Analysis of factors related to prolonged midazolam action: A multicenter, case-control study

Analysis of factors related to prolonged midazolam action: A multicenter, case-control study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Analysis of factors related to prolonged midazolam action: A multicenter, case-control study Takaaki Yano, Shinichi Watanabe, Yuto Mori, Noboru Yamashita, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4304736/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Benzodiazepine midazolam is characterized by a rapid onset of action and a short half-life and is used for deep sedation in critically ill patients; however, hepatic and renal dysfunction, obesity, and prolonged use of midazolam are reported to prolong midazolam action. A few studies have investigated the association between midazolam use and hypoalbuminemia in critically ill patients. Therefore, this study aimed to investigate the effects of patient background on the prolonged action of midazolam by focusing on previously reported factors and albumin levels. Methods A total of 196 patients aged ≥ 18 years who were admitted to the University Hospital and Matsuyama Shimin Hospital intensive care unit between January 2015 and May 2022 and were administered midazolam continuously for ≥ 24 h were enrolled. Patient data, such as background, laboratory test values, and status of sedative drug use, including midazolam, were obtained from medical records. The primary outcome was the time required for improvement of the Richmond Agitation–Sedation Scale score after midazolam administration. Factors related to the prolongation of midazolam action were analyzed using the Mann–Whitney U test and logistic regression analysis. Statistical analyses were performed using EZR (version 1.61). Statistical significance was set at P < 0.05. Result In total, 68 patients were included in this study. The time required for Richmond Agitation–Sedation Scale score improvement after discontinuation of midazolam was 48 h in 16 patients (23.5%).The factors related to prolonged midazolam action were age (P < 0.05), renal function (P < 0.01), risk factors reported in previous studies, and albumin levels (P < 0.01). The multivariate logistic regression analysis revealed that only albumin influenced the prolongation of midazolam activity (odds ratio, 0.61; 95% confidence interval, 0.44–0.85; P < 0.05). Conclusions Renal function, body mass index, age, and duration of midazolam administration are established factors that enhance and prolong the action of midazolam. In this study, the serum albumin level was identified as a new factor of relevance. Therefore, sedation in patients with low albumin levels should be carefully performed to avoid the prolongation and potentiation of midazolam action. Midazolam Albumin Richmond Agitation–Sedation Scale Sedation Figures Figure 1 Background Appropriate sedation and assessment of ventilator management in intensive care have many implications, including reduction of ventilator-induced discomfort, stabilization of hemodynamic status due to reduced oxygen consumption and basal metabolic rate, prevention of delirium, shortening of treatment duration, and reduction in the frequency of post-traumatic stress disorder after intensive care unit (ICU) discharge [ 1 – 4 ]. The most commonly used sedatives are propofol, dexmedetomidine, and midazolam, which are used differently, depending on their characteristics. Benzodiazepine midazolam is frequently used in clinical practice and is characterized by a rapid onset of action of 2–5 min and short half-life of approximately 3 h [ 5 , 6 ]. However, midazolam often causes prolonged sedation, leading to prolonged ventilator management, time to weaning, and ICU hospital stay [ 4 , 7 , 8 ]. ICU admission causes motor, mental, and cognitive dysfunction, leading to increased mortality and reduced quality of life after ICU discharge [ 9 , 10 ]. Delayed rehabilitation and post-traumatic stress disorder have also been identified as risk factors for post-intensive care syndrome (PICS) owing to extended ventilator withdrawal periods and ICU hospital stays [ 11 ]. Prolonged ICU hospital stay due to sedation is a crucial issue. Previous studies have identified hepatic dysfunction, renal dysfunction, obesity, age, and prolonged use of midazolam as factors associated with prolonged action [ 5 , 12 – 15 ], and midazolam should be used with caution in such patients. However, even in patients who were not associated with factors that influenced prolonged midazolam action in previous reports, there were often cases of prolonged midazolam action and delayed weaning from the ventilator. In this study, we focused on albumin as a cause of prolonged midazolam action. Albumin is the main binding protein, and the protein-binding rate of midazolam is approximately 97% [ 16 ]. Therefore, we speculated that when the blood albumin level decreases, the unbound midazolam fraction increases, leading to altered midazolam pharmacokinetics, which may prolong the action of midazolam. Intensive care patients often have reduced albumin due to factors such as increased protein catabolism, leakage of albumin due to increased vascular permeability, and reduced production of albumin due to low nutritional status [ 17 , 18 ]. Although there have been reports on the association between midazolam action and albumin in end-of-life palliative care patients [ 19 ], few studies have assessed the relationship between midazolam action and albumin in intensive care patients using the Richmond Agitation–Sedation Scale (RASS). Avoiding prolonged midazolam action may contribute to improved patient outcomes, including reduced length of ICU stay and hospitalization, reduced healthcare costs, and prevention of PICS. This study aimed to investigate factors that influence the sedative effects of midazolam by focusing on the factors reported in previous studies and albumin levels. Methods Patients This was a case-control study. A total of 196 patients aged ≥ 18 years who were admitted to the Ehime University Hospital and Matsuyama Shimin Hospital ICU between January 2015 and May 2022 and were administered midazolam continuously for ≥ 24 h were enrolled. The exclusion criteria were as follows: 1) patients who were difficult to assess for RASS evaluation after midazolam administration owing to death or transfer to other hospital, 2) patients who did not achieve deep sedation (RASS score of -4 to -5) with midazolam, 3) patients with non-measurable BMI, and 4) patients with acute severe neurological impairment Data collection Age, sex, ICU admission diagnosis, body mass index (BMI), serum albumin level, renal function, hepatic function (Common Terminology Criteria for Adverse Events; aspartate aminotransferase and alanine aminotransferase ≥ Grade1), extracorporeal circulation, ICU hospital stay, midazolam infusion dose and period, and presence of sedative analgesics (fentanyl, propofol, dexmedetomidine, and rocuronium) during and after the administration of midazolam were obtained from the medical records. Outcome The patients’ state of consciousness and sedation were assessed using RASS [ 20 ], with a RASS score ≤ 4 defined as deeply sedated. The evaluation results of the RASS are listed in Table 1 . Table 1 has been modified from previous studies [ 21 ]. The time to improvement from deep sedation to light sedation (RASS ≤-4 to RASS ≥-2) was investigated. The analysis was conducted in two groups: those who showed improvement within 48 h. Table 1 Assessment of the level of consciousness in RASS Score Condition Description 4 Combative Overtly combative or violent; immediate danger to staff 3 Very agitated Pulls on or removes tube(s) or catheter(s) or has aggressive behavior toward staff 2 Agitated Frequent nonpurposeful movement or patient–ventilator dyssynchrony 1 Restless Anxious or apprehensive but movements not aggressive or vigorous 0 Alert and calm -1 Drowsy Not fully alert, but has sustained (> 10 s) awakening, with eye contact, to voice -2 Light sedation Briefly (< 10 s) awakens with eye contact to voice -3 Moderate sedation Any movement (but no eye contact) to voice -4 Deep sedation No response to voice but some movement to physical stimulation -5 Unrousable No response to voice or physical stimulation Evaluate time required for improvement in the RASS ≤-4 to RASS ≥-2 after midazolam administration. Abbreviations : RASS, Richmond Agitation–Sedation Scale; Analysis For between-group comparisons, categorical variables, including sex, extracorporeal circulation, and use of sedative analgesics during and after midazolam administration, were analyzed using the Fisher’s exact test. Continuous variables, including age, BMI, albumin level, ICU hospital stay, renal function, and midazolam infusion dose and period, were analyzed using the Mann–Whitney U test. The analysis was then conducted using a logistic regression model with the risk factors for prolonged action of midazolam reported in previous studies and albumin levels as explanatory variables. The objective variable set was the group with RASS score improvement within 48 h to improve. Furthermore, to confirm statistical robustness, a sensitivity analysis was performed using propensity score matching after adjusting for factors used in the logistic regression analysis, except for albumin levels. Statistical analyses were performed using EZR (version 1.61), and statistical significance was set at P < 0.05. Result The eligible patients included in the study are shown in Fig. 1. This study excluded 54 patients who were difficult to assess for RASS evaluation after midazolam administration, 56 patients who did not achieve deep sedation with midazolam (RASS ≥-3), 9 patients with non-measurable BMI, and 9 patients with severe neurological impairment; thus, 68 patients were eligible for inclusion. The patient characteristics and results of the univariate analysis are shown in Table 2 . After midazolam treatment, the RASS score improved within 48 h for improvement. Age, albumin level, ICU hospital stay, renal function, and rocuronium combination were factors associated with prolonged midazolam administration. Respiratory diseases were the most common diagnoses at ICU admission, followed by cardiovascular diseases. Hepatic function was not examined, because only two patients had hepatic impairment. Table 2 Comparison of the baseline characteristics of patients in terms of RASS improvement time of < 48 h vs. ≥ 48 h variables Overall RASS Improvement Time P-value n = 68 < 48 h (= 52) ≥ 48 h (= 16) Sex (Male), no. (%) 46 (67.6) 38 (73.0) 8 (50.0) 0.126 Age, Median (IQR) 66.0 (55.8–72.3) 63.5 (54.8–70.3) 72.0 (66.8–77.0) 0.02 BMI, Median (IQR) 24.6 (21.7–26.3) 23.9 (21.7–26.1) 25.9 (22.6–28.5) 0.154 Albumin (g/L), Median (IQR) 25.0 (22.0–27.0) 25.0 (23.8–28.0) 22.0 (19.0–23.0) 0.0002 ICU hospital stay (day), Median (IQR) 16.0 (10.3–24.8) 13.1 (8.5–22.2) 27.0 (21.8–54.6) 0.0005 GFR (mL/min/1.73 m 2 ), Median (IQR) 80.6 (46.3–93.9) 81.8 (59.0–96.0) 43.8 (15.1–72.3) 0.0059 Extracorporeal circulation, no. (%) 18 (26.4) 11 (21.1) 7 (43.8) 0.105 Midazolam infusion dose (mg/h), Median (IQR) 7.9 (5.7–9.4) 7.9 (5.7–9.1) 9.0 (6.1–10.6) 0.281 Midazolam infusion period (h), Median (IQR) 102.0 (64.5-165.3) 101.5 (66.8-157.8) 107.0 (47.6-254.3) 0.919 Combination therapy while administering midazolam, no. (%) Dexmedetomidine 28 (41.2) 25 (48.1) 3 (18.8) 0.0454 Propofol 55 (80.1) 45 (86.5) 10 (62.5) 0.063 Rocuronium 25 (36.8) 15 (28.9) 10 (62.5) 0.0197 Fentanyl 58 (85.3) 45 (86.5) 13 (81.3) 0.689 Combination therapy after midazolam administration, no. (%) Dexmedetomidine 47 (69.1) 39 (75.0) 9 (56.3) 0.21 Propofol 39 (57.4) 30 (57.7) 9 (56.3) 1 Rocuronium 0 0 0 0 Fentanyl 51 (75.0) 39 (75.0) 12 (75.0) 1 ICU admission diagnosis, no. (%) Respiratory disease 46 (67.6) 34 (65.4) 12 (75.0) Cardiovascular disease 10 (14.7) 7 (13.5) 3 (18/8) Gastrointestinal disease 4 (5.9) 4 (7.7) 0 Trauma 4 (5.9) 4 (7.7) 0 Epilepsy 1 (1.5) 1 (1.9) 0 Tetanus 1 (1.5) 0 1(6.3) Overdose 1 (1.5) 1(1.9) 0 Hypoglycemic coma 1 (1.5) 1(1.9) 0 Abbreviations : BMI, body mass index; ICU, intensive care unit; IQR, interquartile range; RASS, Richmond Agitation–Sedation Scale; GFR, glomerular filtration rate Analyses were performed using logistic regression models, with patient backgrounds adjusted for renal function, BMI, midazolam administration period, age, sex, albumin level, and ICU hospital stay, as reported in previous studies. The results showed significant effects of the albumin level on the prolonged action of midazolam (odds ratio, 0.61; 95% confidence interval, 0.44-085; P < 0.05) (Table 3 ). Table 3 Multivariate logistic regression analysis Factor Adjusted OR (95% CI) P-value Intercept 11.4 0.633 Age 1.08 (0.98–1.19) 0.115 Sex (Male) 0.39 (0.05–2.95) 0.361 BMI 1.17 (0.92–1.48) 0.208 Albumin (g/L) 0.61 (0.44–0.85) 0.003 GFR (mL/min/1.73 m 2 ) 0.97 (0.94–1.01) 0.173 Midazolam infusion period (h) 1.00 (0.99–1.01) 0.617 ICU hospital stay (day) 1.03 (0.98–1.09) 0.259 Abbreviations : BMI, body mass index; ICU, intensive care unit; OR, odds ratio; CI, confidence interval; GFR, glomerular filtration rate Furthermore, the sensitivity analysis showed that the albumin level was associated with the prolonged action of midazolam, similar to the results obtained in the logistic regression analysis (Table 4 ). Table 4 Comparison of RASS improvement times in terms of albumin in the propensity-matched analysis Factor RASS Improvement Time P-value < 48 h (N = 11) ≥48 h (N = 11) Albumin (g/L) 25.0 (23.5–26.5) 22.0 (17.0-22.5) 0.0108 Abbreviations : RASS, Richmond Agitation–Sedation Scale Discussion The present study investigated the effects of patient background on the prolonged action of midazolam by focusing on previously reported factors and albumin levels. The RASS score required > 48 h to improve in approximately 24% of patients after midazolam administration, suggesting that the prolonged action of midazolam was influenced by the albumin level, which was the focus of the present study, in addition to the factors mentioned in previous studies [ 5 , 12 – 15 ]. Moreover, the results of the multivariate analysis performed using a logistic regression model adjusted for factors reported in previous studies and albumin levels showed that a significant reduction in albumin levels was associated with prolonged action of midazolam. Midazolam binds to benzodiazepine receptors and exerts sedative and anticonvulsant effects by enhancing the binding of gamma-aminobutyric acid to gamma-aminobutyric acid receptors [ 5 ]. Metabolized via cytochrome P450, the metabolite α-hydroxymidazolam has approximately half the action of the parent compound; metabolites are eliminated by the kidneys [ 22 ]. Therefore, in hepatic and renal failure, midazolam and its active metabolites have been reported to accumulate in the body, prolonging the action of midazolam [ 12 , 13 ]. This study also suggests that older patients and those with renal failure are likely to experience prolonged midazolam action; thus, caution should be exercised during midazolam administration as many patients have reduced hepatic and renal function. Critically ill patients with respiratory failure due to various conditions are often managed with deep sedation for prone positioning therapy and ventilator entrainment [ 23 ]. Therefore, the dose and duration of sedation may be prolonged, leading to the prolonged action of midazolam [ 24 , 25 ]. The present study suggests that the sedative effects of dexmedetomidine, propofol, and rocuronium combined with other sedatives may influence the action of midazolam. Although dexmedetomidine has been reported to reduce ventilator duration and maintain mild-to-moderate sedation compared with midazolam [ 4 ], there are no reports of prolonged effects of its combination with midazolam, and the high rate of use in the group without prolonged midazolam effects had little effect on the results of the study. Propofol and midazolam are commonly used to maintain deep sedation; however, their combination has been reported to potentiate the effects of midazolam [ 26 ]. Moreover, similar to dexmedetomidine, the use of midazolam was increased in the group without prolonged midazolam action, which had little effect on the results of the present study. Although the muscle relaxant rocuronium is used in combination with midazolam in ventilator management with deep sedation in some situations [ 27 ], it is not used after midazolam discontinuation in groups with prolonged midazolam action, and the duration of action of rocuronium is short (approximately 60 min) [ 28 ]; therefore, it had little effect on the results of the study. Midazolam is characterized by good tissue translocation as it is converted in vivo to a lipid-soluble drug, passes through the blood–brain barrier, and has a rapid onset of action [ 29 ]. However, the high volume of distribution may cause prolonged action of midazolam in patients with obesity because it accumulates in the adipose tissue and is redistributed into the blood over time [ 14 ]. Furthermore, if albumin levels decrease, midazolam with a high protein-binding rate is expected to have an increased volume of distribution and tissue translocation owing to an increase in non-protein-bound midazolam. Thus, albumin is considered to contribute to the prolonged action of midazolam owing to the redistribution of midazolam in the blood over time. The limitations of the present study include the small number of patients and the factors reported in previous studies that influenced the prolonged action of midazolam, which were incorporated into the multivariate analysis, resulting in overfitting and possibly an inaccurate analysis. In addition, disease severity could not be assessed in critically ill patients; therefore, various biases related to disease severity may have influenced the results of the analysis. Conclusions The results of the present study suggest that reduced albumin levels prolong the action of midazolam in critically ill patients. Moreover, the results of this study underscore the need for careful administration of midazolam, considering albumin levels, age, hepatic and renal dysfunction, obesity, and long-term use. In critically ill patients, albumin levels often decrease, and midazolam must be used carefully, mindful of the influence of albumin on its pharmacological effects. Avoiding prolonged midazolam action may contribute to improved patient outcomes owing to reduced ICU hospital stay, decreased hospitalization, reduced healthcare costs, and prevention of PICS. Furthermore, in order to improve the validity of the results of this study, it is necessary to define the disease severity of the patients and conduct further studies in collaboration with many facilities. Abbreviations ICU Intensive care unit RASS Richmond Agitation–Sedation Scale BMI Body mass index PICS Post-intensive care syndrome Declarations Acknowledgements Not applicable. Author contributions TY planned the study, collected data, conducted statistical analysis, and wrote the manuscript. SW was involved in research guidance and writing of the manuscript. YM and YS performed data collection. NY conducted statistical analysis. SO, NH, TO, and MT provided research guidance and advice. All authors read and approved the final version of the manuscript. Funding Not applicable. Data availability All relevant data were included in the published article. Ethics approval and consent to participate This study was conducted in accordance with the Ethical Guidelines for Life Sciences and Medical Research Involving Human Subjects and was approved by the Clinical Research Ethics Review Committee of Ehime University Hospital (protocol number: 2302006). As this was a retrospective clinical study and obtaining individual informed consent was practically difficult, informed consent was not obtained from research subjects; however, information on the conduct of the study, including the purpose of the study, was disclosed to ensure that research subjects or their surrogates and others have the opportunity to refuse participation. Information was disclosed by posting documents approved by the Ethics Review Committee. 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Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998;114:541–8. Ohmori J, Maeda S, Higuchi H, Ishii M, Arai Y, Tomoyasu Y, et al. Propofol increases the rate of albumin-unbound free midazolam in serum albumin solution. J Anesth. 2011;25:618–20. Chanques G, Constantin JM, Devlin JW, Ely EW, Fraser GL, Gélinas C, et al. Analgesia and sedation in patients with ARDS. Intensive Care Med. 2020;46:2342–56. Magorian T, Flannery KB, Miller RD. Comparison of rocuronium, succinylcholine, and vecuronium for rapid-sequence induction of anesthesia in adult patients. Anesthesiology. 1993;79:913–8. Kanto JH. Midazolam: the first water-soluble benzodiazepine. Pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia. Pharmacotherapy. 1985;5:138–55. Additional Declarations No competing interests reported. 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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-4304736","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":297182178,"identity":"bf055735-2641-468f-bd50-ec3d5a790f03","order_by":0,"name":"Takaaki Yano","email":"","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takaaki","middleName":"","lastName":"Yano","suffix":""},{"id":297182179,"identity":"2010f83d-45b7-4b89-aa32-71bc70995ec9","order_by":1,"name":"Shinichi Watanabe","email":"data:image/png;base64,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","orcid":"","institution":"Matsuyama University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Shinichi","middleName":"","lastName":"Watanabe","suffix":""},{"id":297182180,"identity":"6b50e9e8-a5a9-4563-a62c-66c6100789d2","order_by":2,"name":"Yuto Mori","email":"","orcid":"","institution":"Matsuyama University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuto","middleName":"","lastName":"Mori","suffix":""},{"id":297182181,"identity":"7419b804-363c-43c7-8f90-27223755d25f","order_by":3,"name":"Noboru Yamashita","email":"","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Noboru","middleName":"","lastName":"Yamashita","suffix":""},{"id":297182182,"identity":"9e64116f-7051-410c-b0ef-caffa7319fc7","order_by":4,"name":"Yuya Sakamoto","email":"","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuya","middleName":"","lastName":"Sakamoto","suffix":""},{"id":297182183,"identity":"e1657ca9-70c0-4c37-9dd3-169b02d2bc42","order_by":5,"name":"Shinji Oda","email":"","orcid":"","institution":"Matsuyama Shimin Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shinji","middleName":"","lastName":"Oda","suffix":""},{"id":297182185,"identity":"b70f8e17-f5e8-4f72-a1d5-1843ed199c30","order_by":6,"name":"Noriaki Hidaka","email":"","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Noriaki","middleName":"","lastName":"Hidaka","suffix":""},{"id":297182187,"identity":"7334ecca-6396-4b31-ba85-05372bd7ce93","order_by":7,"name":"Takashi Otsuka","email":"","orcid":"","institution":"Matsuyama Shimin Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Otsuka","suffix":""},{"id":297182189,"identity":"2c683f2c-01b1-4a61-85b2-b225a497a772","order_by":8,"name":"Mamoru Tanaka","email":"","orcid":"","institution":"Ehime University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mamoru","middleName":"","lastName":"Tanaka","suffix":""}],"badges":[],"createdAt":"2024-04-22 09:30:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4304736/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4304736/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56099566,"identity":"289716d8-0f77-4824-b100-0b270ceda800","added_by":"auto","created_at":"2024-05-08 14:26:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":75875,"visible":true,"origin":"","legend":"\u003cp\u003eBMI, body mass index; RASS, Richmond Agitation–Sedation Scale\u003c/p\u003e","description":"","filename":"Slide1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4304736/v1/6379d5863de95ae613f3d7d6.jpg"},{"id":66680103,"identity":"43bdebcd-2014-4e84-bc64-42feffb3270f","added_by":"auto","created_at":"2024-10-15 12:01:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":605152,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4304736/v1/715fdbab-c4bc-4fb7-b41b-c560a6eb1499.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Analysis of factors related to prolonged midazolam action: A multicenter, case-control study","fulltext":[{"header":"Background","content":"\u003cp\u003eAppropriate sedation and assessment of ventilator management in intensive care have many implications, including reduction of ventilator-induced discomfort, stabilization of hemodynamic status due to reduced oxygen consumption and basal metabolic rate, prevention of delirium, shortening of treatment duration, and reduction in the frequency of post-traumatic stress disorder after intensive care unit (ICU) discharge [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe most commonly used sedatives are propofol, dexmedetomidine, and midazolam, which are used differently, depending on their characteristics. Benzodiazepine midazolam is frequently used in clinical practice and is characterized by a rapid onset of action of 2\u0026ndash;5 min and short half-life of approximately 3 h [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, midazolam often causes prolonged sedation, leading to prolonged ventilator management, time to weaning, and ICU hospital stay [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eICU admission causes motor, mental, and cognitive dysfunction, leading to increased mortality and reduced quality of life after ICU discharge [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Delayed rehabilitation and post-traumatic stress disorder have also been identified as risk factors for post-intensive care syndrome (PICS) owing to extended ventilator withdrawal periods and ICU hospital stays [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Prolonged ICU hospital stay due to sedation is a crucial issue. Previous studies have identified hepatic dysfunction, renal dysfunction, obesity, age, and prolonged use of midazolam as factors associated with prolonged action [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and midazolam should be used with caution in such patients.\u003c/p\u003e \u003cp\u003eHowever, even in patients who were not associated with factors that influenced prolonged midazolam action in previous reports, there were often cases of prolonged midazolam action and delayed weaning from the ventilator. In this study, we focused on albumin as a cause of prolonged midazolam action. Albumin is the main binding protein, and the protein-binding rate of midazolam is approximately 97% [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, we speculated that when the blood albumin level decreases, the unbound midazolam fraction increases, leading to altered midazolam pharmacokinetics, which may prolong the action of midazolam. Intensive care patients often have reduced albumin due to factors such as increased protein catabolism, leakage of albumin due to increased vascular permeability, and reduced production of albumin due to low nutritional status [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Although there have been reports on the association between midazolam action and albumin in end-of-life palliative care patients [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], few studies have assessed the relationship between midazolam action and albumin in intensive care patients using the Richmond Agitation\u0026ndash;Sedation Scale (RASS).\u003c/p\u003e \u003cp\u003eAvoiding prolonged midazolam action may contribute to improved patient outcomes, including reduced length of ICU stay and hospitalization, reduced healthcare costs, and prevention of PICS. This study aimed to investigate factors that influence the sedative effects of midazolam by focusing on the factors reported in previous studies and albumin levels.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis was a case-control study. A total of 196 patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years who were admitted to the Ehime University Hospital and Matsuyama Shimin Hospital ICU between January 2015 and May 2022 and were administered midazolam continuously for \u0026ge;\u0026thinsp;24 h were enrolled. The exclusion criteria were as follows: 1) patients who were difficult to assess for RASS evaluation after midazolam administration owing to death or transfer to other hospital, 2) patients who did not achieve deep sedation (RASS score of -4 to -5) with midazolam, 3) patients with non-measurable BMI, and 4) patients with acute severe neurological impairment\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eAge, sex, ICU admission diagnosis, body mass index (BMI), serum albumin level, renal function, hepatic function (Common Terminology Criteria for Adverse Events; aspartate aminotransferase and alanine aminotransferase\u0026thinsp;\u0026ge;\u0026thinsp;Grade1), extracorporeal circulation, ICU hospital stay, midazolam infusion dose and period, and presence of sedative analgesics (fentanyl, propofol, dexmedetomidine, and rocuronium) during and after the administration of midazolam were obtained from the medical records.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOutcome\u003c/h2\u003e \u003cp\u003eThe patients\u0026rsquo; state of consciousness and sedation were assessed using RASS [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], with a RASS score\u0026thinsp;\u0026le;\u0026thinsp;4 defined as deeply sedated. The evaluation results of the RASS are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e has been modified from previous studies [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The time to improvement from deep sedation to light sedation (RASS \u0026le;-4 to RASS \u0026ge;-2) was investigated. The analysis was conducted in two groups: those who showed improvement within \u0026lt;\u0026thinsp;48 h and those who showed improvement within \u0026gt;\u0026thinsp;48 h.\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\u003eAssessment of the level of consciousness in RASS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScore\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCondition\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDescription\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOvertly combative or violent; immediate danger to staff\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVery agitated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulls on or removes tube(s) or catheter(s) or has aggressive behavior toward staff\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAgitated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrequent nonpurposeful movement or patient\u0026ndash;ventilator dyssynchrony\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRestless\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnxious or apprehensive but movements not aggressive or vigorous\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlert and calm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrowsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNot fully alert, but has sustained (\u0026gt;\u0026thinsp;10 s) awakening, with eye contact, to voice\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLight sedation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBriefly (\u0026lt;\u0026thinsp;10 s) awakens with eye contact to voice\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerate sedation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAny movement (but no eye contact) to voice\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDeep sedation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo response to voice but some movement to physical stimulation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnrousable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo response to voice or physical stimulation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eEvaluate time required for improvement in the RASS \u0026le;-4 to RASS \u0026ge;-2 after midazolam administration.\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: RASS, Richmond Agitation\u0026ndash;Sedation Scale;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis\u003c/h2\u003e \u003cp\u003eFor between-group comparisons, categorical variables, including sex, extracorporeal circulation, and use of sedative analgesics during and after midazolam administration, were analyzed using the Fisher\u0026rsquo;s exact test. Continuous variables, including age, BMI, albumin level, ICU hospital stay, renal function, and midazolam infusion dose and period, were analyzed using the Mann\u0026ndash;Whitney U test. The analysis was then conducted using a logistic regression model with the risk factors for prolonged action of midazolam reported in previous studies and albumin levels as explanatory variables. The objective variable set was the group with RASS score improvement within \u0026lt;\u0026thinsp;48 h and the group that required\u0026thinsp;\u0026gt;\u0026thinsp;48 h to improve. Furthermore, to confirm statistical robustness, a sensitivity analysis was performed using propensity score matching after adjusting for factors used in the logistic regression analysis, except for albumin levels. Statistical analyses were performed using EZR (version 1.61), and statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cp\u003eThe eligible patients included in the study are shown in Fig.\u0026nbsp;1. This study excluded 54 patients who were difficult to assess for RASS evaluation after midazolam administration, 56 patients who did not achieve deep sedation with midazolam (RASS \u0026ge;-3), 9 patients with non-measurable BMI, and 9 patients with severe neurological impairment; thus, 68 patients were eligible for inclusion. The patient characteristics and results of the univariate analysis are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. After midazolam treatment, the RASS score improved within \u0026lt;\u0026thinsp;48 h in 52 patients, and 16 patients required\u0026thinsp;\u0026gt;\u0026thinsp;48 h for improvement. Age, albumin level, ICU hospital stay, renal function, and rocuronium combination were factors associated with prolonged midazolam administration. Respiratory diseases were the most common diagnoses at ICU admission, followed by cardiovascular diseases. Hepatic function was not examined, because only two patients had hepatic impairment.\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\u003eComparison of the baseline characteristics of patients in terms of RASS improvement time of \u0026lt;\u0026thinsp;48 h vs. \u0026ge; 48 h\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003evariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eRASS Improvement Time\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;68\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;48 h (=\u0026thinsp;52) \u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;48 h (=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (Male), no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (67.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (73.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, Median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66.0 (55.8\u0026ndash;72.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.5 (54.8\u0026ndash;70.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72.0 (66.8\u0026ndash;77.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, Median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.6 (21.7\u0026ndash;26.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.9 (21.7\u0026ndash;26.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.9 (22.6\u0026ndash;28.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.154\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (g/L), Median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.0 (22.0\u0026ndash;27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.0 (23.8\u0026ndash;28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.0 (19.0\u0026ndash;23.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU hospital stay (day), Median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.0 (10.3\u0026ndash;24.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.1 (8.5\u0026ndash;22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.0 (21.8\u0026ndash;54.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e), Median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80.6 (46.3\u0026ndash;93.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81.8 (59.0\u0026ndash;96.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43.8 (15.1\u0026ndash;72.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtracorporeal circulation, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (26.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMidazolam infusion dose (mg/h), Median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.9 (5.7\u0026ndash;9.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.9 (5.7\u0026ndash;9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.0 (6.1\u0026ndash;10.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.281\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMidazolam infusion period (h), Median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102.0 (64.5-165.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e101.5 (66.8-157.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e107.0 (47.6-254.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.919\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombination therapy while administering midazolam, no. (%)\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDexmedetomidine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (41.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (48.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0454\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePropofol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (80.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (86.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (62.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRocuronium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (36.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (62.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0197\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (85.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (86.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (81.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.689\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombination therapy after midazolam administration, no. (%)\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDexmedetomidine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (69.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (56.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePropofol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (57.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (57.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (56.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRocuronium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU admission diagnosis, no. (%)\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (67.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (65.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (14.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrauma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTetanus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverdose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypoglycemic coma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: BMI, body mass index; ICU, intensive care unit; IQR, interquartile range; RASS, Richmond Agitation\u0026ndash;Sedation Scale; GFR, glomerular filtration rate\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\u003eAnalyses were performed using logistic regression models, with patient backgrounds adjusted for renal function, BMI, midazolam administration period, age, sex, albumin level, and ICU hospital stay, as reported in previous studies. The results showed significant effects of the albumin level on the prolonged action of midazolam (odds ratio, 0.61; 95% confidence interval, 0.44-085; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate logistic regression analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjusted OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntercept\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.633\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08 (0.98\u0026ndash;1.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.115\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (Male)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.39 (0.05\u0026ndash;2.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.361\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.17 (0.92\u0026ndash;1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.61 (0.44\u0026ndash;0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97 (0.94\u0026ndash;1.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.173\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMidazolam infusion period (h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.00 (0.99\u0026ndash;1.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.617\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU hospital stay (day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.03 (0.98\u0026ndash;1.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.259\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: BMI, body mass index; ICU, intensive care unit; OR, odds ratio; CI, confidence interval; GFR, glomerular filtration rate\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\u003eFurthermore, the sensitivity analysis showed that the albumin level was associated with the prolonged action of midazolam, similar to the results obtained in the logistic regression analysis (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of RASS improvement times in terms of albumin in the propensity-matched analysis\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eRASS Improvement Time\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;48 h (N\u0026thinsp;=\u0026thinsp;11) \u0026ge;48 h (N\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.0 (23.5\u0026ndash;26.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.0 (17.0-22.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0108\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: RASS, Richmond Agitation\u0026ndash;Sedation Scale\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study investigated the effects of patient background on the prolonged action of midazolam by focusing on previously reported factors and albumin levels. The RASS score required\u0026thinsp;\u0026gt;\u0026thinsp;48 h to improve in approximately 24% of patients after midazolam administration, suggesting that the prolonged action of midazolam was influenced by the albumin level, which was the focus of the present study, in addition to the factors mentioned in previous studies [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Moreover, the results of the multivariate analysis performed using a logistic regression model adjusted for factors reported in previous studies and albumin levels showed that a significant reduction in albumin levels was associated with prolonged action of midazolam.\u003c/p\u003e \u003cp\u003eMidazolam binds to benzodiazepine receptors and exerts sedative and anticonvulsant effects by enhancing the binding of gamma-aminobutyric acid to gamma-aminobutyric acid receptors [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Metabolized via cytochrome P450, the metabolite α-hydroxymidazolam has approximately half the action of the parent compound; metabolites are eliminated by the kidneys [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, in hepatic and renal failure, midazolam and its active metabolites have been reported to accumulate in the body, prolonging the action of midazolam [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This study also suggests that older patients and those with renal failure are likely to experience prolonged midazolam action; thus, caution should be exercised during midazolam administration as many patients have reduced hepatic and renal function.\u003c/p\u003e \u003cp\u003eCritically ill patients with respiratory failure due to various conditions are often managed with deep sedation for prone positioning therapy and ventilator entrainment [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Therefore, the dose and duration of sedation may be prolonged, leading to the prolonged action of midazolam [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The present study suggests that the sedative effects of dexmedetomidine, propofol, and rocuronium combined with other sedatives may influence the action of midazolam. Although dexmedetomidine has been reported to reduce ventilator duration and maintain mild-to-moderate sedation compared with midazolam [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], there are no reports of prolonged effects of its combination with midazolam, and the high rate of use in the group without prolonged midazolam effects had little effect on the results of the study.\u003c/p\u003e \u003cp\u003ePropofol and midazolam are commonly used to maintain deep sedation; however, their combination has been reported to potentiate the effects of midazolam [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Moreover, similar to dexmedetomidine, the use of midazolam was increased in the group without prolonged midazolam action, which had little effect on the results of the present study.\u003c/p\u003e \u003cp\u003eAlthough the muscle relaxant rocuronium is used in combination with midazolam in ventilator management with deep sedation in some situations [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], it is not used after midazolam discontinuation in groups with prolonged midazolam action, and the duration of action of rocuronium is short (approximately 60 min) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]; therefore, it had little effect on the results of the study.\u003c/p\u003e \u003cp\u003eMidazolam is characterized by good tissue translocation as it is converted in vivo to a lipid-soluble drug, passes through the blood\u0026ndash;brain barrier, and has a rapid onset of action [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. However, the high volume of distribution may cause prolonged action of midazolam in patients with obesity because it accumulates in the adipose tissue and is redistributed into the blood over time [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, if albumin levels decrease, midazolam with a high protein-binding rate is expected to have an increased volume of distribution and tissue translocation owing to an increase in non-protein-bound midazolam. Thus, albumin is considered to contribute to the prolonged action of midazolam owing to the redistribution of midazolam in the blood over time.\u003c/p\u003e \u003cp\u003eThe limitations of the present study include the small number of patients and the factors reported in previous studies that influenced the prolonged action of midazolam, which were incorporated into the multivariate analysis, resulting in overfitting and possibly an inaccurate analysis. In addition, disease severity could not be assessed in critically ill patients; therefore, various biases related to disease severity may have influenced the results of the analysis.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe results of the present study suggest that reduced albumin levels prolong the action of midazolam in critically ill patients. Moreover, the results of this study underscore the need for careful administration of midazolam, considering albumin levels, age, hepatic and renal dysfunction, obesity, and long-term use. In critically ill patients, albumin levels often decrease, and midazolam must be used carefully, mindful of the influence of albumin on its pharmacological effects. Avoiding prolonged midazolam action may contribute to improved patient outcomes owing to reduced ICU hospital stay, decreased hospitalization, reduced healthcare costs, and prevention of PICS. Furthermore, in order to improve the validity of the results of this study, it is necessary to define the disease severity of the patients and conduct further studies in collaboration with many facilities.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.92063492063492%\" valign=\"top\"\u003e\n \u003cp\u003eICU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.07936507936508%\" valign=\"top\"\u003e\n \u003cp\u003eIntensive care unit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.92063492063492%\" valign=\"top\"\u003e\n \u003cp\u003eRASS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.07936507936508%\" valign=\"top\"\u003e\n \u003cp\u003eRichmond Agitation\u0026ndash;Sedation Scale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.92063492063492%\" valign=\"top\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.07936507936508%\" valign=\"top\"\u003e\n \u003cp\u003eBody mass index\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.92063492063492%\" valign=\"top\"\u003e\n \u003cp\u003ePICS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.07936507936508%\" valign=\"top\"\u003e\n \u003cp\u003ePost-intensive care syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTY planned the study, collected data, conducted statistical analysis, and wrote the manuscript. SW was involved in research guidance and writing of the manuscript. YM and YS performed data collection. NY conducted statistical analysis. SO, NH, TO, and MT provided research guidance and advice. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll relevant data were included in the published article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Ethical Guidelines for Life Sciences and Medical Research Involving Human Subjects and was approved by the Clinical Research Ethics Review Committee of Ehime University Hospital (protocol number: 2302006).\u0026nbsp;As this was a retrospective clinical study and obtaining individual informed consent was practically difficult, informed consent was not obtained from research subjects; however, information on the conduct of the study, including the purpose of the study, was disclosed to ensure that research subjects or their surrogates and others have the opportunity to refuse participation. Information was disclosed by posting documents approved by the Ethics Review Committee. The need for written informed consent was waived by the Clinical Research Ethics Review Committee of Ehime University Hospital ethics committee due to retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSydow M, Neumann P. Sedation for the critically ill. Intensive Care Med. 1999;25:634\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTreggiari-Venzi M, Borgeat A, Fuchs-Buder T, Gachoud JP, Suter PM. Overnight sedation with midazolam or propofol in the ICU: effects on sleep quality, anxiety and depression. Intensive Care Med. 1996;22:1186\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalder B, Elia N, Henzi I, Romand JR, Tram\u0026egrave;r MR. A lack of evidence of superiority of propofol versus midazolam for sedation in mechanically ventilated critically ill patients: a qualitative and quantitative systematic review. Anesth Analg. 2001;92:975\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012;307:1151\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpina SP, Ensom MHH. Clinical pharmacokinetic monitoring of midazolam in critically ill patients. Pharmacotherapy. 2007;27:389\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30:119\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDevlin JW, Skrobik Y, G\u0026eacute;linas C, Needham DM, Slooter AJC, Pandharipande PP, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46:e825\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLabuzetta JN, Rosand J, Vranceanu AM. Review: post-intensive care syndrome: unique challenges in the neurointensive care unit. Neurocrit Care. 2019;31:534\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInoue S, Hatakeyama J, Kondo Y, Hifumi T, Sakuramoto H, Kawasaki T, et al. Post-intensive care syndrome: its pathophysiology, prevention, and future directions. Acute Med Surg. 2019;6:233\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee M, Kang J, Jeong YJ. Risk factors for post-intensive care syndrome: A systematic review and meta-analysis. Aust Crit Care. 2020;33:287\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBauer TM, Ritz R, Haberth\u0026uuml;r C, Ha HR, Hunkeler W, Sleight AJ, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet. 1995;346:145\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDriessen JJ, Vree TB, Guelen PJ. The effects of acute changes in renal function on the pharmacokinetics of midazolam during long-term infusion in ICU patients. Acta Anaesthesiol Belg. 1991;42:149\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArcangeli A, Antonelli M, Mignani V, Sandroni C. Sedation in PACU: the role of benzodiazepines. Curr Drug Targets. 2005;6:745\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBremer F, Reulbach U, Schwilden H, Sch\u0026uuml;ttler J. Midazolam therapeutic drug monitoring in intensive care sedation: a 5-year survey. Ther Drug Monit. 2004;26:643\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFragen RJ. Pharmacokinetics and pharmacodynamics of midazolam given via continuous intravenous infusion in intensive care units. Clin Ther 1997;19:405\u0026thinsp;\u0026ndash;\u0026thinsp;19; discussion 367.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNicholson JP, Wolmarans MR, Park GR. The role of albumin in critical illness. Br J Anaesth. 2000;85:599\u0026ndash;610.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVoiriot G, Oualha M, Pierre A, Salmon-Gandonni\u0026egrave;re C, Gaudet A, Jouan Y, et al. Chronic critical illness and post-intensive care syndrome: from pathophysiology to clinical challenges. Ann Intensive Care. 2022;12:58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranken LG, Masman AD, de Winter BCM, Baar FPM, Tibboel D, Van Gelder T, et al. Hypoalbuminaemia and decreased midazolam clearance in terminally ill adult patients, an inflammatory effect? Br J Clin Pharmacol. 2017;83:1701\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166:1338\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKotfis K, Marra A, Ely EW. ICU delirium - a diagnostic and therapeutic challenge in the intensive care unit. Anaesthesiol Intensive Ther. 2018;50:160\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson TN, Rostami-Hodjegan A, Goddard JM, Tanner MS, Tucker GT. Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis. Br J Anaesth. 2002;89:428\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmeets TJL, de Geus HRH, Valkenburg AJ, Baidjoe L, Gommers DAMPJ, Koch BCP, et al. The clearance of midazolam and metabolites during continuous renal replacement therapy in critically ill patients with COVID-19. Blood Purif. 2024;53:107\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArroliga A, Frutos-Vivar F, Hall J, Esteban A, Apeztegu\u0026iacute;a C, Soto L, et al. Use of sedatives and neuromuscular blockers in a cohort of patients receiving mechanical ventilation. Chest. 2005;128:496\u0026ndash;506.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998;114:541\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhmori J, Maeda S, Higuchi H, Ishii M, Arai Y, Tomoyasu Y, et al. Propofol increases the rate of albumin-unbound free midazolam in serum albumin solution. J Anesth. 2011;25:618\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChanques G, Constantin JM, Devlin JW, Ely EW, Fraser GL, G\u0026eacute;linas C, et al. Analgesia and sedation in patients with ARDS. Intensive Care Med. 2020;46:2342\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMagorian T, Flannery KB, Miller RD. Comparison of rocuronium, succinylcholine, and vecuronium for rapid-sequence induction of anesthesia in adult patients. Anesthesiology. 1993;79:913\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanto JH. Midazolam: the first water-soluble benzodiazepine. Pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia. Pharmacotherapy. 1985;5:138\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Midazolam, Albumin, Richmond Agitation–Sedation Scale, Sedation","lastPublishedDoi":"10.21203/rs.3.rs-4304736/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4304736/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBenzodiazepine midazolam is characterized by a rapid onset of action and a short half-life and is used for deep sedation in critically ill patients; however, hepatic and renal dysfunction, obesity, and prolonged use of midazolam are reported to prolong midazolam action. A few studies have investigated the association between midazolam use and hypoalbuminemia in critically ill patients. Therefore, this study aimed to investigate the effects of patient background on the prolonged action of midazolam by focusing on previously reported factors and albumin levels.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 196 patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years who were admitted to the University Hospital and Matsuyama Shimin Hospital intensive care unit between January 2015 and May 2022 and were administered midazolam continuously for \u0026ge;\u0026thinsp;24 h were enrolled. Patient data, such as background, laboratory test values, and status of sedative drug use, including midazolam, were obtained from medical records. The primary outcome was the time required for improvement of the Richmond Agitation\u0026ndash;Sedation Scale score after midazolam administration. Factors related to the prolongation of midazolam action were analyzed using the Mann\u0026ndash;Whitney U test and logistic regression analysis. Statistical analyses were performed using EZR (version 1.61). Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eIn total, 68 patients were included in this study. The time required for Richmond Agitation\u0026ndash;Sedation Scale score improvement after discontinuation of midazolam was \u0026lt;\u0026thinsp;48 h in 52 patients (76.4%) and \u0026gt;\u0026thinsp;48 h in 16 patients (23.5%).The factors related to prolonged midazolam action were age (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), renal function (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01), risk factors reported in previous studies, and albumin levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). The multivariate logistic regression analysis revealed that only albumin influenced the prolongation of midazolam activity (odds ratio, 0.61; 95% confidence interval, 0.44\u0026ndash;0.85; P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eRenal function, body mass index, age, and duration of midazolam administration are established factors that enhance and prolong the action of midazolam. In this study, the serum albumin level was identified as a new factor of relevance. Therefore, sedation in patients with low albumin levels should be carefully performed to avoid the prolongation and potentiation of midazolam action.\u003c/p\u003e","manuscriptTitle":"Analysis of factors related to prolonged midazolam action: A multicenter, case-control study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-08 14:26:41","doi":"10.21203/rs.3.rs-4304736/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"09c406b8-127c-401a-99e6-b78aeeeb9723","owner":[],"postedDate":"May 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-15T11:53:44+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-08 14:26:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4304736","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4304736","identity":"rs-4304736","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}