Effect-site concentration of remifentanil inhibiting hemodynamic response following endotracheal intubation during remimazolam induction

Effect-site concentration of remifentanil inhibiting hemodynamic response following endotracheal intubation during remimazolam induction | 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 Article Effect-site concentration of remifentanil inhibiting hemodynamic response following endotracheal intubation during remimazolam induction Jiyoung Lee, In Kyong Yi, Heejae So, Hyunghwa Yoo, Duk-Hee Chun, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8083305/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Endotracheal intubation often induces rapid increases in blood pressure and heart rate due to sympathetic stimulation. Remifentanil is commonly used to attenuate these responses, yet its optimal effect-site concentration ( Ce ) during remimazolam induction remains unclear. This prospective, double-blinded clinical trial aimed to determine the Ce of remifentanil required to inhibit hemodynamic response to intubation under remimazolam anesthesia. Thirty-four adult patients undergoing elective surgery were enrolled. All patients received remimazolam and target-controlled infusion of remifentanil, with the Ce determined using Dixon’s up-and-down sequential allocation method. A positive response was defined as a ≥ 20% increase in mean arterial pressure (MAP) or heart rate (HR) within 1 minute after intubation compared to baseline. Based on the responses of 30 patients included in the final analysis, the EC₅₀ and EC₉₅ of remifentanil were estimated as 5.70 ng/mL (83% CI: 5.50–6.00) and 6.40 ng/mL (95% CI: 6.00–6.50), respectively, using isotonic regression and the pooled-adjacent violators algorithm. No patient experienced bradycardia or hypotension requiring treatment. These findings suggest that a remifentanil Ce of 6.40 ng/mL is effective in blunting the hemodynamic response to intubation in 95% of patients during remimazolam-based induction. Health sciences/Cardiology Health sciences/Diseases Health sciences/Medical research Biological sciences/Physiology Remimazolam Remifentanil Endotracheal intubation Effect-site concentration Hemodynamic response Figures Figure 1 Figure 2 Figure 3 Introduction Remimazolam is an ultra-short-acting benzodiazepine recently introduced for clinical use. Its utilization has been steadily increasing in general anesthesia and procedural sedation due to several pharmacologic advantages, including minimal accumulation, minimal influence from hepatic or renal function, and reversibility with flumazenil 1 . Compared with propofol, currently the most widely used induction agent, several clinical studies have reported that remimazolam is associated with a significantly lower incidence of hypotension during anesthetic induction 2 – 4 During endotracheal intubation, the rapid sympathetic activation can cause significant hemodynamic surges, including abrupt elevations in heart rate (HR) and blood pressure, which may lead to arrhythmias, myocardial ischemia, or even infarction 5 . To attenuate these hemodynamic responses, various pharmacologic agents have been used, including beta blockers, calcium channel blockers, lidocaine, and opioids 6 . Remifentanil is a potent and selective opioid µ-receptors agonist which has a rapid onset and short duration of action. It is non-specifically hydrolyzed by esterase in blood and tissues and has a context-sensitive half-life of approximately 3 min. Owing to these characteristics, remifentanil is widely used to blunt the sympathetic response during endotracheal intubation 7 . Given the relatively stable hemodynamic profile of remimazolam compared with propofol, a higher dose of remifentanil may be required to adequately blunt the sympathetic response to endotracheal intubation. While the effect-site concentration ( Ce ) of remifentanil has been studied with inhalational agents and propofol 8 , 9 , the optimal Ce has not yet been determined for remimazolam. Therefore, this study aimed to evaluate the effective Ce of remifentanil required to suppress cardiovascular responses to endotracheal intubation during remimazolam anesthesia, and to estimate the Ce of remifentanil required to suppress cardiovascular responses to endotracheal intubation in 50% of patients (EC 50 ) and 95% of patients (EC 95 ) in this setting. Results Patient characteristics Although the study was designed to conclude after six crossover points, a total of seven pairs were observed due to continuous enrollment. Of the 34 enrolled patients, four were excluded from EC₅₀ and EC₉₅ estimation to avoid PAVA violation caused by unexpected ineffective responses at higher concentrations. Figure 1 illustrates the flow of participants through the study according to the CONSORT 2010 flow diagram. “Effective” indicates a negative hemodynamic response (MAP or HR increase ≤ 20% from baseline within 1 min after intubation). “Ineffective” indicates a positive hemodynamic response (MAP or HR increase > 20%). There were no significant differences in patient characteristics including age, sex, and underlying disease such as hypertension between the effective group and ineffective group (Table 1 ). Table 1 Patient characteristics Variable Ineffective (N = 16) Effective (N = 14) P -value Age (yr) 49.3 ± 14.96 45.1 ± 15.28 0.46 Sex M/F (n) 9/7 6/8 0.71 ASA 1/2 (n) 7/9 10/4 0.25 Height (cm) 165.8 ± 6.22 163.16 ± 7.75 0.33 Weight (kg) 67.43 ± 8.39 62.56 ± 11.94 0.22 BMI (kg/m 2 ) 24.54 ± 2.83 23.47 ± 4.00 0.41 HTN, n (%) 2 (12.5%) 2 (14.3%) > 0.99 DM, n (%) 5 (31.2%) 1 (7.1%) 0.18 Values are presented as mean ± standard deviation for the numerical variables and n for the categorical variables. ASA, American Society of Anesthesiologists; BMI, Body Mass Index; HTN, Hypertension; DM, Diabetes Mellitus. Figure 2 showed the up-and-down sequence in consecutive patients, in which six crossover points (reversals in response direction). All data points were included in the analysis, as no distinct adaptation phase was observed. In the end, there were 14 patients in the effective group (negative hemodynamic response) and 16 patients in the ineffective group (positive hemodynamic response). Primary and secondary outcome The EC₅₀ of remifentanil for blunting cardiovascular responses to intubation during remimazolam anesthesia was estimated as 4.15 ± 1.56 ng/mL based on Dixon’s up-and-down method, using the mean remifentanil concentration at six crossover pairs. Additionally, using isotonic regression with PAVA-adjusted response rates, the EC₅₀ and EC₉₅ were calculated as 5.70 ng/mL (83% CI: 5.50–6.00) and 6.40 ng/mL (95% CI: 6.00–6.50), respectively (Fig. 3 ). Hemodynamic changes during anesthesia induction MAP significantly decreased from baseline before intubation in both groups but returned close to baseline after intubation. MAP values were consistently higher in the ineffective group compared to the effective group at baseline, 1 min, and 5 min after intubation, although the between-group differences did not reach statistical significance after adjustment. In particular, MAP at 1 min after intubation tended to be higher in the ineffective group (98.1 ± 16.3 vs. 85.3 ± 15.8 mmHg), and the between-group difference approached statistical significance; however, it did not remain significant after Bonferroni correction for multiple comparisons. HR also increased after intubation in both groups, but the magnitude of increase was more pronounced in the ineffective group (baseline 68.2 ± 7.1 to 90.8 ± 7.6 bpm) than in the effective group (baseline 72.6 ± 16.7 to 80.4 ± 16.4 bpm) at 1 min after intubation. Oxygen saturation (SpO₂) remained stable and comparable between the groups throughout the study period. Bispectral index (BIS) showed a marked decrease after induction and remained suppressed throughout the observation period in both groups, without significant differences between the groups (Table 2 ). Table 2 Hemodynamic changes during anesthesia induction Variable Ineffective (N = 16) Effective (N = 14) Adjusted P -value† MAP, mmHg Baseline 96.3 ± 7.6 90.6 ± 9.1 0.29 Before intubation 81.8 ± 16.7 * 73.8 ± 9.2 * 0.44 1 min after intubation 98.1 ± 16.3 85.3 ± 15.8 0.15 5 min after intubation 84.6 ± 14.3 * 76.5 ± 9.1 * 0.29 HR, bpm Baseline 68.2 ± 7.1 72.6 ± 16.7 > 0.99 Before intubation 72.3 ± 7.3 * 70.7 ± 11.8 > 0.99 1 min after intubation 90.8 ± 7.6 * 80.4 ± 16.4 * 0.17 5 min after intubation 79.9 ± 9.7 * 74.4 ± 13.6 0.85 SpO 2 , % Baseline 98.9 ± 1.5 99.3 ± 0.9 > 0.99 Before intubation 99.7 ± 0.7 * 100 ± 0* 0.39 1 min after intubation 99.8 ± 0.4 * 100 ± 0* 0.33 5 min after intubation 99.7 ± 0.6 99.9 ± 0.3 0.65 BIS Baseline 99.9 ± 0.2 99.8 ± 0.4 > 0.99 Before intubation 55.8 ± 7.0 * 59.1 ± 6.0 * 0.66 1 min after intubation 58.4 ± 7.2 * 59.9 ± 7.0 * > 0.99 5 min after intubation 56.2 ± 4.5 * 54.3 ± 5.1 * > 0.99 * P < 0.05 compared with baseline within the same group (three comparisons, adjusted by multiplying raw P values by 3). † Adjusted P values for between-group comparisons were calculated using Bonferroni correction for multiple comparisons (adjusted by multiplying raw P values by 4) Values are presented as mean ± standard deviation for continuous variables. MAP, mean arterial pressure; HR, heart rate; SpO 2 , peripheral oxygen saturation; BIS, bispectral index. Adverse events During the study period, all patients were successfully ventilated with the one-hand mask method, and none required an oral or nasal airway. Two-handed mask ventilation was not required in any case. Endotracheal intubation was achieved smoothly using a videolaryngoscope and stylet, with no difficult airways encountered. From baseline to 5 min after intubation, vital signs were stable without bradycardia (HR slower than 45 beats/min) nor hypotension (MAP equal or blow 50 mmHg) requiring intervention. Discussion This is the first randomized, double-blinded study to investigate the EC 50 and EC 95 inhibiting hemodynamic response following endotracheal intubation during remimazolam induction in adult patients. In the current study demonstrated that, the EC 50 and EC 95 of remifentanil required to blunt the cardiovascular response to intubation during remimazolam induction were 5.70 ng/ml and 6.40 ng/mL, respectively. Our results showed that, as expected, higher concentration of remifentanil was required with remimazolam than with propofol. Yoon et al 10 reported that Ce of remifentanil required to attenuate cardiovascular responses during nasotracheal intubation using a video laryngoscope under propofol bolus anesthetic induction were 3.22 ng/mL for EC 50 and 4.25 ng/mL for EC 95 which were lower than those observed in our study. A recent meta-analysis by Wu et al. 11 demonstrated that remimazolam resulted in less hypotension and bradycardia than propofol during induction, supporting our finding that higher remifentanil concentrations were required with remimazolam than propofol bolus administration. In contrast, based on the study by Kwak et al. 9 , the EC 50 and EC 95 values for remifentanil during orotracheal intubation under propofol anesthesia were 5.40 ng/mL and 6.85 ng/mL, respectively. These findings were unexpectedly similar to those in our study, where the EC 50 and EC 95 of remifentanil were 5.70 ng/mL and 6.40 ng/mL, respectively.​ This similarity between the two studies may be attributed to the use of TCI for propofol administration. TCI allows reducing the total dose of propofol required for induction therefore increasing induction time compared to bolus administration 12 . This interpretation, however, should be considered with caution. In a randomized controlled trial directly comparing remimazolam infusion with propofol TCI during thyroidectomy, remimazolam was associated with more stable hemodynamics, with significantly higher MAP and fewer hypotensive events than propofol, while remifentanil was maintained at the same target concentration in both groups 13 . In the effective group, the remifentanil concentration that blunted the tachycardic response also appeared to reduce blood pressure, as MAP 1 min after intubation fell below baseline, although this was not statistically significant. Although no patient required intervention for bradycardia or hypotension, the lowest MAP observed before intubation was 58 mmHg. These findings suggest that the remifentanil Ce sufficient to blunt the tachycardic response may have concurrently caused excessive suppression of sympathetic tone, leading to a decrease in blood pressure- namely, MAP and HR both within 20% of baseline. As observed in our both effective and ineffective group, it is common for MAP to fall below baseline values approximately 5 min after intubation, likely reflecting the hemodynamic effects of anesthetic agents following the resolution of the initial sympathetic surge 3 , 14 . The potential for hemodynamic instability should be considered, especially in more vulnerable patient populations like ASA physical status Ⅲ or more. These findings emphasize the importance of balancing the suppression of undesirable sympathetic responses while avoiding excessive hemodynamic depression. This study also has several limitations. First, remimazolam was infused at a fixed rate of 6 mg/kg/h until loss of consciousness in this study. Although this regimen accounts for body weight, the time to LOC can vary among individuals, leading to variability in the total cumulative dose actually administered. Because this was not recorded, its potential influence on baseline blood pressure and subsequent hemodynamic responses cannot be excluded. On the other hand, this protocol reflects real-world anesthetic practice, which strengthens the external validity of our findings. Second, the study population consisted exclusively of ASA I–II patients, limiting generalizability to higher-risk populations. Third, the up-and-down sequential design, while suitable for estimating EC₅₀ and EC₉₅, does not ensure full randomization and may be affected by numerical baseline imbalances, such as the observed difference in baseline MAP, although this was not statistically significant. Future studies may evaluate remifentanil dosing under remimazolam anesthesia in patients with higher ASA physical status (III–IV), those with cardiovascular comorbidities, or in emergency airway management setting to enhance the generalizability of our findings. Additionally, comparative studies using other induction agents such as propofol may help contextualize the remifentanil requirement observed in the current study. In summary, our study demonstrated that TCI of remifentanil at 5.70 ng/mL and 6.40 ng/mL was effective in blunting hemodynamic responses in 50% and 95% of ASA physical status I-II adult patients respectively, when induction with remimazolam. These findings may serve as a reference for optimizing opioid dosing during anesthetic induction using remimazolam. Methods Study Design and Participants This study was approved by the institutional review board of CHA Bundang Medical Center, CHA University, Seongnam, Korea (approval number CHAMC 2023-05-037-002, approval date 07/07/2023) and was performed in accordance with the tenets of the Declaration of Helsinki. Before the enrollment of the first patient, we registered this study at the Clinical Research Information Service ( https://cris.nih.go.kr , Registration No. KCT 0008697, Registered Date: 07/10/2023). Written informed consent was obtained from every eligible participant in the aforementioned trial. This study was conducted between July 13, 2023, and August 28, 2023. Patients aged 19–65 years with an American Society of Anesthesiologists (ASA) physical status classification of I or II, who were scheduled for an elective ear nose and throat surgery under general anesthesia were included. The exclusion criteria were as follows: allergy to study drugs or dextran 40; acute narrow-angle glaucoma; sleep apnea; heart, lung, kidney, cerebrovascular, or psychiatric disease; chronic use of opioids or alcohols; pregnancy or breast-feeding; galactose or lactase deficiency; or other ASA physical status Ⅲ or more. Endotracheal intubation was performed by Investigator 1 (J Lee), who was blinded to the remifentanil concentration and did not observe the monitor during the procedure. Immediately after completing the intubation, the Investigator 1 exited the operating room to avoid influencing the hemodynamic assessment. A positive response was defined as an increase in mean arterial pressure (MAP) or HR of more than 20% from baseline within 1 min of intubation. Investigator 2 (DH Chun), who was not blinded, managed the target effect-site concentration ( Ce ) of remifentanil according to the up-and-down method protocol. During the study period, vital signs and BIS values were recorded by Investigator 3 (H So), who was blinded to the remifentanil concentration. Anesthesia and intubation protocol Patients entered the operating room without premedication. Standard monitoring applied including pulse oximetry, electrocardiography, and bispectral index (BIS™, Medtronic, Minneapolis, MN, USA) were initiated. Automated noninvasive blood pressure (NIBP) was measured on the patient’s upper arm using an oscillometric method with a GE anesthesia monitoring system (GE Healthcare, Chicago, IL, USA). At the start of a 3 min preoxygenation period with 100% oxygen at flow rate of 6 L/min, remifentanil infusion was initiated at a target Ce predetermined by the study protocol using Minto model of target-controlled infusion (TCI). TCI was performed with the Agilia SP TIVA infusion pump (Fresenius Kabi, Fresenius Kabi AG, Bad Homburg, Hessen, Germany). Remimazolam 6 mg/kg/h was infused continuously for anesthesia induction. After confirming loss of consciousness via the eyelash reflex, remimazolam was reduced to 2 mg/kg/h, If the BIS value decreased below 60, the rate was further reduced to 1 mg/kg/h, and the BIS was maintained between 40 and 60. Rocuronium 0.6 mg/kg was administered after loss of consciousness. Manual ventilation was initiated using one hand method until endotracheal intubation, maintaining a peak inspiratory pressure below 25 cmH 2 O and end-tidal CO 2 (EtCO 2 ) was maintained as close to 35 mmHg as possible. Two min later, the Ce of remifentanil reached the target level, and endotracheal intubation was performed by a single experienced anesthesiologist with over 15 years of clinical experience (Investigator 1, J Lee), using a KoMAC videolaryngoscope (KoMAC Co., Ltd., Seoul, Republic of Korea). A size 4 blade was used for male patients and a size 3 blade for female patients. A cuffed endotracheal tube was used, with an internal diameter of 7.5 mm for male patients and 6.5 mm for female patients (Shiley™ endotracheal tube with TaperGuard™ cuff, Covidien, USA). The adult stylet that comes as a set with the UE videolaryngoscope (Zhejiang Lingyang Medical Apparatus Co., Ltd., China) was used to facilitate intubation. Mechanical ventilation was initiated as soon as possible after intubation. The inspired oxygen fraction was set to 0.4 with fresh gas flow of 2 L/min. Tidal volume was set at 7 ml/kg of predicted body weight, with a positive end-expiratory pressure (PEEP) of 5 cmH 2 O. Respiratory rate was adjusted to maintain an EtCO 2 of 35 mmHg. Determination of remifentanil effect-site concentration MAP, HR, peripheral oxygen saturation (SpO 2 ), and BIS were recorded at the following time points: baseline (T0, prior to anesthetic induction), just before intubation (T1), 1 min after intubation (T2), and 5 min after intubation (T3). The Ce of remifentanil was determined using Dixon’s up-and-down sequential allocation method, with an initial effect-site concentration of 4.0 ng/mL administered to the first patient. If either the MAP or HR at T2 increased by more than 20% compared with the baseline value (T0), the response was considered positive (ineffective group), and the Ce of remifentanil for the next patient was increased by 0.5 ng/mL. Conversely, both MAP and HR at T2 increased by 20% or less compared with baseline, the response was considered negative (effective group), and the Ce for the next patient was decreased by 0.5 ng/mL. The selected starting dose and step size were based on previous endotracheal intubation studies using desflurane or propofol, which reported EC₅₀ values of 4.4 ± 0.7 8 and 3.11 ± 0.38 ng/mL 15 , respectively. An anesthesiologist (Investigator 2, DH Chun), unblinded to the remifentanil Ce and uninvolved in outcome assessment provided routine intraoperative care, while vital signs and BIS values were recorded by Investigator 3 (H So), who was blinded to the remifentanil concentration. The primary outcome of this study was the Ce of remifentanil required to suppress cardiovascular responses to endotracheal intubation in 50% of patients (EC 50 ) and the secondary outcome was the Ce required for 95% of patients (EC 95 ). Both EC 50 and EC 95 values were estimated using isotonic regression based on the up-and-down response data. Statistical analysis The total number of participants was determined based on Dixon’s up-and-down method 16 which requires at least six crossover points (i.e., reversals in patients response from effective to ineffective or vice versa) for statistical analysis 17 . Sample sizes are typically limited to 20–40 18 . Given the unknown distribution of the response data, a conservative estimation of the sample size was applied. Previous studies using this method reported that approximately 30 to 35 participants were sufficient to determine the target Ce 19,20 ; therefore, a total of 34 patients were enrolled in this study. The t-test was used to compare parametric data. Categorical variables were analyzed by the Chi‑square test or Fisher’s exact test. Post-hoc pairwise comparisons were adjusted with Bonferroni correction. An adjusted response probability was calculated using the pooled adjacent-violators algorithm (PAVA) 21 . EC 50 (83% confidence interval [CI]) and EC 95 (95% CI) of hemodynamic stability after intubation was determined by the isotonic regression method 21 . The 83% CI for EC₅₀ was used because it provides a statistically equivalent precision to the 95% CI for EC₉₅ in the up-and-down sequential design. Data were expressed as mean ± standard deviation (s.d.) or numbers (%). All statistical analyses were performed by use of R software, version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org/ ). A P-value less than .05 was considered to be statistically significant. Declarations Acknowledgments We are grateful to the staff and colleagues in the anesthesiology and pain medicine department, otolaryngology-head and neck surgery department, and post-anesthesia care unit for their co-operation in data collection. The authors used ChatGPT to assist language refinement. Final wording and interpretation were determined solely by the authors. Author contributions J.L. and I.K.Y. contributed equally to this work and are considered co-first authors. J.L. was responsible for the conception and design of the study, methodology, and drafting of the manuscript. I.K.Y. performed the statistical analysis, contributed to software, and critically revised and supplemented the manuscript. H.S. contributed to data acquisition. H.Y. was responsible for data visualization. D.H.C. contributed to data curation and provided resources. J.Y.K. supervised the entire study, administered the project, and provided overall guidance. All authors reviewed and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. Data availability statement The full WHO-format trial protocol can be found in Supplementary Methods S1. The completed CONSORT 2010 checklist supporting the reporting of this clinical trial is provided in Supplementary File S2. 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Supplementary Files SupplementaryMethodsS1.docx SupplementaryFileS2.doc Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 09 May, 2026 Reviews received at journal 28 Mar, 2026 Reviewers agreed at journal 18 Mar, 2026 Reviewers invited by journal 06 Mar, 2026 Editor assigned by journal 03 Mar, 2026 Editor invited by journal 19 Nov, 2025 Submission checks completed at journal 16 Nov, 2025 First submitted to journal 16 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-8083305","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":602305884,"identity":"e86cfee8-c8a5-4d7c-b928-e907753d00f4","order_by":0,"name":"Jiyoung Lee","email":"","orcid":"","institution":"CHA Bundang Medical Center, CHA University","correspondingAuthor":false,"prefix":"","firstName":"Jiyoung","middleName":"","lastName":"Lee","suffix":""},{"id":602305885,"identity":"1531a16f-4a52-42e2-98c1-7725a95c8f5f","order_by":1,"name":"In Kyong Yi","email":"","orcid":"","institution":"Ajou University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"In","middleName":"Kyong","lastName":"Yi","suffix":""},{"id":602305886,"identity":"6593bc7c-a5fa-4895-9ceb-1772379dce70","order_by":2,"name":"Heejae So","email":"","orcid":"","institution":"CHA Bundang Medical Center, CHA University","correspondingAuthor":false,"prefix":"","firstName":"Heejae","middleName":"","lastName":"So","suffix":""},{"id":602305887,"identity":"7d8a8403-44b7-4f3d-a480-19125c71faef","order_by":3,"name":"Hyunghwa Yoo","email":"","orcid":"","institution":"CHA Bundang Medical Center, CHA University","correspondingAuthor":false,"prefix":"","firstName":"Hyunghwa","middleName":"","lastName":"Yoo","suffix":""},{"id":602305888,"identity":"4134be17-dc06-4529-bf4a-8fcdde6b913e","order_by":4,"name":"Duk-Hee Chun","email":"","orcid":"","institution":"CHA Bundang Medical Center, CHA University","correspondingAuthor":false,"prefix":"","firstName":"Duk-Hee","middleName":"","lastName":"Chun","suffix":""},{"id":602305889,"identity":"bc52ecaf-bff9-4495-8d02-996f9de3fe4c","order_by":5,"name":"Jong Yeop Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYBACCYYDIMqGgbEBImBArJY0krSAwWG4AGEtko1nDB983HFenrm9x4DhRw2DsXkDAS3SDGeMDWeeuW3Y2HPGgLHnGIOZzAECWuQYzphJ87bdZmyckWPAwNvAYCNByGFALea/edvO2YO0MP4lRgvQYWbMvG0HEkFamIG2mBHUItlwrFhy5pnk5MaeYwWHZY5JGBPUInHj8MYPH3fY2W5sb9748E2NjeEMQloYJE4YgKPREIgPwOMJL+BvfwDWIk+E2lEwCkbBKBihAABAnEBJT+L8ogAAAABJRU5ErkJggg==","orcid":"","institution":"Ajou University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jong","middleName":"Yeop","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2025-11-11 06:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8083305/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8083305/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104780372,"identity":"323a2fdd-f056-45bb-802b-ff77091b4e63","added_by":"auto","created_at":"2026-03-17 07:52:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":137451,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT 2010 Flow Diagram.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8083305/v1/172d8b623b57e52ba69b387a.png"},{"id":104472313,"identity":"1396f517-a36a-433f-963c-e1fd317c00f4","added_by":"auto","created_at":"2026-03-12 07:31:46","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":18019,"visible":true,"origin":"","legend":"\u003cp\u003eData of consecutive intubation over predetermined doses of remifentanil (with the initial remifentanil being 4.0 ng/mL for the first patient).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8083305/v1/0afe30c875149b14fc155eb7.jpeg"},{"id":104780365,"identity":"a21c5ab9-8eb3-413c-a65a-b92a61732e5e","added_by":"auto","created_at":"2026-03-17 07:52:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":44151,"visible":true,"origin":"","legend":"\u003cp\u003ePooled-adjacent violators algorithm (PAVA) response rate calculated by isotonic regression. Black dots represent the response probability of each dose of remifentanil. The dashed line represents a response rate of 0.5 (EC\u003csub\u003e50\u003c/sub\u003e, 5.70; 83% CI [5.50, 6.00]) and 0.95 (EC\u003csub\u003e95\u003c/sub\u003e, 6.40; 95% CI [6.00, 6.50]), respectively.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8083305/v1/b63986c8d0229da51abd55c8.png"},{"id":104784530,"identity":"68d35f30-eae3-4baf-b02b-ff400fa2780c","added_by":"auto","created_at":"2026-03-17 08:08:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":991093,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8083305/v1/565889c6-71d4-4123-98bf-84a0443b3451.pdf"},{"id":104472311,"identity":"b84abefa-bdb2-4d1f-8b9c-22966cd66386","added_by":"auto","created_at":"2026-03-12 07:31:46","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":19843,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMethodsS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8083305/v1/7283f85de2e6a93e36af9ce1.docx"},{"id":104780709,"identity":"db032511-c84c-444b-bf31-cabee5febbc6","added_by":"auto","created_at":"2026-03-17 07:53:39","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":223744,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFileS2.doc","url":"https://assets-eu.researchsquare.com/files/rs-8083305/v1/b48bd183ab7b2af99a79c113.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect-site concentration of remifentanil inhibiting hemodynamic response following endotracheal intubation during remimazolam induction","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRemimazolam is an ultra-short-acting benzodiazepine recently introduced for clinical use. Its utilization has been steadily increasing in general anesthesia and procedural sedation due to several pharmacologic advantages, including minimal accumulation, minimal influence from hepatic or renal function, and reversibility with flumazenil \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Compared with propofol, currently the most widely used induction agent, several clinical studies have reported that remimazolam is associated with a significantly lower incidence of hypotension during anesthetic induction \u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDuring endotracheal intubation, the rapid sympathetic activation can cause significant hemodynamic surges, including abrupt elevations in heart rate (HR) and blood pressure, which may lead to arrhythmias, myocardial ischemia, or even infarction \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. To attenuate these hemodynamic responses, various pharmacologic agents have been used, including beta blockers, calcium channel blockers, lidocaine, and opioids \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Remifentanil is a potent and selective opioid \u0026micro;-receptors agonist which has a rapid onset and short duration of action. It is non-specifically hydrolyzed by esterase in blood and tissues and has a context-sensitive half-life of approximately 3 min. Owing to these characteristics, remifentanil is widely used to blunt the sympathetic response during endotracheal intubation \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eGiven the relatively stable hemodynamic profile of remimazolam compared with propofol, a higher dose of remifentanil may be required to adequately blunt the sympathetic response to endotracheal intubation. While the effect-site concentration (\u003cem\u003eCe\u003c/em\u003e) of remifentanil has been studied with inhalational agents and propofol \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, the optimal Ce has not yet been determined for remimazolam. Therefore, this study aimed to evaluate the effective \u003cem\u003eCe\u003c/em\u003e of remifentanil required to suppress cardiovascular responses to endotracheal intubation during remimazolam anesthesia, and to estimate the \u003cem\u003eCe\u003c/em\u003e of remifentanil required to suppress cardiovascular responses to endotracheal intubation in 50% of patients (EC\u003csub\u003e50\u003c/sub\u003e) and 95% of patients (EC\u003csub\u003e95\u003c/sub\u003e) in this setting.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eAlthough the study was designed to conclude after six crossover points, a total of seven pairs were observed due to continuous enrollment. Of the 34 enrolled patients, four were excluded from EC₅₀ and EC₉₅ estimation to avoid PAVA violation caused by unexpected ineffective responses at higher concentrations. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the flow of participants through the study according to the CONSORT 2010 flow diagram.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u0026ldquo;Effective\u0026rdquo; indicates a negative hemodynamic response (MAP or HR increase\u0026thinsp;\u0026le;\u0026thinsp;20% from baseline within 1 min after intubation).\u003c/p\u003e \u003cp\u003e\u0026ldquo;Ineffective\u0026rdquo; indicates a positive hemodynamic response (MAP or HR increase\u0026thinsp;\u0026gt;\u0026thinsp;20%).\u003c/p\u003e \u003cp\u003eThere were no significant differences in patient characteristics including age, sex, and underlying disease such as hypertension between the effective group and ineffective group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIneffective\u003c/p\u003e \u003cp\u003e (N\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEffective\u003c/p\u003e \u003cp\u003e (N\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (yr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45.1\u0026thinsp;\u0026plusmn;\u0026thinsp;15.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex M/F (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9/7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASA 1/2 (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e165.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e163.16\u0026thinsp;\u0026plusmn;\u0026thinsp;7.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.43\u0026thinsp;\u0026plusmn;\u0026thinsp;8.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.56\u0026thinsp;\u0026plusmn;\u0026thinsp;11.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.47\u0026thinsp;\u0026plusmn;\u0026thinsp;4.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHTN, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (31.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eValues are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation for the numerical variables and n for the categorical variables. ASA, American Society of Anesthesiologists; BMI, Body Mass Index; HTN, Hypertension; DM, Diabetes Mellitus.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e showed the up-and-down sequence in consecutive patients, in which six crossover points (reversals in response direction). All data points were included in the analysis, as no distinct adaptation phase was observed. In the end, there were 14 patients in the effective group (negative hemodynamic response) and 16 patients in the ineffective group (positive hemodynamic response).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePrimary and secondary outcome\u003c/h3\u003e\n\u003cp\u003e \u003c/p\u003e \u003cp\u003eThe EC₅₀ of remifentanil for blunting cardiovascular responses to intubation during remimazolam anesthesia was estimated as 4.15\u0026thinsp;\u0026plusmn;\u0026thinsp;1.56 ng/mL based on Dixon\u0026rsquo;s up-and-down method, using the mean remifentanil concentration at six crossover pairs. Additionally, using isotonic regression with PAVA-adjusted response rates, the EC₅₀ and EC₉₅ were calculated as 5.70 ng/mL (83% CI: 5.50\u0026ndash;6.00) and 6.40 ng/mL (95% CI: 6.00\u0026ndash;6.50), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eHemodynamic changes during anesthesia induction\u003c/h3\u003e\n\u003cp\u003eMAP significantly decreased from baseline before intubation in both groups but returned close to baseline after intubation. MAP values were consistently higher in the ineffective group compared to the effective group at baseline, 1 min, and 5 min after intubation, although the between-group differences did not reach statistical significance after adjustment. In particular, MAP at 1 min after intubation tended to be higher in the ineffective group (98.1\u0026thinsp;\u0026plusmn;\u0026thinsp;16.3 vs. 85.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.8 mmHg), and the between-group difference approached statistical significance; however, it did not remain significant after Bonferroni correction for multiple comparisons. HR also increased after intubation in both groups, but the magnitude of increase was more pronounced in the ineffective group (baseline 68.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1 to 90.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 bpm) than in the effective group (baseline 72.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.7 to 80.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4 bpm) at 1 min after intubation. Oxygen saturation (SpO₂) remained stable and comparable between the groups throughout the study period. Bispectral index (BIS) showed a marked decrease after induction and remained suppressed throughout the observation period in both groups, without significant differences between the groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHemodynamic changes during anesthesia induction\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIneffective\u003c/p\u003e \u003cp\u003e (N\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEffective\u003c/p\u003e \u003cp\u003e (N\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted\u003c/p\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u0026dagger;\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e96.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e90.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e81.8\u0026thinsp;\u0026plusmn;\u0026thinsp;16.7 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e73.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 min after intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e98.1\u0026thinsp;\u0026plusmn;\u0026thinsp;16.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e85.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 min after intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e84.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.3 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e76.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR, bpm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e68.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e72.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e72.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e70.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 min after intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e90.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e80.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 min after intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e79.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e74.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpO\u003csub\u003e2\u003c/sub\u003e, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e98.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e99.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e99.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e100\u0026thinsp;\u0026plusmn;\u0026thinsp;0*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 min after intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e99.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e100\u0026thinsp;\u0026plusmn;\u0026thinsp;0*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 min after intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e99.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e99.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBIS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e99.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e99.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e55.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e59.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 min after intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e58.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e59.9\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 min after intubation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e56.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e54.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1 *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e* \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 compared with baseline within the same group (three comparisons, adjusted by multiplying raw \u003cem\u003eP\u003c/em\u003e values by 3).\u003c/p\u003e \u003cp\u003e\u0026dagger; Adjusted \u003cem\u003eP\u003c/em\u003e values for between-group comparisons were calculated using Bonferroni correction for multiple comparisons (adjusted by multiplying raw \u003cem\u003eP\u003c/em\u003e values by 4)\u003c/p\u003e \u003cp\u003eValues are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation for continuous variables. MAP, mean arterial pressure; HR, heart rate; SpO\u003csub\u003e2\u003c/sub\u003e, peripheral oxygen saturation; BIS, bispectral index.\u003c/p\u003e\n\u003ch3\u003eAdverse events\u003c/h3\u003e\n\u003cp\u003e During the study period, all patients were successfully ventilated with the one-hand mask method, and none required an oral or nasal airway. Two-handed mask ventilation was not required in any case. Endotracheal intubation was achieved smoothly using a videolaryngoscope and stylet, with no difficult airways encountered. From baseline to 5 min after intubation, vital signs were stable without bradycardia (HR slower than 45 beats/min) nor hypotension (MAP equal or blow 50 mmHg) requiring intervention.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first randomized, double-blinded study to investigate the EC\u003csub\u003e50\u003c/sub\u003e and EC\u003csub\u003e95\u003c/sub\u003e inhibiting hemodynamic response following endotracheal intubation during remimazolam induction in adult patients. In the current study demonstrated that, the EC\u003csub\u003e50\u003c/sub\u003e and EC\u003csub\u003e95\u003c/sub\u003e of remifentanil required to blunt the cardiovascular response to intubation during remimazolam induction were 5.70 ng/ml and 6.40 ng/mL, respectively.\u003c/p\u003e \u003cp\u003eOur results showed that, as expected, higher concentration of remifentanil was required with remimazolam than with propofol. Yoon et al \u003csup\u003e10\u003c/sup\u003e reported that \u003cem\u003eCe\u003c/em\u003e of remifentanil required to attenuate cardiovascular responses during nasotracheal intubation using a video laryngoscope under propofol bolus anesthetic induction were 3.22 ng/mL for EC\u003csub\u003e50\u003c/sub\u003e and 4.25 ng/mL for EC\u003csub\u003e95\u003c/sub\u003e which were lower than those observed in our study. A recent meta-analysis by Wu et al. \u003csup\u003e11\u003c/sup\u003e demonstrated that remimazolam resulted in less hypotension and bradycardia than propofol during induction, supporting our finding that higher remifentanil concentrations were required with remimazolam than propofol bolus administration.\u003c/p\u003e \u003cp\u003eIn contrast, based on the study by Kwak et al.\u003csup\u003e9\u003c/sup\u003e, the EC\u003csub\u003e50\u003c/sub\u003e and EC\u003csub\u003e95\u003c/sub\u003e values for remifentanil during orotracheal intubation under propofol anesthesia were 5.40 ng/mL and 6.85 ng/mL, respectively. These findings were unexpectedly similar to those in our study, where the EC\u003csub\u003e50\u003c/sub\u003e and EC\u003csub\u003e95\u003c/sub\u003e of remifentanil were 5.70 ng/mL and 6.40 ng/mL, respectively.​ This similarity between the two studies may be attributed to the use of TCI for propofol administration. TCI allows reducing the total dose of propofol required for induction therefore increasing induction time compared to bolus administration \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This interpretation, however, should be considered with caution. In a randomized controlled trial directly comparing remimazolam infusion with propofol TCI during thyroidectomy, remimazolam was associated with more stable hemodynamics, with significantly higher MAP and fewer hypotensive events than propofol, while remifentanil was maintained at the same target concentration in both groups \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the effective group, the remifentanil concentration that blunted the tachycardic response also appeared to reduce blood pressure, as MAP 1 min after intubation fell below baseline, although this was not statistically significant. Although no patient required intervention for bradycardia or hypotension, the lowest MAP observed before intubation was 58 mmHg. These findings suggest that the remifentanil \u003cem\u003eCe\u003c/em\u003e sufficient to blunt the tachycardic response may have concurrently caused excessive suppression of sympathetic tone, leading to a decrease in blood pressure- namely, MAP and HR both within 20% of baseline. As observed in our both effective and ineffective group, it is common for MAP to fall below baseline values approximately 5 min after intubation, likely reflecting the hemodynamic effects of anesthetic agents following the resolution of the initial sympathetic surge \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. The potential for hemodynamic instability should be considered, especially in more vulnerable patient populations like ASA physical status Ⅲ or more. These findings emphasize the importance of balancing the suppression of undesirable sympathetic responses while avoiding excessive hemodynamic depression.\u003c/p\u003e \u003cp\u003eThis study also has several limitations. First, remimazolam was infused at a fixed rate of 6 mg/kg/h until loss of consciousness in this study. Although this regimen accounts for body weight, the time to LOC can vary among individuals, leading to variability in the total cumulative dose actually administered. Because this was not recorded, its potential influence on baseline blood pressure and subsequent hemodynamic responses cannot be excluded. On the other hand, this protocol reflects real-world anesthetic practice, which strengthens the external validity of our findings. Second, the study population consisted exclusively of ASA I–II patients, limiting generalizability to higher-risk populations. Third, the up-and-down sequential design, while suitable for estimating EC₅₀ and EC₉₅, does not ensure full randomization and may be affected by numerical baseline imbalances, such as the observed difference in baseline MAP, although this was not statistically significant.\u003c/p\u003e \u003cp\u003eFuture studies may evaluate remifentanil dosing under remimazolam anesthesia in patients with higher ASA physical status (III–IV), those with cardiovascular comorbidities, or in emergency airway management setting to enhance the generalizability of our findings. Additionally, comparative studies using other induction agents such as propofol may help contextualize the remifentanil requirement observed in the current study.\u003c/p\u003e \u003cp\u003eIn summary, our study demonstrated that TCI of remifentanil at 5.70 ng/mL and 6.40 ng/mL was effective in blunting hemodynamic responses in 50% and 95% of ASA physical status I-II adult patients respectively, when induction with remimazolam. These findings may serve as a reference for optimizing opioid dosing during anesthetic induction using remimazolam.\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003eStudy Design and Participants\u003c/h2\u003e\u003cp\u003e This study was approved by the institutional review board of CHA Bundang Medical Center, CHA University, Seongnam, Korea (approval number CHAMC 2023-05-037-002, approval date 07/07/2023) and was performed in accordance with the tenets of the Declaration of Helsinki. Before the enrollment of the first patient, we registered this study at the Clinical Research Information Service (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cris.nih.go.kr\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, Registration No. KCT 0008697, Registered Date: 07/10/2023). Written informed consent was obtained from every eligible participant in the aforementioned trial. This study was conducted between July 13, 2023, and August 28, 2023. Patients aged 19–65 years with an American Society of Anesthesiologists (ASA) physical status classification of I or II, who were scheduled for an elective ear nose and throat surgery under general anesthesia were included. The exclusion criteria were as follows: allergy to study drugs or dextran 40; acute narrow-angle glaucoma; sleep apnea; heart, lung, kidney, cerebrovascular, or psychiatric disease; chronic use of opioids or alcohols; pregnancy or breast-feeding; galactose or lactase deficiency; or other ASA physical status Ⅲ or more.\u003c/p\u003e\u003cp\u003eEndotracheal intubation was performed by Investigator 1 (J Lee), who was blinded to the remifentanil concentration and did not observe the monitor during the procedure. Immediately after completing the intubation, the Investigator 1 exited the operating room to avoid influencing the hemodynamic assessment. A positive response was defined as an increase in mean arterial pressure (MAP) or HR of more than 20% from baseline within 1 min of intubation. Investigator 2 (DH Chun), who was not blinded, managed the target effect-site concentration (\u003cem\u003eCe\u003c/em\u003e) of remifentanil according to the up-and-down method protocol. During the study period, vital signs and BIS values were recorded by Investigator 3 (H So), who was blinded to the remifentanil concentration.\u003c/p\u003e\u003ch3\u003eAnesthesia and intubation protocol\u003c/h3\u003e\u003cp\u003ePatients entered the operating room without premedication. Standard monitoring applied including pulse oximetry, electrocardiography, and bispectral index (BIS™, Medtronic, Minneapolis, MN, USA) were initiated. Automated noninvasive blood pressure (NIBP) was measured on the patient’s upper arm using an oscillometric method with a GE anesthesia monitoring system (GE Healthcare, Chicago, IL, USA). At the start of a 3 min preoxygenation period with 100% oxygen at flow rate of 6 L/min, remifentanil infusion was initiated at a target \u003cem\u003eCe\u003c/em\u003e predetermined by the study protocol using Minto model of target-controlled infusion (TCI). TCI was performed with the Agilia SP TIVA infusion pump (Fresenius Kabi, Fresenius Kabi AG, Bad Homburg, Hessen, Germany).\u003c/p\u003e\u003cp\u003eRemimazolam 6 mg/kg/h was infused continuously for anesthesia induction. After confirming loss of consciousness via the eyelash reflex, remimazolam was reduced to 2 mg/kg/h, If the BIS value decreased below 60, the rate was further reduced to 1 mg/kg/h, and the BIS was maintained between 40 and 60. Rocuronium 0.6 mg/kg was administered after loss of consciousness. Manual ventilation was initiated using one hand method until endotracheal intubation, maintaining a peak inspiratory pressure below 25 cmH\u003csub\u003e2\u003c/sub\u003eO and end-tidal CO\u003csub\u003e2\u003c/sub\u003e (EtCO\u003csub\u003e2\u003c/sub\u003e) was maintained as close to 35 mmHg as possible. Two min later, the \u003cem\u003eCe\u003c/em\u003e of remifentanil reached the target level, and endotracheal intubation was performed by a single experienced anesthesiologist with over 15 years of clinical experience (Investigator 1, J Lee), using a KoMAC videolaryngoscope (KoMAC Co., Ltd., Seoul, Republic of Korea). A size 4 blade was used for male patients and a size 3 blade for female patients. A cuffed endotracheal tube was used, with an internal diameter of 7.5 mm for male patients and 6.5 mm for female patients (Shiley™ endotracheal tube with TaperGuard™ cuff, Covidien, USA). The adult stylet that comes as a set with the UE videolaryngoscope (Zhejiang Lingyang Medical Apparatus Co., Ltd., China) was used to facilitate intubation.\u003c/p\u003e\u003cp\u003eMechanical ventilation was initiated as soon as possible after intubation. The inspired oxygen fraction was set to 0.4 with fresh gas flow of 2 L/min. Tidal volume was set at 7 ml/kg of predicted body weight, with a positive end-expiratory pressure (PEEP) of 5 cmH\u003csub\u003e2\u003c/sub\u003eO. Respiratory rate was adjusted to maintain an EtCO\u003csub\u003e2\u003c/sub\u003e of 35 mmHg.\u003c/p\u003e\u003ch2\u003eDetermination of remifentanil effect-site concentration\u003c/h2\u003e\u003cp\u003eMAP, HR, peripheral oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e), and BIS were recorded at the following time points: baseline (T0, prior to anesthetic induction), just before intubation (T1), 1 min after intubation (T2), and 5 min after intubation (T3).\u003c/p\u003e\u003cp\u003eThe \u003cem\u003eCe\u003c/em\u003e of remifentanil was determined using Dixon’s up-and-down sequential allocation method, with an initial effect-site concentration of 4.0 ng/mL administered to the first patient. If either the MAP or HR at T2 increased by more than 20% compared with the baseline value (T0), the response was considered positive (ineffective group), and the \u003cem\u003eCe\u003c/em\u003e of remifentanil for the next patient was increased by 0.5 ng/mL. Conversely, both MAP and HR at T2 increased by 20% or less compared with baseline, the response was considered negative (effective group), and the \u003cem\u003eCe\u003c/em\u003e for the next patient was decreased by 0.5 ng/mL. The selected starting dose and step size were based on previous endotracheal intubation studies using desflurane or propofol, which reported EC₅₀ values of 4.4 ± 0.7 \u003csup\u003e8\u003c/sup\u003e and 3.11 ± 0.38 ng/mL \u003csup\u003e15\u003c/sup\u003e, respectively. An anesthesiologist (Investigator 2, DH Chun), unblinded to the remifentanil \u003cem\u003eCe\u003c/em\u003e and uninvolved in outcome assessment provided routine intraoperative care, while vital signs and BIS values were recorded by Investigator 3 (H So), who was blinded to the remifentanil concentration.\u003c/p\u003e\u003cp\u003eThe primary outcome of this study was the \u003cem\u003eCe\u003c/em\u003e of remifentanil required to suppress cardiovascular responses to endotracheal intubation in 50% of patients (EC\u003csub\u003e50\u003c/sub\u003e) and the secondary outcome was the \u003cem\u003eCe\u003c/em\u003e required for 95% of patients (EC\u003csub\u003e95\u003c/sub\u003e). Both EC\u003csub\u003e50\u003c/sub\u003e and EC\u003csub\u003e95\u003c/sub\u003e values were estimated using isotonic regression based on the up-and-down response data.\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe total number of participants was determined based on Dixon’s up-and-down method \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e which requires at least six crossover points (i.e., reversals in patients response from effective to ineffective or vice versa) for statistical analysis \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Sample sizes are typically limited to 20–40 \u003csup\u003e18\u003c/sup\u003e. Given the unknown distribution of the response data, a conservative estimation of the sample size was applied. Previous studies using this method reported that approximately 30 to 35 participants were sufficient to determine the target \u003cem\u003eCe\u003c/em\u003e \u003csup\u003e19,20\u003c/sup\u003e; therefore, a total of 34 patients were enrolled in this study.\u003c/p\u003e\u003cp\u003eThe t-test was used to compare parametric data. Categorical variables were analyzed by the Chi‑square test or Fisher’s exact test. Post-hoc pairwise comparisons were adjusted with Bonferroni correction. An adjusted response probability was calculated using the pooled adjacent-violators algorithm (PAVA)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. EC\u003csub\u003e50\u003c/sub\u003e (83% confidence interval [CI]) and EC\u003csub\u003e95\u003c/sub\u003e (95% CI) of hemodynamic stability after intubation was determined by the isotonic regression method \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The 83% CI for EC₅₀ was used because it provides a statistically equivalent precision to the 95% CI for EC₉₅ in the up-and-down sequential design. Data were expressed as mean ± standard deviation (s.d.) or numbers (%). All statistical analyses were performed by use of R software, version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.R-project.org/\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). A P-value less than .05 was considered to be statistically significant.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the staff and colleagues in the anesthesiology and pain medicine department, otolaryngology-head and neck surgery department, and post-anesthesia care unit for their co-operation in data collection. The authors used ChatGPT to assist language refinement. Final wording and interpretation were determined solely by the authors. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.L. and I.K.Y. contributed equally to this work and are considered co-first authors.\u003c/p\u003e\n\u003cp\u003eJ.L. was responsible for the conception and design of the study, methodology, and drafting of the manuscript.\u003c/p\u003e\n\u003cp\u003eI.K.Y. performed the statistical analysis, contributed to software, and critically revised and supplemented the manuscript.\u003c/p\u003e\n\u003cp\u003eH.S. contributed to data acquisition.\u003c/p\u003e\n\u003cp\u003eH.Y. was responsible for data visualization.\u003c/p\u003e\n\u003cp\u003eD.H.C. contributed to data curation and provided resources.\u003c/p\u003e\n\u003cp\u003eJ.Y.K. supervised the entire study, administered the project, and provided overall guidance.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe full WHO-format trial protocol can be found in Supplementary Methods S1. The completed CONSORT 2010 checklist supporting the reporting of this clinical trial is provided in Supplementary File S2. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional Information\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchuttler, J. et al. Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part I. 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Advances in and Limitations of Up-and-down Methodology: A Pr\u0026eacute;cis of Clinical Use, Study Design, and Dose Estimation in Anesthesia Research. \u003cem\u003eAnesthesiology\u003c/em\u003e \u003cb\u003e107\u003c/b\u003e, 144\u0026ndash;152. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/01.anes.0000267514.42592.2a\u003c/span\u003e\u003cspan address=\"10.1097/01.anes.0000267514.42592.2a\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2007).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Remimazolam, Remifentanil, Endotracheal intubation, Effect-site concentration, Hemodynamic response","lastPublishedDoi":"10.21203/rs.3.rs-8083305/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8083305/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEndotracheal intubation often induces rapid increases in blood pressure and heart rate due to sympathetic stimulation. Remifentanil is commonly used to attenuate these responses, yet its optimal effect-site concentration (\u003cem\u003eCe\u003c/em\u003e) during remimazolam induction remains unclear. This prospective, double-blinded clinical trial aimed to determine the \u003cem\u003eCe\u003c/em\u003e of remifentanil required to inhibit hemodynamic response to intubation under remimazolam anesthesia. Thirty-four adult patients undergoing elective surgery were enrolled. All patients received remimazolam and target-controlled infusion of remifentanil, with the \u003cem\u003eCe\u003c/em\u003e determined using Dixon\u0026rsquo;s up-and-down sequential allocation method. A positive response was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;20% increase in mean arterial pressure (MAP) or heart rate (HR) within 1 minute after intubation compared to baseline. Based on the responses of 30 patients included in the final analysis, the EC₅₀ and EC₉₅ of remifentanil were estimated as 5.70 ng/mL (83% CI: 5.50\u0026ndash;6.00) and 6.40 ng/mL (95% CI: 6.00\u0026ndash;6.50), respectively, using isotonic regression and the pooled-adjacent violators algorithm. No patient experienced bradycardia or hypotension requiring treatment. These findings suggest that a remifentanil \u003cem\u003eCe\u003c/em\u003e of 6.40 ng/mL is effective in blunting the hemodynamic response to intubation in 95% of patients during remimazolam-based induction.\u003c/p\u003e","manuscriptTitle":"Effect-site concentration of remifentanil inhibiting hemodynamic response following endotracheal intubation during remimazolam induction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-12 07:31:35","doi":"10.21203/rs.3.rs-8083305/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"235229276578896964030802224490512699229","date":"2026-05-09T16:10:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-29T01:36:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222677257146653462037612681310630370603","date":"2026-03-18T10:03:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-06T12:59:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-03T16:00:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-19T17:43:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-17T03:35:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-11-17T03:32:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5c592fe6-37ee-4b74-adfb-c318ee09e032","owner":[],"postedDate":"March 12th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"235229276578896964030802224490512699229","date":"2026-05-09T16:10:33+00:00","index":102,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64099799,"name":"Health sciences/Cardiology"},{"id":64099800,"name":"Health sciences/Diseases"},{"id":64099801,"name":"Health sciences/Medical research"},{"id":64099802,"name":"Biological sciences/Physiology"}],"tags":[],"updatedAt":"2026-03-12T07:31:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-12 07:31:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8083305","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8083305","identity":"rs-8083305","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}