{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:24:03Z","timestamp":1790879043696,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T00:00:00Z","timestamp":1717632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background. Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended, with an anti-activated factor X (anti-Xa) targeting 0.3 to 0.7 IU\/mL. Owing to heparin\u2019s heterogeneous pharmacokinetic properties, anti-Xa is unpredictable, generating a challenge in anticoagulation practices. The aim of this study was to build a pharmacokinetic model of heparin accounting for potential confounders, and derive an optimized dosing regimen for a given anti-Xa target. Methods. Adult patients undergoing VA-ECMO were included between January 2020 and June 2021. Anticoagulation was managed with an initial 100 IU\/kg heparin loading dose followed by a continuous infusion targeting 0.2 to 0.7 IU\/mL anti-Xa. The data were split into model development and model validation cohorts. Statistical analysis was performed using a nonlinear mixed effects modeling population approach. Model-based simulations were performed to develop an optimized dosing regimen targeting the desired anti-Xa. Results. A total of 74 patients were included, with 1703 anti-Xa observations. A single-compartment model best fitted the data. Interpatient variability for distribution volume was best explained by body weight, C-reactive protein and ECMO indication (post-cardiotomy shock or medical cardiogenic shock), and interpatient variability for elimination clearance was best explained by serum creatinine and C-reactive protein. Simulations using the optimized regimen according to these covariates showed accurate anti-Xa target attainment. Conclusion. In adult patients on VA-ECMO, heparin\u2019s effect increased with serum creatinine and medical indication, whereas it decreased with body weight and systemic inflammation. We propose an optimized dosing regimen accounting for key covariates, capable of accurately predicting a given anti-Xa target.<\/jats:p>","DOI":"10.3390\/pharmaceutics16060770","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T06:40:26Z","timestamp":1717656026000},"page":"770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Heparin Dosing Regimen Optimization in Veno-Arterial Extracorporeal Membrane Oxygenation: A Pharmacokinetic Analysis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1324-3701","authenticated-orcid":false,"given":"Julien","family":"Lanoisel\u00e9e","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Saint-Etienne University Hospital, F-42055 Saint-Etienne, France"},{"name":"INSERM U1059, Dysfonction Vasculaire et H\u00e9mostase, F-42055 Saint-Etienne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8363-7983","authenticated-orcid":false,"given":"J\u00e9r\u00e9my","family":"Mourer","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, CHU Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Jungling","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, CHU Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Molliex","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Saint-Etienne University Hospital, F-42055 Saint-Etienne, France"},{"name":"INSERM U1059, Dysfonction Vasculaire et H\u00e9mostase, F-42055 Saint-Etienne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise","family":"Thellier","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, CHU Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Tabareau","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, CHU Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Jeanpierre","sequence":"additional","affiliation":[{"name":"Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Robin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, CHU Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Susen","sequence":"additional","affiliation":[{"name":"Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Tavernier","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, CHU Lille, F-59000 Lille, France"},{"name":"ULR 2694-METRICS, \u00c9valuation des Technologies de Sant\u00e9 et des Pratiques M\u00e9dicales, University of Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Vincentelli","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, CHU Lille, F-59000 Lille, France"},{"name":"Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, University of Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6925-2941","authenticated-orcid":false,"given":"Edouard","family":"Ollier","sequence":"additional","affiliation":[{"name":"INSERM U1059, Dysfonction Vasculaire et H\u00e9mostase, F-42055 Saint-Etienne, France"},{"name":"Unit\u00e9 de Recherche Clinique Innovation et Pharmacologie, Saint-Etienne University Hospital, F-42270 Saint-Etienne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mouhamed Djahoum","family":"Moussa","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, CHU Lille, F-59000 Lille, France"},{"name":"ULR 2694-METRICS, \u00c9valuation des Technologies de Sant\u00e9 et des Pratiques M\u00e9dicales, University of Lille, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e004905","DOI":"10.1161\/CIRCHEARTFAILURE.118.004905","article-title":"Venoarterial Extracorporeal Membrane Oxygenation for Cardiogenic Shock and Cardiac Arrest","volume":"11","author":"Rao","year":"2018","journal-title":"Circ. 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