng Xu and Chunyu Li , the corresponding author of this article in charge of the study, was responsible for the design of the study and modified the manuscript. Luoyun Li and Baichun Xing and Guoping Wang contributed equally. Luoyun Li and Baichun Xing and Guoping Wang are joint first authors, responsible for the experiment, data analysis and writing the original draft of the manuscript. All authors were involved in the implementation of the study and patient data collection.All authors critically revised the manuscript and approved the submission of the final version of the manuscript. Author details LLY and BCX and GPW contributed equally. LLY and BCX and GPW are joint first authors. *Correspondence to: Correspondence to Jin Zhang; [email protected] Correspondence to Fangsheng Xu; [email protected] Correspondence to Chunyu Li; [email protected] 1 Department of Neurology,The First Hospital of Shanxi Medical University,Taiyuan, Shanxi ,China 2 Neurology Intensive Care Unit,Department of Neurology,Heping Hospital Affiliated to Changzhi Medical College,Changzhi, Shanxi,China 3 Department of Anesthesiology,Heping Hospital Affiliated to Changzhi Medical College,Changzhi, Shanxi,China 4 Department of Anesthesiology,Changzhi People's Hospital Affiliated to Shanxi Medical University, Changzhi, Shanxi,China 5 Department of Anesthesiology, Affiliated Changshu Hospital of Nantong University, Changshu,Jiangsu, China References Zbinden AM, Petersen-Felix S, Thomson DA. Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia. II. Hemodynamic responses. Anesthesiology. 1994;80:261-7. 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The effect-site concentration of remifentanil blunting endotracheal intubation responses during anesthesia induction with etomidate: a dose-finding study. BMC Anesthesiol. 2023;23(1):225. Kutlesic MS, Kutlesic RM, Mostic-Ilic T. Attenuation of cardiovascular stress response to endotracheal intubation by the use of remifentanil in patients undergoing Cesarean delivery. J Anesth. 2016;30(2):274-83. Liu HC, Tao WK, Zeng RF, et al. Dose requirements of remifentanil for intubation in nonparalyzed Chinese children. Paediatr Anaesth. 2014;24(5):505-9. N.L. Pace, M.P. Stylianou. Advances in and limitations of up-and-down methodology: a precis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology. 2007;107(1):144-152. Oron AP, Souter MJ, Flournoy N. Understanding Research Methods: Up-and-down Designs for Dose-finding. Anesthesiology. 2022 ;137(2):137-150. Sviggum HP, Arendt KW, Jacob AK, et al. Intrathecal Hydromorphone and Morphine for Postcesarean Delivery Analgesia: Determination of the ED90 Using a Sequential Allocation Biased-Coin Method. Anesth Analg. 2016;123(3):690-7. Au K, Shippam W, Taylor J, et al. Determining the effective pre-oxygenation interval in obstetric patients using high-flow nasal oxygen and standard flow rate facemask: a biased-coin up-down sequential allocation trial. Anaesthesia. 2020;75(5):609-616. Zhang J, Chen Y, Li S,et al. The 90% effective dose of intranasal dexmedetomidine for procedural sedation in children with congenital heart disease before and after surgery: A biased-coin design up-and-down sequential allocation trial. Acta Anaesthesiol Scand. 2021;65(2):188-194. Wesselink EJ, Koopman SJ, Vegt RV, et al. ED90 of spinal 2-chloroprocaine 1% in ambulatory knee arthroscopy up to 45 min: a randomized biased-coin- up-and-down sequential allocation trial. Reg Anesth Pain Med. 2022;47(4):212-216. Gao W, Chen Y, Wang W, et al. The 90% minimum effective volume and concentration of ropivacaine for ultrasound-guided median nerve block in children aged 1-3 years: A biased-coin design up-and-down sequential allocation trial. J Clin Anesth. 2022;79:110754. Sharawi N, Tan HS, Taylor C, et al. ED 90 of Intrathecal Chloroprocaine With Fentanyl for Prophylactic Cervical Cerclage: A Sequential Allocation Biased-Coin Design. Anesth Analg. 2022 ;134(4):834-842. Zhou D, Yang XD, Wu HY, et al. Determination of the ED90 of Dexmedetomidine Infusion to Prevent Emergence Agitation in Children Undergoing Dental Rehabilitation With Sevoflurane Anesthesia: A Biased-Coin Up-and-Down Sequential Allocation Trial.Anesth Analg. 2024 Oct 1;139(4):761-769. Maeda A, Villela-Franyutti D, Lumbreras-Marquez MI, et al. Labor Analgesia Initiation With Dural Puncture Epidural Versus Conventional Epidural Techniques: A Randomized Biased-Coin Sequential Allocation Trial to Determine the Effective Dose for 90% of Patients of Bupivacaine. Anesth Analg. 2024 Jun 1;138(6):1205-1214. Assaf P Oron, Peter D Hoff. The k-in-a-row up-and-down design,revisited.Stat Med. 2009;28(13):1805-20. Treutwein B. Minireview: adaptive psychophysical procedures. Vision Research. 1995; 35:2503-2522. Garc`ıa-Perez M. Forced-choice staircases with fixed step sizes: asymptotic and small-sample properties. Vision Research. 1998; 38:1861-1881. Stylianou MP, Flournoy N. "Dose finding using the biased coin up-and-down design and isotonic regression". Biometrics.2002;58 (1): 171-177. Chan AW, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:1-42. Markaryan, T., Rosenberger, W. F. Exact properties of Efron’s biased coin randomization procedure. Annals of Statistics, 2010;38:1546-1567. Durham SD, Flournoy N: Random walks for quantile estimation. Statistical Decision Theory and Related Topics V (West Lafayette, IN, 1992). Berlin, Springer, 1994; 467-476. Durham SD, Flournoy N, Rosenberger WF. A random walk rule for phase I clinical trials. Biometrics 1997; 53:745–60. Zou ZY, Zhao YL, Yang XL,et al. Effects of different remifentanil target concentrations on MAC BAR of sevoflurane in gynaecological patients with CO2 pneumoperitoneum stimulus.Br J Anaesth. 2015;114(4):634-9. Jiang P, Tang J, Zhang M, et al.Effects of Transverse Abdominis Plane (TAP) Block on the MAC(BAR) of Sevoflurane in Gynecologic Patients with Laparoscopic Pneumoperitoneal Stimulation: An Up-Down Sequential Allocation Study.J Pain Res. 2024;17:2689-2699. Chen C, Pang Q, Tu A, et al. Effect of low-dose ketamine on MAC(BAR) of sevoflurane in laparoscopic cholecystectomy: A randomized controlled trial.J Clin Pharm Ther. 2021;46(1):121-127. Jong Hae Kim, Eun Kyung Jwa, Youjin Choung, et al. Comparison of Pupillometry With Surgical Pleth Index Monitoring on Perioperative Opioid Consumption and Nociception During Propofol–Remifentanil Anesthesia: A Prospective Randomized Controlled Trial. Anesth Analg. 2020;131(5):1589-1598. Tae Kyong Kim, Deok Man Hong, Seo Hee Lee, et al. Effect-site concentration of remifentanil required to blunt haemodynamic responses during tracheal intubation: A randomized comparison between single-and double-lumen tubes. Journal of International Medical Research. 2018;46(1): 430-439. Jeong Uk Han, Sangyun Cho, Woo Jae Jeon, et al. The optimal effect-site concentration of remifentanil for lightwand tracheal intubation during propofol induction without muscle relaxation. Journal of Clinical Anesthesia. 2011; 23:379–383. Andrea Albertin, Andrea Casati, Lombardo Federica, et al. The effect-site concentration of remifentanil blunting cardiovascular responses to tracheal intubation and skin incision during bispectral index-guided propofol anesthesia. Anesth Analg. 2005;101(1):125-30. Fu Y, Xu T, Xie K, et al. Comparative Evaluation of a New Depth of Anesthesia Index in ConView System and the Bispectral Index during Total Intravenous Anesthesia: A Multicenter Clinical Trial. Biomed Res Int. 2019;2019:1014825. Minto CF, Schnider TW, Shafer SL. Pharmacokinetics and pharmacodynamics of remifentanil: II. Model application. ANESTHESIOLOGY. 1997; 86:24–33. Schnider TW, Minto CF, Gambus PL,et al. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. ANESTHESIOLOGY. 1998;88:1170-82. Mario Stylianou, Nancy Flournoy. Dose finding using the biased coin up-and-down design and isotonic regression. Biometrics. 2002;58(1):171-7. Table 1 Table 1 is available in the Supplementary Files section. Supplementary Files SPIRIT2013checklist.docx Table1.docx Cite Share Download PDF Status: Posted Version 1 posted 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-5192866","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":430498910,"identity":"c6cfdc54-1343-43e7-bea0-fb22dcad17ef","order_by":0,"name":"Luoyun Li","email":"","orcid":"","institution":"First Hospital of Shanxi Medical University;Heping Hospital Affiliated to Changzhi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Luoyun","middleName":"","lastName":"Li","suffix":""},{"id":430498911,"identity":"bed4ce8e-17de-4818-a5c6-32b5b589e214","order_by":1,"name":"Baichun Xing","email":"","orcid":"","institution":"Heping Hospital Affiliated to Changzhi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Baichun","middleName":"","lastName":"Xing","suffix":""},{"id":430498912,"identity":"0ce5c0d6-6fbb-420f-adfa-f15f0dee965d","order_by":2,"name":"Guoping Wang","email":"","orcid":"","institution":"changzhishi peoples hospital affiliated to shanxi medical university","correspondingAuthor":false,"prefix":"","firstName":"Guoping","middleName":"","lastName":"Wang","suffix":""},{"id":430498913,"identity":"37dd95da-6579-4af9-acc4-6871261154b5","order_by":3,"name":"Jin Zhang","email":"","orcid":"","institution":"First Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"","lastName":"Zhang","suffix":""},{"id":430498914,"identity":"dfaff7cf-b281-4aa1-9d2c-109eb3972897","order_by":4,"name":"Qin Fan","email":"","orcid":"","institution":"Heping Hospital Affiliated to Changzhi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Fan","suffix":""},{"id":430498915,"identity":"2571b531-32e1-446f-b13c-898bc4973e32","order_by":5,"name":"Jianing Guo","email":"","orcid":"","institution":"Heping Hospital Affiliated to Changzhi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Jianing","middleName":"","lastName":"Guo","suffix":""},{"id":430498916,"identity":"31caab62-044c-4c9f-b53a-8f074a754b58","order_by":6,"name":"Zehua Wang","email":"","orcid":"","institution":"Heping Hospital Affiliated to Changzhi Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zehua","middleName":"","lastName":"Wang","suffix":""},{"id":430498917,"identity":"229c0dc6-fb66-4321-873e-07c9333c96d1","order_by":7,"name":"Fangsheng Xu","email":"","orcid":"","institution":"Affiliated Changshu Hospital of Natong University","correspondingAuthor":false,"prefix":"","firstName":"Fangsheng","middleName":"","lastName":"Xu","suffix":""},{"id":430498918,"identity":"6399773a-ba90-426e-90b1-f65c084d2408","order_by":8,"name":"Chunyu Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYBACPmYGNjCDHyrA2EBICxtMi2QD0VoYoFoMDhCthZ352WPeHYcTNx8//nTDDwYb2Q0HmJ89wO8wNnNj3jOHE7edSUi72cOQZrzhAJu5AX4tPGzSvG1ALTcYjt1mYDicuOEAD5sEUVo2z2BsA2r5T4KWDRLMbEAtB4jRwmYmObct3XjGmTS2mz0GycYzD7OZ4dXCz3/4mcTbNmvZ/vbjz278qLCT7Tve/AyvFihohtKgoGImQj0Q1BGnbBSMglEwCkYmAAAEX0KrJvTwtQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-2726-851X","institution":"Heping Hospital Affiliated to Changzhi Medical College","correspondingAuthor":true,"prefix":"","firstName":"Chunyu","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-10-02 12:27:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5192866/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5192866/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79561859,"identity":"49e4596b-957d-4e37-9797-0f9d675dc2bf","added_by":"auto","created_at":"2025-03-31 08:54:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":200258,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of enrollment of participants, and populations of analysis. KRD=K-in-a-Row Design; BCD=Biased-Coin Design; EC90=90% Effective Concentration; 90%CIs=90% confidence intervals\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5192866/v1/ada8d1eae8d4e731b2e76ba6.png"},{"id":79564147,"identity":"8dd82f28-6c9b-4ead-b37a-6fb81d290323","added_by":"auto","created_at":"2025-03-31 09:10:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":445821,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic diagram of dose-response curve and target estimates(target percentile, and 90% confidence interval).The Y-axis shows the probability of success.The X-axis shows Ce level. Data (blue circls); True F(x) (red curve); Isotonic Regression (black dashed curve); Centered Rsotonic Regression (blue curve); EC90=90% Effective Concentration ( green square);90%CIs=90% Confidence Intervals( green line)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5192866/v1/286f41ec36823f975dc74295.png"},{"id":86158411,"identity":"5c8adada-e573-430d-b2ad-3ff6267aec44","added_by":"auto","created_at":"2025-07-07 11:47:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1678191,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5192866/v1/f287004b-7a67-488f-9881-3fb88242566a.pdf"},{"id":79561869,"identity":"bbb9e92c-1770-4fab-af8f-f5c141b8c196","added_by":"auto","created_at":"2025-03-31 08:54:22","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":36034,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRIT2013checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-5192866/v1/94da0164df99ecce91100536.docx"},{"id":79561858,"identity":"fe8aea57-b2f4-4d7b-9c1a-bcfd75508a3d","added_by":"auto","created_at":"2025-03-31 08:54:22","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23984,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5192866/v1/9c8611e8834a2c6267fbedb9.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eDetermination of the EC90 of remifentanil for blocking the adrenergic responses to intubation when administered with propofol: an up-down sequential allocation study protocol using the k-in-a-row design versus biased-coin design\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThe noxious stimulus to EI can activate sympathetic adrenergic system, and lead to hemodynamic instability, such as hypertension and tachycardia\u003csup\u003e[1]\u003c/sup\u003e. It is crucial for maintaining an optimal target range of hemodynamic indicators during EI.\u003c/p\u003e \u003cp\u003eIt has been suggested that various pharmacological strategies control cardiovascular responses induced by these noxious stimuli\u003csup\u003e[2\u0026ndash;3]\u003c/sup\u003e. Because of its unique pharmacokinetic and pharmacodynamic properties, remifentanil and propofol are commonly used for TCI in clinical anesthesia induction and maintenance\u003csup\u003e[4,5]\u003c/sup\u003e. Compared to fentanyl and sufentani, remifentanil can inhibit more effectively adrenergic responses to EI\u003csup\u003e[4\u0026ndash;8]\u003c/sup\u003e. It is essential to use dose-response relationship in anesthesia induction to determine how drug action changes with increasing dose.\u003c/p\u003e \u003cp\u003eIn recent years, it is mainly focused on the dose-response relationship of the median effective dose(ED50) that remifentanil inhibit the cardiovascular responses to EI in, and using the ED50 to estimate the ED95\u003csup\u003e[9\u0026ndash;13]\u003c/sup\u003e. However, there has been little on dose-finding study of the EC\u003csub\u003e90\u003c/sub\u003e BAR\u003csub\u003eEI\u003c/sub\u003e of remifentanil using KRD versus BCD undergoing propofol anesthesia induction. The non-median target percentile dose-finding is also very popular in biomedical studies, and the EC90 or ED90-finding has become a hotspot in anesthesiology research recently\u003csup\u003e[14\u0026ndash;23]\u003c/sup\u003e. KRD versus BCD are commonly used designs in the UDMs, mainly used for evaluation designs of non-median target percentile(hign percentile) dose-finding in anesthesiology study\u003csup\u003e[14,15,24\u0026ndash;27]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eUsing dose escalation study methods, the study sought to understand the EC90 of dose-response relationship of remifentanil required to control cardiovascular responses to EI with UDMs using KRD versus BCD during propofol anesthesia induction. This study aim to determine and assess the EC\u003csub\u003e90\u003c/sub\u003e BAR\u003csub\u003eEI\u003c/sub\u003e of remifentanil using KRD versus BCD UDMs when administered with propofol.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy design, ethics, and trial registration\u003c/h2\u003e\n \u003cp\u003eThis study is an prospective, randomized adaptive dose-finding trial to determine and assess the EC\u003csub\u003e90\u003c/sub\u003e BAR\u003csub\u003eEI\u003c/sub\u003e of remifentanil using KRD versus BCD UDMs when administered with propofol at a tertiary hospital. The Ethics Committee of Heping Hospital Affiliated to Changzhi Medical College approved this study. The study protocol was developed in accordance with the SPIRIT 2013 Statement\u003csup\u003e[28]\u003c/sup\u003e. This trial is registered at the Chinese Clinical Trial Registry, (ChiCTR: 2300078275). [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.chictr.org.cn/searchproj.html\u003c/span\u003e\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eInclusion criteria\u003c/h2\u003e\n \u003cp\u003eInclusion criteria are participants scheduled for elective surgeries under general endotracheal anaesthesia in an academic hospital (Heping Hospital Affiliated to Changzhi Medical College), with American Society of anaesthesiologists physical status I-II, aged 18\u0026ndash;64 years\u003csup\u003e[11]\u003c/sup\u003e and agree to sign informed consent.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eExclusion criteria\u003c/h3\u003e\n\u003cp\u003ePatients who deemed to have one or more of the following will be excluded:\u003c/p\u003e\n\u003cp\u003e-- Patients who have allergies or contraindications to opioids, propofol and their components.\u003c/p\u003e\n\u003cp\u003e-- Patients who use of other sedatives such as propofol or midazolam within 24 hours before surgery.\u003c/p\u003e\n\u003cp\u003e-- Patients with severe central nervous system, respiratory or circulatory system diseases.\u003c/p\u003e\n\u003cp\u003e-- Patients with difficult airway, Liver dysfunction, renal dysfunction, mental disorders, long-term use of psychotropic drugs, cognitive dysfunction, long-term use of psychotropic or sedative-hypnotic drugs, drug abuse and drinking.\u003c/p\u003e\n\u003cp\u003e-- Patients with Allen test positive, Hypertension, Hemodynamic instability(systolic blood pressure [SBP]\u0026thinsp;\u0026lt;\u0026thinsp;90mmHg or \u0026gt;\u0026thinsp;180mmHg, diastolic blood pressure DBP\u0026thinsp;\u0026gt;\u0026thinsp;110mmHg, peripheral blood oxygen saturation [SpO2]\u0026thinsp;\u0026lt;\u0026thinsp;90%).\u003c/p\u003e\n\u003cp\u003e-- Participants who participate in other clinical studies within recent one month.\u003c/p\u003e\n\u003cp\u003e-- Patients with a history of difficult endotracheal intubation.\u003c/p\u003e\n\u003cp\u003e-- Patients who are judged or suspected to be difficult endotracheal intubation, defined as a Mallampati class IV airway; retrognathia; restricted neck movements; or more than two criteria among the following(e.g,Mallampati class III airway, mouth opening less than 35mm, or thyromental distance less than 65mm). All of these parameters were estimated by an experienced anesthesiologist.\u003c/p\u003e\n\u003cp\u003eEnrollment of participants and allocation\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eConsent to participate, enrollment of participants\u003c/h2\u003e\n \u003cp\u003eWe will require written informed consent from participants or their authorized representatives to be included in this trial. The doctors among the researchers will attempt to invite all eligible patients who meet the above criteria to participate in this trial. Each trial is conducted by a trial team. The trial team consists of three people, including one professional physician, one assistant physician, and one physician.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eAllocation\u003c/h3\u003e\n\u003cp\u003eIn this study, participants will be randomly assigned. Firstly, a statistician who did not participate in this experiment created an allocation list for each trial team using a 1:1 KRD versus BCD ratio based on a computer-generated random number table before the trial began. Second, a secretary who is not involved in this trial will conceal the Ce of the allocated drugs within the lists with un-stickable tapes, and distribute the respective allocation lists to each trial team before enrollment of the first patient in the trial. Finally, when consent for trial participation is obtained from a participant, the physician will write besides the identification number of the participant\u0026apos;s electronic health record, age, gender, primary disease and type of surgery on the list in sequential order before unsealing the tapes to avoid allocation again and confirm their allocation.\u003c/p\u003e\n\u003ch3\u003eRandomization and blinding\u003c/h3\u003e\n\u003cp\u003eThis study is an adaptive dose-finding trial with KRD versus BCD sequential allocation methods.In adaptive clinical trials with KRD versus BCD UDMs, randomization is often not used in the traditional sense. Instead of randomly assigning participants to different treatment groups, the two designs adapts the treatment allocation based on the outcomes observed during the trial. The next participant\u0026apos;s treatment assignment may depend on the response of the previous participant, creating a sequence of adaptive treatment allocations. While the two designs were not based on randomization in the conventional sense, it still aim to minimize bias and ensure the validity of the study results by adjusting the treatment allocation based on observed responses.\u003c/p\u003e\n\u003cp\u003eThe random walk rules for the sequential allocation of dose levels to participants in this trial were implemented using the KRD versus BCD UDMs\u003csup\u003e[15,24,27,29\u0026ndash;31]\u003c/sup\u003e. Participants are sequentially assigned the next higher, same, or next lower dose level according to the transition rules of KRD versus BCD UDMs, which is determined by ethical considerations as well as the response of the participant\u0026apos;s binary endpoints\u003csup\u003e[14,15]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe participants and the professional physician for EI were not aware of the Ce of remifentanil. An assistant physician was responsible for the TCI of remifentanil, recording various data and calculating the Ce of remifentanil according to the previous participant\u0026apos;s response.\u003c/p\u003e\n\u003cp\u003eParticipants were enrolled, and participants to interventions were assigned by Luoyun Li, Baichun Xing, Zehua Wang, Qin Fan and Chunyu Li. The random allocation sequence were generated using SPSS 27.0 by Jianing Guo and Guoping Wang. Data was analysised by Fangsheng Xu and Jin Zhang who were blinded to the interventions.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eProtocols of investigational drug administration\u003c/h2\u003e\n \u003cp\u003eThe detailed administration protocols of two designs are as follows (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSystolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate(HR), pulse oximetry(SpO2) and Ai were recorded 1 min before induction, 2 min and 1 min before EI, at EI and at each min for 3 min after EI. The pre-induction baseline value was defined as MAP and HR at 1 min before induction. The pre-EI baseline values was defined as the average values of MAP and HR at 1 min before EI. The changes of MAP and HR during EI (delta MAP and delta HR ) were defined as the difference between the pre-EI baseline values and the maximal value within the first 3 min following post-EI.\u003c/p\u003e\n \u003cp\u003eThe binary endpoint of adrenergic responses to EI was defined as the changes of hemodynamic(delta MAP, delta HR ) between the pre-EI baseline values and the maximal value within the first 3 min following post-EI, including negative responses(delta MAP versus delta HR is 20% higher than the pre-EI value) and positive responses(delta MAP or delta HR of post-EI is 20% less than or equal the pre-EI value)\u003csup\u003e[11,32\u0026ndash;34]\u003c/sup\u003e. If the adrenergic responses to EI was negative, the binary endpoint was defined as failure; Conversely, if the adrenergic responses to EI was positive, the binary endpoint was defined as success.\u003c/p\u003e\n \u003cp\u003eBased on previous study and our clinical experience\u003csup\u003e[35\u0026ndash;38]\u003c/sup\u003e, remifentanil was administered at initial Ce 2ng/ml to the first participant in each group(Ruijie; Yichang Renfu Pharmaceutical Co., Ltd., Hubei, China), and the step change of Ce was definded as 0.5 ng/ml in the study.\u003c/p\u003e\n \u003cp\u003eRemifentanil Ce of next participant were determined by the binary endpoint evaluation of the previous subject,as per the KRD versus BCD UDMs\u003csup\u003e[15]\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eKRD group\u003c/h2\u003e\n \u003cp\u003eAccording to defined binary endpoint, participant\u0026apos;s dose was assigned for target the EC90 with the transition rule of KRD (This study used K\u0026thinsp;=\u0026thinsp;6 from literature recommend) in KRD group\u003csup\u003e[15]\u003c/sup\u003e:\u003c/p\u003e\n \u003cp\u003eIf a participant was negative response,\u003c/p\u003e\n \u003cp\u003e-- Increase Ce of TCI remifentanil.\u003c/p\u003e\n \u003cp\u003eIf a participant was positive response,\u003c/p\u003e\n \u003cp\u003e-- Decrease Ce of TCI remifentanil (but only after observing 6 consecutive positive responses at the same Ce of TCI remifentanil ).\u003c/p\u003e\n \u003cp\u003e-- Otherwise, remain the same Ce of TCI remifentanil.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eBCD group\u003c/h2\u003e\n \u003cp\u003eAccording to defined binary endpoint, participant\u0026apos;s dose was assigned for target the EC90 using the transition rule of BCD in BCD group\u003csup\u003e[15]\u003c/sup\u003e :\u003c/p\u003e\n \u003cp\u003eIf a participant was negative response,\u003c/p\u003e\n \u003cp\u003e-- Increase the Ce of TCI remifentanil.\u003c/p\u003e\n \u003cp\u003eIf a participant was positive response,\u0026ldquo;toss a biased coin\u0026rdquo; (draw a random number) and then either:\u003c/p\u003e\n \u003cp\u003e-- Decrease the Ce of TCI remifentanil with probability inverse to the odds of positive response at the target(with a probability of 0.1);\u003c/p\u003e\n \u003cp\u003e-- Otherwise, remain the same Ce of TCI remifentanil(with a probability of 1-0.1\u0026thinsp;=\u0026thinsp;0.9) .\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eOutcomes measures\u003c/h2\u003e\n \u003cp\u003eFollowing is the definition of different timepoints in the trial. Time 1 (T\u003csub\u003e1\u003c/sub\u003e) was defined as 1 min before induction, Time 2(T\u003csub\u003e2\u003c/sub\u003e) was defined as after administering remifentanil(reaching equilibrium between plasma and effect-site concentrations), Time 3 (T\u003csub\u003e3\u003c/sub\u003e) was defined as after administering propofol(reaching equilibrium between plasma and effect-site concentrations), Time 4(T\u003csub\u003e4\u003c/sub\u003e) was defined as 1 min before EI, Time 5(T\u003csub\u003e5\u003c/sub\u003e) was defined as within the first 3 min following EI, Time 6(T\u003csub\u003e6\u003c/sub\u003e) was defined as during postoperative 48 h.\u003c/p\u003e\n \u003cp\u003eFollowing is the summary of outcomes in the trial(Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e--Proportion of participants who achieve the success and Ce of remifentanil blocking adrenergic responses to EI when administered with propofol in 90% participants between two groups (e.g.,T\u003csub\u003e4\u003c/sub\u003e,T\u003csub\u003e5\u003c/sub\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSecondary outcomes\u003c/h2\u003e\n \u003cp\u003eSecondary outcomes of this study will include the following:\u003c/p\u003e\n \u003cp\u003e--The changes of the hemodynamic parameter(HR, MAP, SBP ,DBP) and sedation level (Ai values) at different time points(e.g.,T\u003csub\u003e1\u003c/sub\u003e,T\u003csub\u003e2\u003c/sub\u003e,T\u003csub\u003e3\u003c/sub\u003e,T\u003csub\u003e4\u003c/sub\u003e,T\u003csub\u003e5\u003c/sub\u003e).\u003c/p\u003e\n \u003cp\u003e--The changes of MOAA/S score and Ai values during anesthesia induction.\u003c/p\u003e\n \u003cp\u003e--Adverse events related to remifentanil with propofol during anesthesia induction, include great hemodynamic change, hypoxemia, muscle tremor, symptoms of chest wall rigidity, choking cough, and postoperative nausea and vomiting during postoperative 48 h.\u003c/p\u003e\n \u003cp\u003e--Time and frequency of rescue medication consumption.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy conductance\u003c/h2\u003e\n \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e\n \u003ch2\u003ePreparation before general anesthesia\u003c/h2\u003e\n \u003cp\u003eAll participants were routinely fasted of food and water without any premedication before surgery. A standard monitoring and anesthetic technique was applied to all participants in this study. Study conductance is displayed in a flow diagram(Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). After arrival at the operating room, the participants are given inhaled oxygen and conventional fluid infusion(10 ml/kg Ringer\u0026apos;s solution before anesthesia induction) and monitors will be attached including an electrocardiograms (ECG), pulse oximetry (SpO2), heart rate (HR), invasive blood pressure (IBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and end-tidal carbon dioxide (PetCO2)(BeneVision M15 Monitor, Mindray,China), Ai for the depth of anesthesia (ConView YY-106; Pearlcare Medical Technology Company Limited, Zhejiang, China), and MOAA/S\u003csup\u003e[39]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eThe invasive arterial blood pressure is established under local anesthesia in participants with a negative Allen test. Sedation was assessed using Ai and MOAA/S. Target sedation in the trial was defined as a Ai target between 40 to 60 (Ai is quite the same as BIS does)\u003csup\u003e[39]\u003c/sup\u003e and MOAA/S score of less than or equal to 1.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eAnesthesia induction\u003c/h2\u003e\n \u003cp\u003eFollowing is the order of anesthesia induction in the trial: remifentanil-propofol-rocuronium bromide (Table.1).Before anesthesia induction, preoxygenation of patients with 100% oxygen and remove nitrogen and oxygen via facial masks for 3min is applied. Drugs were administered via TCI with an infusion pump(Fresenius Kabi, France) driven by STANPUMP. Remifentanil and propofol were administered via TCI (Ce) according to the Minto model and Schnider model, respectively\u003csup\u003e[40,41]\u003c/sup\u003e. Sedation level is assessed by the professional physician every 10 seconds after propofol TCI until target sedation (Ai between 60\u0026thinsp;\u0026minus;\u0026thinsp;40), and bolus rocuronium (0.6mg/kg) was given within 30 seconds, and artificial ventilation was initiated. EI is performed under visual laryngoscopy after 2 minutes of bolus rocuronium.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSafety, Rescue therapy\u003c/strong\u003e and \u003cstrong\u003eCriteria for withdrawal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eWe define each safety issue when one or more of the following respective criteria are met during data collection. Rescue therapy is needed.\u003c/p\u003e\n \u003cp\u003e-- Excessive hemodynamic changes include: systolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;80 or \u0026gt;\u0026thinsp;180mmHg; HR\u0026thinsp;\u0026lt;\u0026thinsp;50 bpm or \u0026gt;\u0026thinsp;120 bpm.\u003c/p\u003e\n \u003cp\u003e-- Hypoxia is defined as SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026le;\u0026thinsp;92% for more than 10 seconds.\u003c/p\u003e\n \u003cp\u003e-- Criteria for withdrawal: If the patient experiences excessive hemodynamic changes, hypoxemia, severe muscle tremors, or persistent chest wall stiffness, we will handle it according to the emergency disposal plan, and the patient will withdraw from this study.\u003c/p\u003e\n \u003cp\u003e-- The following cases will be treated with the same concentration of remifentanil.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eData collection and management and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003eData collection\u003c/h2\u003e\n \u003cp\u003eData collected from standard monitoring and assessment at different timepoint included: SpO\u003csub\u003e2\u003c/sub\u003e, HR, SBP, DBP, MAP, EtCO\u003csub\u003e2\u003c/sub\u003e, Ai, MOAA/S and remifentanil Ce. Patient demographics was collected during the medical consultation with the professional physician.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003eData management\u003c/h2\u003e\n \u003cp\u003eAll of this data will be stored in electronic files. The accuracy of the input data will be confirmed by another person. Only individuals with permission from the principal investigator are allowed to access the database. We will provide each participant with a research identification number in the electronic file for anonymity. The table that display a list of the identification numbers of this study and the corresponding participant\u0026apos;s electronic health records, respectively, will be stored in a locked cabinet in a secure area.The Research Management Committee will have access to the final trial dataset. After the trial is completed, the raw data and results will be submitted to the Research Management Committee.They will be disclosed to the public after the results are announced.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003eData monitoring\u003c/h2\u003e\n \u003cp\u003eThe Data Monitoring Committee (DMC) is composed of a physician responsible for data collection and organization, a trial manager and a statistician. The DMC will hold three meetings annually throughout the entire trial process. The DMC is responsible for safeguarding the interests of trial participants, evaluating the safety of intervention measures, and monitoring the overall trial progress.Any deviation from the plan will be recorded in the report. Any modification to all major plan will be discussed and agreed upon by the researchers, and then submitted to the Certified Review Board (CRB) of the Heping Hospital Affiliated to Changzhi Medical College for approval, and will be updated in the trial registration book and communicated to relevant parties. The trial team has designed and prepared for experimental implementation, and will publish the results. The research team holds regular monthly meetings to discuss project progress. The DMC physician will record the actual number of enrolled participants, excluded cases, demographic and other baseline characteristics, incidence of complications and combination therapy, and comprehensive efficacy evaluation, analysis of compliance and safety. The DMC physician will also describe the participant\u0026apos;s demographic characteristics, history of medical and treatment.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistics\u003c/h2\u003e\n \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\n \u003ch2\u003eStatistical analyses\u003c/h2\u003e\n \u003cp\u003eStatistical analysis was performed using SPSS software, version 27.0 (SPSS, Inc, Chicago, IL). Normally distributed continuous variables are described as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), while nonnormally distributed continuous variables are described as the medians [interquartile range (IQR)].Categorical variables are described as numbers (%). The trial will use Student\u0026apos;s t-test, analysis of variance, Mann Whitney test, or Kruskal Wallis test to compare continuous variables, and chi square test to compare categorical variables. The EC90 and 90% confidence intervals(CIs) were estimated by R-Foundation CIR and the PAVA with bootstrapping(Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The PAVA algorithm is most commonly used for solving isotonic regression.Unless using larger sample sizes (n\u0026thinsp;\u0026gt;\u0026thinsp;100), it is not recommended to report CIs at the 95% confidence level. It is recommended to use 90% or less\u003csup\u003e[15]\u003c/sup\u003e. Therefore, statistical results are presented as point estimates (90% CI) in this trial.\u003c/p\u003e\n \u003cp\u003eEC90 was calculated using CIR with a bias-corrected Morris 90% confidence interval(CI) derived by bootstrapping using\u0026ldquo;dosefind\u0026rdquo; and\u0026ldquo;quickinverse\u0026rdquo; commands in the CIR R package(R\u0026rsquo;s \u0026lsquo;cir\u0026rsquo; Package authored and maintained by Dr. Oron)\u003csup\u003e[15]\u003c/sup\u003e.PAVA-adjusted response rates were estimated using the weighted isotonic regression method\u003csup\u003e[15,42]\u003c/sup\u003e. This trial generates binary(positive/negative) response data. The proportion of negative responses at each dose is calculated and plotted by a dose-response plot. Targeting the EC90, from the dose-response observation pairs, isotonic regression methods are used to estimate the dose-response curve\u003csup\u003e[15,42]\u003c/sup\u003e.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n \u003ch2\u003eSample size estimation\u003c/h2\u003e\n \u003cp\u003eIt is suggested in previous studies that including at least 50 to 60 participants will provide stable estimates of the target dose for EC90\u003csup\u003e[15]\u003c/sup\u003e. This trial will be recruiting 120 cases in two groups, there are 60 cases in each group.\u003c/p\u003e\n \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\n \u003ch2\u003eAdverse event reporting and harms\u003c/h2\u003e\n \u003cp\u003eAdverse events(AEs) are defined as all undesirable or nonintended diseases and signs that may have a potential causal relationship with the investigational drug. All AEs were shared with the researchers, and will be dealt with appropriately. Serious AEs related to this trial will be reported to the Heping Hospital Affiliated to Changzhi Medical College CRB within 15 days.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\n \u003ch2\u003ePatient and public participation\u003c/h2\u003e\n \u003cp\u003eIn our previous pilot trials, the project of this trial was reviewed by patients with scheduled for elective surgery. During the scheme design phase, we solicited opinions from participating medical centers on the content of ethical and safety assessments.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e\n \u003ch2\u003eDissemination plan\u003c/h2\u003e\n \u003cp\u003eThe results of this trial will be announced at anesthesia conferences (local and international). The main research results of this trial will be informed at the trial registration office. The complete research report will be published in national and/or international conferences as well as peer-reviewed journals.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first prospective, random sequential allocation adaptive dose-finding trial to determine and assess the EC\u003csub\u003e90\u003c/sub\u003e BAR\u003csub\u003eEI\u003c/sub\u003e of remifentanil using KRD versus BCD UDMs when administered with propofol.\u003c/p\u003e \u003cp\u003eThe results of this study could help to optimize anti-noxious management and remifentanil TCI strategy during EI. This study also contribute to analyzing the efficacy of two rule-based designs for high percentile dose-finding in anesthesiology research as the basis for rational drug administration schemes.\u003c/p\u003e \u003cp\u003eUsing dose escalation study methods, the study sought to understand the EC90 of dose-response relationship of remifentanil with propofol required to blunt cardiovascular responses to EI.\u003c/p\u003e \u003cp\u003eIf there is no difference between the two designs for quantify EC90, KRD and BCD will be used to evaluate and recognize dose-response relationship (high percentage dose-finding) in anesthesiology study.\u003c/p\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003ePatient recruitment began in Jan 2025. The trial was expected to end in Dec 2025, but we estimate that patient recruitment will be completed in Dec 2025 due to slow accrual. The current protocol is version 2.0, dated 3 Sep 2024.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eEI\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Endotracheal Intubation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eED90\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Effective Dose in 90% patients\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCe\u0026nbsp;\u003c/strong\u003e\u0026nbsp; Effect-site Concentration\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBAR\u0026nbsp;\u003c/strong\u003e Block Adrenergic Response\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEC90\u0026nbsp;\u003c/strong\u003e\u0026nbsp; Effective-site Concentration in 90% patients\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEC\u003csub\u003e90\u003c/sub\u003e BAR\u003csub\u003eEI\u0026nbsp;\u003c/sub\u003e\u003c/strong\u003e\u003csub\u003e\u0026nbsp;\u003c/sub\u003eEffect-site Concentration to Block Adrenergic Response to Endotracheal Intubation\u003csub\u003e\u0026nbsp;\u003c/sub\u003ein 90% patients\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUDM\u003c/strong\u003e\u0026nbsp; \u0026nbsp; Up-and-Down Methods\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKRD\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; K-in-a-Row Design\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBCD\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Biased-Coin Design\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAi\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Anesthesia index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMOAA/S\u003c/strong\u003e\u0026nbsp; Modified Observer Assessment of Alertness and Sedation Scale\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e90%CIs\u003c/strong\u003e\u0026nbsp; \u0026nbsp;90% confidence intervals\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCIR\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; Centered Isotonic Regression\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePAVA\u0026nbsp;\u003c/strong\u003e\u0026nbsp; Pooled Adjacent Violators Algorithm\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTCI\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Target Controlled Infusion\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSD\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Standard Deviation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIQR\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Interquartile Range\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAEs\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Adverse Events\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRB\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; Certified Review Board\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial protocol has received approval from the Ethics Committee of Heping Hospital Affiliated to Changzhi Medical College(approval number: 2024 No.086)on 3rd September 2024. The protocol of this trial was registered at the Chinese Clinical Trial Registry(ChiCTR:2300078275). This trial will be implemented in accordance with the ethical principles stated in the Declaration of Helsinki. The researchers will identify eligible participants according to the inclusion criteria. Eligible participants will receive written and oral information and will be included after researcher has obtained informed written consent. These materials are available from the corresponding author on request. Confidentiality of the data of trial and the results of monitoring will be protected. Any changes to the protocol or AEs will be reported to the DMC. If any harm related to this study occurs, participants can get free treatment provided by the affiliated Heping Hospital of Changzhi Medical College, which will handle it in accordance with relevant laws and regulations.\u003c/p\u003e\n\u003cp\u003eThe qualification screening of surgical patients will be conducted before surgery. Researchers will provide participants with a detailed introduction to the trial, including the purpose, process, and requirements after qualification confirmation. All participants will voluntarily participate in the trial and sign an informed consent form. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol amendments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny significant modifications to the trial plan will be promptly reported to the Ethics Committee of Heping Hospital Affiliated to Changzhi Medical College,and updated on ChiCTR.gov.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent or assent: ancillary studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no relevant plans.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be assigned a unique identifier after registration, replacing the need for participants names in the data collection process. This unique identifier is only meaningful to the trial team and ensures the confidentiality of participants. The chief researcher will be in charge of these unique identifiers securely storing and protecting at the end of the trial according to the research guidelines. Any publications produced by the study will not include any participants personally identifiable information and will always secure the privacy of participants. The trial database will allow Li Chunyu\u0026apos;s application to access the final trial dataset.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination policy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial results will be prepared for submission to an international peer-reviewed journal. This process involves compiling data into a comprehensive manuscript outlining the methods, findings, and impacts of the experiment. The public can access the complete protocol through ChiCTR.gov.website (ChiCTR2300078275), but it does not involve the participants personal information. This database will allow reasonable applications of the corresponding authors to access the final experimental dataset.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to sincerely thank Jintai Jia, Ping Wu and Dongzheng Gai for their support in conduction of the study, and also thank all staff members in the anesthesia department and operating room for care of the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset generated from the current study will be available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003econtributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJin Zhang,Fangsheng Xu and Chunyu Li , the corresponding author of this article in charge of the study, was responsible for the design of the study and modified the manuscript. Luoyun Li and Baichun Xing and Guoping Wang contributed equally. Luoyun Li and Baichun Xing and Guoping Wang are joint first authors, responsible for the experiment, data analysis and writing the original draft of the manuscript. All authors were involved in the implementation of the study and patient data collection.All authors critically revised the manuscript and approved the submission of the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLLY and BCX and GPW contributed equally. LLY and BCX and GPW are joint first authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e*Correspondence to:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Jin Zhang; [email protected]\u003c/p\u003e\n\u003cp\u003eCorrespondence to Fangsheng Xu; [email protected]\u003c/p\u003e\n\u003cp\u003eCorrespondence to Chunyu Li; [email protected]\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Neurology,The First Hospital of Shanxi Medical University,Taiyuan, Shanxi ,China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eNeurology Intensive Care Unit,Department of Neurology,Heping Hospital Affiliated to Changzhi Medical College,Changzhi, Shanxi,China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Anesthesiology,Heping Hospital Affiliated to Changzhi Medical College,Changzhi, Shanxi,China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u003c/sup\u003eDepartment of Anesthesiology,Changzhi People\u0026apos;s Hospital Affiliated to Shanxi Medical University, Changzhi, Shanxi,China\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e5\u003c/sup\u003eDepartment of Anesthesiology, Affiliated Changshu Hospital of Nantong University, Changshu,Jiangsu, China \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZbinden AM, Petersen-Felix S, Thomson DA. 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Median effective dose of remifentanil for awake laryngoscopy and intubation. Chin Med J (Engl). 2009 Jul 5;122(13):1507-12.\u003c/li\u003e\n\u003cli\u003eSantos L, Zheng H, Singhal S, et al. Remifentanil for tracheal intubation without neuromuscular blocking drugs in adult patients: a systematic review and meta-analysis.Anaesthesia. 2024 Jul;79(7):759-769.\u003c/li\u003e\n\u003cli\u003eJiang Z, Xiao J, Wang X, et al. The effect-site concentration of remifentanil blunting endotracheal intubation responses during anesthesia induction with etomidate: a dose-finding study. BMC Anesthesiol. 2023;23(1):225.\u003c/li\u003e\n\u003cli\u003eKutlesic MS, Kutlesic RM, Mostic-Ilic T. Attenuation of cardiovascular stress response to endotracheal intubation by the use of remifentanil in patients undergoing Cesarean delivery. J Anesth. 2016;30(2):274-83.\u003c/li\u003e\n\u003cli\u003eLiu HC, Tao WK, Zeng RF, et al. Dose requirements of remifentanil for intubation in nonparalyzed Chinese children. Paediatr Anaesth. 2014;24(5):505-9.\u003c/li\u003e\n\u003cli\u003eN.L. Pace, M.P. Stylianou. Advances in and limitations of up-and-down methodology: a precis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology. 2007;107(1):144-152.\u003c/li\u003e\n\u003cli\u003eOron AP, Souter MJ, Flournoy N. Understanding Research Methods: Up-and-down Designs for Dose-finding. Anesthesiology. 2022 ;137(2):137-150.\u003c/li\u003e\n\u003cli\u003eSviggum HP, Arendt KW, Jacob AK, et al. Intrathecal Hydromorphone and Morphine for Postcesarean Delivery Analgesia: Determination of the ED90 Using a Sequential Allocation Biased-Coin Method. Anesth Analg. 2016;123(3):690-7.\u003c/li\u003e\n\u003cli\u003eAu K, Shippam W, Taylor J, et al. Determining the effective pre-oxygenation interval in obstetric patients using high-flow nasal oxygen and standard flow rate facemask: a biased-coin up-down sequential allocation trial. Anaesthesia. 2020;75(5):609-616.\u003c/li\u003e\n\u003cli\u003eZhang J, Chen Y, Li S,et al. The 90% effective dose of intranasal dexmedetomidine for procedural sedation in children with congenital heart disease before and after surgery: A biased-coin design up-and-down sequential allocation trial. Acta Anaesthesiol Scand. 2021;65(2):188-194.\u003c/li\u003e\n\u003cli\u003eWesselink EJ, Koopman SJ, Vegt RV, et al. ED90 of spinal 2-chloroprocaine 1% in ambulatory knee arthroscopy up to 45 min: a randomized biased-coin- up-and-down sequential allocation trial. Reg Anesth Pain Med. 2022;47(4):212-216.\u003c/li\u003e\n\u003cli\u003eGao W, Chen Y, Wang W, et al. The 90% minimum effective volume and concentration of ropivacaine for ultrasound-guided median nerve block in children aged 1-3 years: A biased-coin design up-and-down sequential allocation trial. J Clin Anesth. 2022;79:110754.\u003c/li\u003e\n\u003cli\u003eSharawi N, Tan HS, Taylor C, et al. ED 90 of Intrathecal Chloroprocaine With Fentanyl for Prophylactic Cervical Cerclage: A Sequential Allocation Biased-Coin Design. Anesth Analg. 2022 ;134(4):834-842.\u003c/li\u003e\n\u003cli\u003eZhou D, Yang XD, Wu HY, et al. Determination of the ED90 of Dexmedetomidine Infusion to Prevent Emergence Agitation in Children Undergoing Dental Rehabilitation With Sevoflurane Anesthesia: A Biased-Coin Up-and-Down Sequential Allocation Trial.Anesth Analg. 2024 Oct 1;139(4):761-769. \u003c/li\u003e\n\u003cli\u003eMaeda A, Villela-Franyutti D, Lumbreras-Marquez MI, et al. Labor Analgesia Initiation With Dural Puncture Epidural Versus Conventional Epidural Techniques: A Randomized Biased-Coin Sequential Allocation Trial to Determine the Effective Dose for 90% of Patients of Bupivacaine. Anesth Analg. 2024 Jun 1;138(6):1205-1214.\u003c/li\u003e\n\u003cli\u003eAssaf P Oron, Peter D Hoff. The k-in-a-row up-and-down design,revisited.Stat Med. 2009;28(13):1805-20.\u003c/li\u003e\n\u003cli\u003eTreutwein B. Minireview: adaptive psychophysical procedures. Vision Research. 1995; 35:2503-2522.\u003c/li\u003e\n\u003cli\u003eGarc`ıa-Perez M. Forced-choice staircases with fixed step sizes: asymptotic and small-sample properties. Vision Research. 1998; 38:1861-1881.\u003c/li\u003e\n\u003cli\u003eStylianou MP, Flournoy N. \u0026quot;Dose finding using the biased coin up-and-down design and isotonic regression\u0026quot;. Biometrics.2002;58 (1): 171-177. \u003c/li\u003e\n\u003cli\u003eChan AW, Tetzlaff JM, G\u0026oslash;tzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:1-42.\u003c/li\u003e\n\u003cli\u003eMarkaryan, T., Rosenberger, W. F. Exact properties of Efron\u0026rsquo;s biased coin randomization procedure. Annals of Statistics, 2010;38:1546-1567.\u003c/li\u003e\n\u003cli\u003eDurham SD, Flournoy N: Random walks for quantile estimation. Statistical Decision Theory and Related Topics V (West Lafayette, IN, 1992). Berlin, Springer, 1994; 467-476.\u003c/li\u003e\n\u003cli\u003eDurham SD, Flournoy N, Rosenberger WF. A random walk rule for phase I clinical trials. Biometrics 1997; 53:745\u0026ndash;60.\u003c/li\u003e\n\u003cli\u003eZou ZY, Zhao YL, Yang XL,et al. Effects of different remifentanil target concentrations on MAC BAR of sevoflurane in gynaecological patients with CO2 pneumoperitoneum stimulus.Br J Anaesth. 2015;114(4):634-9.\u003c/li\u003e\n\u003cli\u003eJiang P, Tang J, Zhang M, et al.Effects of Transverse Abdominis Plane (TAP) Block on the MAC(BAR) of Sevoflurane in Gynecologic Patients with Laparoscopic Pneumoperitoneal Stimulation: An Up-Down Sequential Allocation Study.J Pain Res. 2024;17:2689-2699.\u003c/li\u003e\n\u003cli\u003eChen C, Pang Q, Tu A, et al. Effect of low-dose ketamine on MAC(BAR) of sevoflurane in laparoscopic cholecystectomy: A randomized controlled trial.J Clin Pharm Ther. 2021;46(1):121-127.\u003c/li\u003e\n\u003cli\u003eJong Hae Kim, Eun Kyung Jwa, Youjin Choung, et al. Comparison of Pupillometry With Surgical Pleth Index Monitoring on Perioperative Opioid Consumption and Nociception During Propofol\u0026ndash;Remifentanil Anesthesia: A Prospective Randomized Controlled Trial. Anesth Analg. 2020;131(5):1589-1598.\u003c/li\u003e\n\u003cli\u003eTae Kyong Kim, Deok Man Hong, Seo Hee Lee, et al. Effect-site concentration of remifentanil required to blunt haemodynamic responses during tracheal intubation: A randomized comparison between single-and double-lumen tubes. Journal of International Medical Research. 2018;46(1): 430-439.\u003c/li\u003e\n\u003cli\u003eJeong Uk Han, Sangyun Cho, Woo Jae Jeon, et al. The optimal effect-site concentration of remifentanil for lightwand tracheal intubation during propofol induction without muscle relaxation. Journal of Clinical Anesthesia. 2011; 23:379\u0026ndash;383.\u003c/li\u003e\n\u003cli\u003eAndrea Albertin, Andrea Casati, Lombardo Federica, et al. The effect-site concentration of remifentanil blunting cardiovascular responses to tracheal intubation and skin incision during bispectral index-guided propofol anesthesia. Anesth Analg. 2005;101(1):125-30. \u003c/li\u003e\n\u003cli\u003eFu Y, Xu T, Xie K, et al. Comparative Evaluation of a New Depth of Anesthesia Index in ConView System and the Bispectral Index during Total Intravenous Anesthesia: A Multicenter Clinical Trial. Biomed Res Int. 2019;2019:1014825.\u003c/li\u003e\n\u003cli\u003eMinto CF, Schnider TW, Shafer SL. Pharmacokinetics and pharmacodynamics of remifentanil: II. Model application. ANESTHESIOLOGY. 1997; 86:24\u0026ndash;33.\u003c/li\u003e\n\u003cli\u003eSchnider TW, Minto CF, Gambus PL,et al. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. ANESTHESIOLOGY. 1998;88:1170-82.\u003c/li\u003e\n\u003cli\u003eMario Stylianou, Nancy Flournoy. Dose finding using the biased coin up-and-down design and isotonic regression. Biometrics. 2002;58(1):171-7.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Effective concentration in 90% patients, Block adrenergic response, Endotracheal Intubation, Dose-finding, K-in-a-row design, Biased coin design, Up-and-down method, Remifentanil, Propofol, Target controlled infusion","lastPublishedDoi":"10.21203/rs.3.rs-5192866/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5192866/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u0026nbsp; \u003c/strong\u003eEndotracheal intubation(EI), as a noxious stimulus, can cause significant adrenergic responses. Remifentanil and propofol have excellent controllable pharmacokinetic characteristics and are commonly used in anesthesia induction. It is vital to assess how drug effects change with increasing doses using dose-response characterisation in anesthesia induction. It has a great clinical significance for optimizing medication strategies to reduce cardiovascular response during EI that determine effect-site concentration (Ce) of remifentanil to block adrenergic responses (BAR) to EI in 90% participants (EC\u003csub\u003e90\u003c/sub\u003e BAR\u003csub\u003eEI\u003c/sub\u003e) and establish a dose-response curve. However, the EC\u003csub\u003e90\u003c/sub\u003e BAR\u003csub\u003eEI \u003c/sub\u003eof remifentanil using the k-in-a-row design (KRD) versus biased-coin design (BCD) up-and-down methods (UDM) when administered with propofol has not been established. The present study was designed to determine and evaluate the EC\u003csub\u003e90\u003c/sub\u003e BAR\u003csub\u003eEI\u003c/sub\u003e of remifentanil using BCD versus KRD undergoing propofol anesthesia induction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u0026nbsp; \u003c/strong\u003eThis is a prospective, randomized sequential allocation dose-finding trial to determine and evaluate the EC\u003csub\u003e90\u003c/sub\u003e of remifentanil required to BAR to EI using the KRD versus BCD UDMs when administered with propofol. We will recruit patients who are Implemented elective surgery for EI under general anesthesia, and randomly allocate them in a 1:1 ratio to the KRD versus BCD groups in advance. The Ce for the follow-up participants increased, decreased or remain same according to the 'negative' or 'positive' response of the previous participant, based on the dose-transition rules of the KRD versus BCD sequential UDMs. Positive response was defined as success. The primary outcomes are the rate of success and Ce of remifentanil blocking adrenergic responses to EI when administered with propofol using KRD versus BCD UDMs in 90% participants. Secondary outcomes include changes of hemodynamic indicators, sedation levels, and safety during anesthesia induction and EI. We plan to enroll 120 participants undergoing elective surgery for EI under general anesthesia and receive one of the KRD versus BCD UDMs. The EC90\u0026nbsp;and 90% confidence intervals(90%CIs) were estimated using R-Foundation centered isotonic regression (CIR) and the pooled adjacent violators algorithm(PAVA) with bootstrapp.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u0026nbsp; \u003c/strong\u003eThis is the first prospective, randomized adaptive dose-finding trial to quantify and assess the EC\u003csub\u003e90\u003c/sub\u003e BAR\u003csub\u003eEI\u003c/sub\u003e of remifentanil using KRD versus BCD UDMs undergoing propofol anesthesia induction. The results of this study contribute to optimizing the target controlled infusion(TCI) strategy of remifentanil during EI, and analyzing the efficacy of two rule-based designs for high percentile dose-finding in anesthesiology research as the basis for rational drug administration schemes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eChinese Clinical Trial Registry, ChiCTR2300078275.Registered on 3rd December 2023.\u003c/p\u003e","manuscriptTitle":"Determination of the EC90 of remifentanil for blocking the adrenergic responses to intubation when administered with propofol: an up-down sequential allocation study protocol using the k-in-a-row design versus biased-coin design","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-31 08:54:17","doi":"10.21203/rs.3.rs-5192866/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a8973117-0b25-4c65-b740-48021dc23a03","owner":[],"postedDate":"March 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-07T11:39:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-31 08:54:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5192866","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5192866","identity":"rs-5192866","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}