{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T12:31:41Z","timestamp":1779107501861,"version":"3.51.4"},"reference-count":26,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T00:00:00Z","timestamp":1759536000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Anesthesia"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Clonidine and midazolam are routinely used in the pediatric intensive care unit for pain and sedation management, but target concentration and optimal dose are poorly defined for both drugs. The CloSed study is a multicenter, double\u2010blind, randomized, active\u2010controlled noninferiority trial with a 1:1 randomization between clonidine and midazolam.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Data from the prematurely terminated CloSed trial were used to study the population pharmacokinetic\u2013pharmacodynamic relationships for clonidine and midazolam to inform the optimal use of both drugs in mechanically ventilated children.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Twenty\u2010eight patients (0\u20136\u2009years) were included; 13 received midazolam, and 15 received clonidine. Morphine was administered to all patients as background analgesia. A total of 317 and 306 observed COMFORT\u2010B scores for midazolam and clonidine, respectively, were available to build the pharmacokinetic\u2013pharmacodynamic model. Pharmacokinetic models were developed using findings from previously published pharmacokinetic studies to augment the trial data. A one\u2010compartment model described clonidine pharmacokinetics, while a single compartment for midazolam and its metabolite described its pharmacokinetics. A joint inhibitory sigmoid model that included a postanesthesia effect was used to describe the concentration\u2013effect relationship, using the COMFORT\u2010B score as the pharmacodynamic endpoint.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The final models adequately described the observed data. Simulations based on the final models showed that a clonidine dose of 4\u2009\u03bcg\/kg loading dose followed by a 3\u2009\u03bcg\/kg\/h infusion, and a midazolam dose of 200\u2009\u03bcg\/kg loading dose followed by a 200\u2009\u03bcg\/kg\/h infusion would be required to achieve adequate sedation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The CloSed data suggest that higher doses of clonidine and midazolam than are commonly used in clinical practice should be considered to provide adequate sedation in critically ill children.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/pan.70050","type":"journal-article","created":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T07:33:46Z","timestamp":1759563226000},"page":"1053-1062","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive Care"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4067-2744","authenticated-orcid":false,"given":"Maddlie","family":"Bardol","sequence":"first","affiliation":[{"name":"Institute of Child Health University College London  London UK"},{"name":"Pharmetheus AB  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yucheng","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy University College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Baarslag","sequence":"additional","affiliation":[{"name":"Erlangen\/N\u00fcrnberg Erlangen, Germany, Intensive Care and Department of Pediatric Surgery Erasmus MC  Rotterdam the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana","family":"Ceci","sequence":"additional","affiliation":[{"name":"Department of Research Gianni Benzi Pharmacological Research Foundation  Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"D\u00f6rje","sequence":"additional","affiliation":[{"name":"Pharmacy Department Universit\u00e4tsklinikum Erlangen  Erlangen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari\u2010Liis","family":"Ilmoja","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care Tallinn Children's Hospital  Tallinn Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3143-6643","authenticated-orcid":false,"given":"Peter","family":"Larsson","sequence":"additional","affiliation":[{"name":"Department of Pediatric Perioperative Medicine and Intensive Care Karolinska University Hospital  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Per\u2010Arne","family":"L\u00f6nnqvist","sequence":"additional","affiliation":[{"name":"Department of Pediatric Perioperative Medicine and Intensive Care Karolinska University Hospital  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuuli","family":"Methsvat","sequence":"additional","affiliation":[{"name":"Department of Microbiology University of Tartu  Tartu Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavla","family":"Pokorna","sequence":"additional","affiliation":[{"name":"Department of Pediatrics General Faculty Hospital Prague, First Faculty of Medicine Charles University  Prague Czech Republic"},{"name":"Department of Physiology and Pharmacology Karolinska University Hospital  Stockholm 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