{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:49:58Z","timestamp":1760057398489,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background: Midazolam is widely used in clinical anesthesia, but its effects on the Bispectral Index (BIS) and propofol concentration at the effector site (CeP) are underexplored. This study investigates the pharmacodynamic interaction between midazolam and propofol in total intravenous anesthesia (TIVA) with target-controlled infusion (TCI), focusing on Schnider and Eleveld models. Methods: This prospective study included breast surgery patients receiving TIVA-TCI. BIS and CeP were assessed at loss of responsiveness (LoR), during maintenance (MA), and at return of responsiveness (RoR). Incidences of unwanted spontaneous responsiveness (USRE), burst suppression episodes (BSuppE), and postoperative delirium (POD) were recorded. Results: Midazolam premedication significantly reduced propofol doses and CeP at LoR and during MA, without affecting CeP at RoR. In the Schnider model, midazolam reduced total propofol dose, while in the Eleveld model, it lowered BIS at LoR. Unwanted anesthesia events occurred in 36.2% of patients, including USRE (10%), BSuppE (26.2%), and POD (1.2%). BSuppE rates were lower in the Schnider model and reduced in the midazolam group in the Eleveld model. Conclusions: Midazolam premedication influences CeP and BIS in TIVA-TCI, with model-specific variations, optimizing propofol management and improving patient outcomes.<\/jats:p>","DOI":"10.3390\/life15020219","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T05:36:32Z","timestamp":1738560992000},"page":"219","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluating Midazolam\u2019s Influence on Bispectral Index and Propofol Concentrations Using Schnider and Eleveld Models in Target-Controlled Infusion General Anesthesia: A Prospective Observational Study"],"prefix":"10.3390","volume":"15","author":[{"given":"Federico","family":"Linassi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35128 Padua, Italy"},{"name":"Department of Anesthesia and Intensive Care, Ca\u2019 Foncello Treviso Regional Hospital, 31100 Treviso, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Zanatta","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Intensive Care, Ca\u2019 Foncello Treviso Regional Hospital, 31100 Treviso, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-3556","authenticated-orcid":false,"given":"Matthias","family":"Kreuzer","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, School of Medicine and Health, TUM Universit\u00e4tsklinikum, Technical University of Munich, 80333 M\u00fcnchen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Ciavattini","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Intensive Care, Ca\u2019 Foncello Treviso Regional Hospital, 31100 Treviso, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Rizzetto","sequence":"additional","affiliation":[{"name":"Department of Breast Oncologic Surgery, Ca\u2019 Foncello Treviso Regional Hospital, 31100 Treviso, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5104-4124","authenticated-orcid":false,"given":"Michele","family":"Carron","sequence":"additional","affiliation":[{"name":"Section of Anesthesiology and Intensive Care, Department of Medicine\u2014DIMED, University of Padua, 35122 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S0736-4679(97)00022-X","article-title":"Midazolam: A review of therapeutic uses and toxicity","volume":"15","author":"Nordt","year":"1997","journal-title":"J. Emerg. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Linassi, F., Obert, D.P., Maran, E., Tellaroli, P., Kreuzer, M., Sanders, R.D., and Carron, M. (2021). Implicit Memory and Anesthesia: A Systematic Review and Meta-Analysis. Life, 11.","DOI":"10.3390\/life11080850"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"193","DOI":"10.4097\/kjae.1999.37.2.193","article-title":"The effect of co-administration of midazolam on induction and recovery using continuous propofol infusion","volume":"37","author":"Kim","year":"1999","journal-title":"Korean J. Anesthesiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1016\/j.clinph.2019.05.035","article-title":"Influence of midazolam premedication on intraoperative EEG signatures in elderly patients","volume":"130","author":"Windmann","year":"2019","journal-title":"Clin. Neurophysiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1007\/BF03011809","article-title":"Midazolam and awareness with recall during total intravenous anesthesia","volume":"43","author":"Miller","year":"1996","journal-title":"Can. J. Anaesth."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1093\/bjaed\/mkv074","article-title":"Principles of total intravenous anesthesia: Practical aspects of using total intravenous anesthesia","volume":"16","author":"Mulvey","year":"2016","journal-title":"BJA Educ."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Vandemoortele, O., Hannivoort, L.N., Vanhoorebeeck, F., Struys, M.M.R.F., and Vereecke, H.E.M. (2022). General Purpose Pharmacokinetic-Pharmacodynamic Models for Target-Controlled Infusion of anesthetic Drugs: A Narrative Review. J. Clin. Med., 11.","DOI":"10.3390\/jcm11092487"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/j.1365-2044.1998.53s101.x","article-title":"Influence of pre-anesthetic medication on target propofol concentration using a \u2019Diprifusor\u2019 TCI system during ambulatory surgery","volume":"53","author":"Struys","year":"1998","journal-title":"Anaesthesia"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Linassi, F., Zanatta, P., Spano, L., Burelli, P., Farnia, A., and Carron, M. (2023). Schnider and Eleveld Models for Propofol Target-Controlled Infusion Anesthesia: A Clinical Comparison. Life, 13.","DOI":"10.3390\/life13102065"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"111045","DOI":"10.1016\/j.jclinane.2022.111045","article-title":"Unwanted spontaneous responsiveness and burst suppression in patients undergoing entropy-guided total intravenous anesthesia with target-controlled infusion: An observational prospective trial","volume":"86","author":"Linassi","year":"2023","journal-title":"J. Clin. Anesth."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Linassi, F., Kreuzer, M., Maran, E., Farnia, A., Zanatta, P., Navalesi, P., and Carron, M. (2020). Age influences on Propofol estimated brain concentration and entropy during maintenance and at return of consciousness during total intravenous anesthesia with target-controlled infusion in unparalyzed patients: An observational prospective trial. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0244145"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Spielberger, C.D. State-Trait Anxiety Inventory for Adults (STAI-AD) [Database record]. APA PsycTests., 1983.","DOI":"10.1037\/t06496-000"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111113","DOI":"10.1016\/j.jclinane.2023.111113","article-title":"The association between midazolam premedication and postoperative delirium\u2014A retrospective cohort study","volume":"92","author":"Zarour","year":"2024","journal-title":"J. Clin. Anesth."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jclinane.2003.07.003","article-title":"Preoperative intravenous midazolam: Benefits beyond anxiolysis","volume":"16","author":"Bauer","year":"2004","journal-title":"J. Clin. Anesth."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1093\/bja\/aep143","article-title":"Pharmacokinetic models for propofol--defining and illuminating the devil in the detail","volume":"103","author":"Absalom","year":"2009","journal-title":"Br. J. Anaesth."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1111\/anae.12711","article-title":"Monitoring the brain: Processed electroencephalogram and peri-operative outcomes","volume":"69","author":"Escallier","year":"2014","journal-title":"Anaesthesia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1097\/00000542-199805000-00006","article-title":"The influence of method of administration and covariates on the pharmacokinetics of Propofol in adult volunteers","volume":"88","author":"Schnider","year":"1998","journal-title":"Anesthesiology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.bja.2018.01.018","article-title":"Pharmacokinetic-pharmacodynamic model for propofol for broad application in anesthesia and sedation","volume":"120","author":"Eleveld","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1097\/00000542-199701000-00005","article-title":"Pharmacokinetics and pharmacodynamics of Remifentanil II. Model Application","volume":"86","author":"Minto","year":"1997","journal-title":"Anesthesiology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1177\/147323000903700118","article-title":"The effects of midazolam on the bispectral index after fetal expulsion in caesarean section under general anaesthesia with sevoflurane","volume":"37","author":"Ok","year":"2009","journal-title":"J. Int. Med. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1093\/bja\/aei040","article-title":"Double-blind randomized controlled trial to determine extent of amnesia with midazolam given immediately before general anesthesia","volume":"94","author":"Bulach","year":"2005","journal-title":"Br. J. Anesth."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/BF03020731","article-title":"Midazolam premedication reduces propofol requirements for sedation during regional anesthesia","volume":"47","author":"Nakagawa","year":"2000","journal-title":"Can. J. Anaesth."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1177\/0310057X0002800507","article-title":"Timing of midazolam and propofol administration for co-induction of anesthesia","volume":"28","author":"Ong","year":"2000","journal-title":"Anaesth. Intensive Care"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1097\/00000542-200409000-00033","article-title":"Coadministration of propofol and midazolam decreases bispectral index value as a result of synergic muscle relaxant action on the motor system","volume":"101","author":"Fodale","year":"2004","journal-title":"Anesthesiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.cgh.2007.10.005","article-title":"Bispectral index monitoring of conscious sedation with the combination of meperidine and midazolam during endoscopy","volume":"6","author":"Qadeer","year":"2008","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1097\/00000542-200401000-00029","article-title":"Low bispectral index values in awake volunteers receiving a combination of propofol and midazolam","volume":"100","author":"Vuyk","year":"2004","journal-title":"Anesthesiology"},{"key":"ref_27","unstructured":"Medical Advisory Secretariat (2004). Bispectral index monitor: An evidence-based analysis. Ont. Health Technol. Assess. Ser., 4, 1\u201370."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1001\/jamasurg.2023.6479","article-title":"Preoperative Midazolam and Patient-Centered Outcomes of Older Patients: The I-PROMOTE Randomized Clinical Trial","volume":"159","author":"Kowark","year":"2024","journal-title":"JAMA Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e059915","DOI":"10.1136\/bmjopen-2021-059915","article-title":"Effect of intramuscular midazolam premedication on patient satisfaction in women undergoing general anaesthesia: A randomised control trial","volume":"12","author":"Song","year":"2022","journal-title":"BMJ Open"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"302","DOI":"10.4103\/0259-1162.143117","article-title":"Efficacy of intravenous midazolam versus clonidine as premedicants on bispectral index guided propofol induction of anesthesia in laparoscopic cholecystectomy: A randomized control trial","volume":"8","author":"Agrawal","year":"2014","journal-title":"Anesth. Essays Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"619","DOI":"10.4097\/kjae.2009.56.6.619","article-title":"The effects of midazolam and remifentanil on induction of anesthesia and hemodynamics during tracheal intubation under target-controlled infusion of propofol","volume":"56","author":"Son","year":"2009","journal-title":"Korean J. Anesthesiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13741-022-00253-4","article-title":"Effect of sedative premedication with oral midazolam on postanesthesia care unit delirium in older adults: A secondary analysis following an uncontrolled before-after design","volume":"11","author":"Stuff","year":"2022","journal-title":"Perioper. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1097\/ALN.0000000000005276","article-title":"The effect of intraoperative midazolam on postoperative delirium in older surgical patients: A prospective, multicentre cohort study","volume":"142","author":"Li","year":"2024","journal-title":"Anesthesiology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Peter, J.U., Dieudonn\u00e9, P., and Zolk, O. (2024). Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example. Pharmaceuticals, 17.","DOI":"10.3390\/ph17040473"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1213\/00000539-198804000-00016","article-title":"Sedative doses of midazolam depress hypoxic ventilatory responses in humans","volume":"67","author":"Alexander","year":"1988","journal-title":"Anesth. Analg."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gonzalez Castro, L.N., Mehta, J.H., Brayanov, J.B., and Mullen, G.J. (2017). Quantification of respiratory depression during pre-operative administration of midazolam using a non-invasive respiratory volume monitor. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172750"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1136\/rapm-2021-102989","article-title":"Association of perioperative midazolam use and complications: A population-based analysis","volume":"47","author":"Athanassoglou","year":"2022","journal-title":"Reg. Anesth. Pain. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1097\/00000542-198107000-00019","article-title":"The effective dose of midazolam","volume":"55","author":"Reves","year":"1981","journal-title":"Anesthesiology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1111\/j.1365-2044.1996.tb12558.x","article-title":"Induction of anaesthesia with midazolam and a target-controlled propofol infusion","volume":"51","author":"Tzabar","year":"1996","journal-title":"Anaesthesia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1053\/cp.1999.v66.100038001","article-title":"Propofol decreases the clearance of midazolam by inhibiting CYP3A4: An in vivo and in vitro study","volume":"66","author":"Hamaoka","year":"1999","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1093\/bja\/67.5.539","article-title":"Propofol and midazolam act synergistically in combination","volume":"67","author":"Short","year":"1991","journal-title":"Br. J. Anaesth."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1093\/bja\/72.1.62","article-title":"Pharmacokinetic interactions between midazolam and propofol: An infusion study","volume":"72","author":"Teh","year":"1994","journal-title":"Br. J. Anaesth."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1213\/ane.0b013e31819e4058","article-title":"Mixed-effects modeling of the influence of midazolam on propofol pharmacokinetics","volume":"108","author":"Vuyk","year":"2009","journal-title":"Anesth. Analg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/S1734-1140(12)70874-5","article-title":"Potential pitfalls of propofol target controlled infusion delivery related to its pharmacokinetics and pharmacodynamics","volume":"64","author":"Bienert","year":"2012","journal-title":"Pharmacol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.bja.2020.10.027","article-title":"Prospective clinical validation of the Eleveld propofol pharmacokinetic-pharmacodynamic model in general anesthesia","volume":"126","author":"Vellinga","year":"2021","journal-title":"Br. J. Anaesth."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/cpt.2162","article-title":"The Drug Titration Paradox: Correlation of More Drug With Less Effect in Clinical Data","volume":"110","author":"Schnider","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e172","DOI":"10.1016\/j.bja.2021.02.004","article-title":"Clinical validation of pharmacokinetic and pharmacodynamic models for propofol infusion. Comment on Br J Anaesth 2021, 126, 386\u2013394","volume":"126","author":"Schnider","year":"2021","journal-title":"Br. J. Anaesth."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.bja.2024.06.041","article-title":"Predictive pharmacodynamic performance of the Eleveld pharmacokinetic-pharmacodynamic model for propofol: Comparison of predicted and measured bispectral index","volume":"133","author":"Coetzee","year":"2024","journal-title":"Br. J. Anaesth."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s10877-023-01083-5","article-title":"Evaluating inter-individual variability captured by the Eleveld pharmacokinetics model","volume":"38","author":"Hosseinirad","year":"2024","journal-title":"J. Clin. Monit. Comput."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1007\/s40520-023-02460-5","article-title":"Correlation between burst suppression and postoperative delirium in elderly patients: A prospective study","volume":"35","author":"Ren","year":"2023","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/nep.13742","article-title":"Evidence-based medicine-When observational studies are better than randomized controlled trials","volume":"25","author":"Bosdriesz","year":"2020","journal-title":"Nephrology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1097\/00000542-200406000-00006","article-title":"Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy","volume":"100","author":"Bouillon","year":"2004","journal-title":"Anesthesiology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/0952-8180(92)90068-C","article-title":"Midazolam in combination with propofol for sedation during local anesthesia","volume":"4","author":"Taylor","year":"1992","journal-title":"J. Clin. Anesth."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1213\/00000539-199912000-00003","article-title":"Preoperative anxiety and intraoperative anesthetic requirements","volume":"89","author":"Maranets","year":"1999","journal-title":"Anesth. Analg."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1093\/bja\/aer305","article-title":"Preoperative anxiety and pain sensitivity are independent predictors of propofol and sevoflurane requirements in general anaesthesia","volume":"108","author":"Kil","year":"2012","journal-title":"Br. J. Anaesth."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.1016\/j.bja.2022.05.001","article-title":"Anesthetic depth and delirium after major surgery. Comment on Br J Anaesth 2022, 127, 704\u2013712","volume":"129","author":"Linassi","year":"2022","journal-title":"Br. J. Anaesth."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/2\/219\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:25:11Z","timestamp":1760027111000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/2\/219"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,31]]},"references-count":56,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["life15020219"],"URL":"https:\/\/doi.org\/10.3390\/life15020219","relation":{},"ISSN":["2075-1729"],"issn-type":[{"type":"electronic","value":"2075-1729"}],"subject":[],"published":{"date-parts":[[2025,1,31]]}}}