{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:02:54Z","timestamp":1793329374221,"version":"4.5.0"},"reference-count":10,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2004,12,14]],"date-time":"2004-12-14T00:00:00Z","timestamp":1102982400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2004,12,14]],"date-time":"2004-12-14T00:00:00Z","timestamp":1102982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Crit Care"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Midazolam is used routinely to sedate patients in the intensive care unit (ICU). We suspected that midazolam over-sedation was occurring in the ICU of the Guy's and St. Thomas' Trust and that it could be difficult to differentiate this from underlying neurological damage. A sensitive assay for detecting midazolam and 1-hydroxymidazolam glucuronide (1-OHMG) in serum was developed and applied in the clinical setting.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>In the present study we evaluated a series of cases managed in a mixed medical, surgical and trauma ICU. Serum was collected from 26 patients who received midazolam, were 'slow to wake' and in whom there was suspicion of neurological damage. Patient outcome was followed in terms of mortality, neurological recovery and neurological damage on discharge.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>Out of 26 patients, 13 had detectable serum levels of midazolam and\/or 1-OHMG after a median of 67 hours (range 36\u2013146 hours) from midazolam cessation. Of these 13 patients in whom midazolam\/1-OHMG was detectable, 10 made a full neurological recovery. Of the remaining 13 patients with no detectable midazolam\/1-OHMG, three made a full neurological recovery; 10 patients were subsequently found to have suffered neurological damage (<jats:italic>P<\/jats:italic> &lt; 0.002), eight of whom died and two were discharged from the ICU with profound neurological damage.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusion<\/jats:title>\n                        <jats:p>These findings confirm that prolonged sedation after midazolam therapy should be considered in the differential diagnosis of neurological damage in the ICU. This can be reliably detected by the assay method described. The effects of midazolam\/1-OHMG persist days after administration of midazolam has ceased. After prolonged sedation has been excluded in this patient group, it is highly likely that neurological damage has occurred.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/cc3010","type":"journal-article","created":{"date-parts":[[2005,1,12]],"date-time":"2005-01-12T16:25:14Z","timestamp":1105547114000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Differentiating midazolam over-sedation from neurological damage in the intensive care unit"],"prefix":"10.1186","volume":"9","author":[{"given":"Catherine A","family":"McKenzie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"McKinnon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Declan P","family":"Naughton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Treacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary J","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J","family":"Hilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2004,12,14]]},"reference":[{"key":"3003_CR1","volume-title":"Pharm World Sci","author":"CA McKenzie","year":"2004","unstructured":"McKenzie CA, McKinnon W, Naughton DP, Treacher DF, Davies JG, Philips G, Hilton PJ: Differentiating over-sedation from neurological insult in an adult intensive care unit (ICU).\n                           Pharm World Sci 2004, in press."},{"key":"3003_CR2","volume-title":"Therapeutic Drugs","year":"1991","unstructured":"Dollery C, editor: Therapeutic Drugs. Volume 2. New York: Churchill Livingston; 1991."},{"key":"3003_CR3","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/S0140-6736(95)91209-6","volume":"346","author":"TM Bauer","year":"1995","unstructured":"Bauer TM, Ritz R, Haberthur C, Ha HR, Hunkeler W, Sleight AJ, Scollo-Lavizzari G, Haefeli WE: Prolonged sedation due to accumulation of conjugated metabolites of midazolam.\n                           Lancet 1995, 346: 145-147. 10.1016\/S0140-6736(95)91209-6","journal-title":"Lancet"},{"key":"3003_CR4","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1248\/yakushi.123.811","volume":"123","author":"K Hirata","year":"2003","unstructured":"Hirata K, Matsumoto Y, Kurokawa A, Onda M, Shimizu M, Fukuoka M, Hirano M, Yamamoto Y: Possible influence of midazolam sedation on the diagnosis of brain death: concentration of active metabolites after cessation of midazolam.\n                           Yakugaku Zasshi 2003, 123: 811-815. 10.1248\/yakushi.123.811","journal-title":"Yakugaku Zasshi"},{"key":"3003_CR5","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/clpt.1988.31","volume":"43","author":"H Oldenhof","year":"1988","unstructured":"Oldenhof H, Jong M, Steenhoek A, Janknegt R: Clinical pharmacokinetics of midazolam in intensive care patients, a wide inter patient variability?\n                           Clin Pharmacol Ther 1988, 43: 263-268.","journal-title":"Clin Pharmacol Ther"},{"key":"3003_CR6","doi-asserted-by":"publisher","first-page":"347","DOI":"10.2165\/00003088-198814060-00003","volume":"14","author":"A Bodenham","year":"1988","unstructured":"Bodenham A, Shelly MP, Park GR: The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients.\n                           Clin Pharmacokinet 1988, 14: 347-373.","journal-title":"Clin Pharmacokinet"},{"key":"3003_CR7","doi-asserted-by":"publisher","first-page":"422","DOI":"10.2165\/00003088-198308050-00004","volume":"8","author":"LE Mather","year":"1983","unstructured":"Mather LE: Clinical pharmacokinetics of fentanyl and its newer derivatives.\n                           Clin Pharmacokinet 1983, 8: 422-446.","journal-title":"Clin Pharmacokinet"},{"key":"3003_CR8","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1097\/00003246-199206000-00006","volume":"20","author":"FX Breheny","year":"1992","unstructured":"Breheny FX: Reversal of midazolam sedation with flumazenil.\n                           Crit Care Med 1992, 20: 736-739.","journal-title":"Crit Care Med"},{"key":"3003_CR9","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1081\/CLT-120030946","volume":"42","author":"Dl Seger","year":"2004","unstructured":"Seger Dl: Flumazenil: treatment or toxin.\n                           J Toxicol Clin Toxicol 2004, 42: 209-216. 10.1081\/CLT-120030946","journal-title":"J Toxicol Clin Toxicol"},{"key":"3003_CR10","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1097\/00003246-200201000-00020","volume":"30","author":"J Jacobi","year":"2002","unstructured":"Jacobi J, Fraser GL, Coursin DB, Ricker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke S, Coplin WM, et al.: Clinical practice guidelines for sustained use of sedatives and analgesics in the critically ill adult.\n                           Crit Care Med 2002, 30: 119-141. 10.1097\/00003246-200201000-00020","journal-title":"Crit Care Med"}],"container-title":["Critical 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