{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:45:24Z","timestamp":1792806324353,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pmed.1003658","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T00:00:00Z","timestamp":1624233600000}}],"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T00:00:00Z","timestamp":1623024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jon Moulton Charity Trust"},{"name":"Jon Moulton Charity Trust"},{"name":"Jon Moulton Charity Trust"},{"name":"Jon Moulton Charity Trust"},{"name":"Jon Moulton Charity Trust"},{"name":"UK Medical Research Foundation","award":["MC_UU_00002\/15"],"award-info":[{"award-number":["MC_UU_00002\/15"]}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods and findings<\/jats:title><jats:p>We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\" xlink:type=\"simple\">ClinicalTrials.gov<\/jats:ext-link>Identifier: NCT03532594).<\/jats:p><jats:p>Participants were recruited between April 2018 and August 2019. Those in the intervention\/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes;<jats:italic>p<\/jats:italic>= 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78\u20131.14] vs. 0.75 [IQR 0.57\u20130.99];<jats:italic>p<\/jats:italic>&lt; 0.001). We found no evidence of a difference in median mediastinal\/pleural drainage at 4 hours postoperatively (140 [IQR 75\u2013245] vs. 135 [IQR 94\u2013222] mL;<jats:italic>p<\/jats:italic>= 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%]<jats:italic>p<\/jats:italic>= 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160\u2013210] vs. 280 [IQR 250\u2013300] mg;<jats:italic>p<\/jats:italic>&lt; 0.001).<\/jats:p><jats:p>Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight &gt;120 kg, and patients requiring therapeutic hypothermia to &lt;28\u00b0C).<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Conclusions<\/jats:title><jats:p>Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal\/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Trial registration<\/jats:title><jats:p>ClinicalTrials.gov Unique identifier<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03532594\" xlink:type=\"simple\">NCT03532594<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pmed.1003658","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T17:49:06Z","timestamp":1623088146000},"page":"e1003658","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":38,"title":["Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2044-5560","authenticated-orcid":true,"given":"Lachlan F.","family":"Miles","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiana","family":"Burt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Arrowsmith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1711-4034","authenticated-orcid":true,"given":"Mikel A.","family":"McKie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia S.","family":"Villar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1948-9155","authenticated-orcid":true,"given":"Pooveshnie","family":"Govender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Shaylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5602-2231","authenticated-orcid":true,"given":"Zihui","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"De Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7870-1136","authenticated-orcid":true,"given":"Florian","family":"Falter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,7]]},"reference":[{"key":"pmed.1003658.ref001","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.athoracsur.2017.09.061","article-title":"The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: Clinical Practice Guidelines\u2014Anticoagulation During Cardiopulmonary Bypass","volume":"105","author":"LJ Shore-Lesserson","year":"2018","journal-title":"Ann Thorac Surg"},{"key":"pmed.1003658.ref002","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1182\/blood-2009-05-222109","article-title":"Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation","volume":"114","author":"F Ni Ainle","year":"2009","journal-title":"Blood"},{"key":"pmed.1003658.ref003","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1177\/0267659118763043","article-title":"The effect of protamine dosing variation on bleeding and transfusion after heparinisation for cardiopulmonary bypass","volume":"33","author":"SA Kunz","year":"2018","journal-title":"Perfusion"},{"key":"pmed.1003658.ref004","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1160\/TH16-02-0117","article-title":"Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. 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