{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:19:49Z","timestamp":1787908789657,"version":"build-2784847793"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007469","name":"Alfred Benzon Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007469","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Anaesthesiol Scand"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Acute respiratory failure (ARF) is common in critically ill patients, and 50% of patients in intensive care units require mechanical ventilation [3, 4]. The COVID\u201019 pandemic revealed that COVID\u201019 infection induced ARF caused by damage to the microvascular pulmonary endothelium. In a randomized clinical trial, mechanically ventilated COVID\u201019 patients with severe endotheliopathy, as defined by soluble thrombomodulin (sTM)\u2009\u2265\u20094\u2009ng\/mL, were randomized to evaluate the effect of a 72\u2010h infusion of low\u2010dose prostacyclin 1\u2009ng\/kg\/min or placebo. Twenty\u2010eight\u2010day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (RR 0.50; CI 0.24 to 0.96\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.06).\n                    <\/jats:p>\n                    <jats:p>The aim of the current trial is to investigate if this beneficial effect and safety of prostacyclin also are present in any patient with suspected pulmonary infection requiring mechanical ventilation and concomitant severe endotheliopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>This is a multi\u2010center, randomized, blinded, clinical investigator\u2010initiated phase 3 trial in mechanically ventilated patients with suspected pulmonary infection and severe endotheliopathy, as defined by sTM \u22654\u2009ng\/mL. Patients are randomized 1:1 to a 72\u2010h infusion of low\u2010dose prostacyclin (iloprost) 1\u2009ng\/kg\/min or placebo (an equal volume of saline). Four\u2010hundred fifty patients will be included.<\/jats:p>\n                    <jats:p>The primary endpoint is 28\u2010day all\u2010cause mortality. Secondary endpoints include 90\u2010day mortality, days alive without vasopressor, mechanical ventilation, and renal replacement therapy in the ICU within 28 and 90\u2009days, and the number of serious adverse reactions or serious adverse events within the first 7\u2009days.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This trial will investigate the efficacy and safety of prostacyclin vs. placebo for 72\u2010hours in mechanically ventilated patients with any suspected pulmonary infection and severe endotheliopathy, as defined by sTM \u22654\u2009ng\/mL. Trial endpoints focus on the potential effect of prostacyclin to reduce 28\u2010day all\u2010cause mortality.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aas.14565","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T06:27:42Z","timestamp":1734676062000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Efficacy and safety of a 72\u2010h infusion of prostacyclin (1\u2009ng\/kg\/min) in mechanically ventilated patients with pulmonary infection and endotheliopathy\u2014protocol for the multicenter randomized, placebo\u2010controlled, blinded, investigator\u2010initiated\n                    <scp>COMBAT<\/scp>\n                    \u2010\n                    <scp>ARF<\/scp>\n                    trial"],"prefix":"10.1111","volume":"69","author":[{"given":"Peter","family":"S\u00f8e\u2010Jensen","sequence":"first","affiliation":[{"name":"Department of Anaesthesia and Intensive Care Copenhagen University Hospital\u2013Herlev and Gentofte  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels E.","family":"Clausen","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia and Intensive Care Copenhagen University Hospital\u2013Bispebjerg and Frederiksberg  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten H.","family":"Bestle","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia and Intensive Care Copenhagen University Hospital\u2013North Zealand  Hilleroed Denmark"},{"name":"Department of Clinical Medicine University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars P. K.","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine University of Copenhagen  Copenhagen Denmark"},{"name":"Department of Anaesthesia and Intensive Care Zealand University Hospital\u2013K\u00f8ge  K\u00f8ge Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theis","family":"Lange","sequence":"additional","affiliation":[{"name":"Section of Biostatistics University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9778-5964","authenticated-orcid":false,"given":"P\u00e4r I.","family":"Johansson","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine University of Copenhagen  Copenhagen Denmark"},{"name":"CAG Center for Endotheliomics, Department of Clinical Immunology Copenhagen University Hospital\u2013Rigshospitalet  Copenhagen 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