{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:09:33Z","timestamp":1772168973894,"version":"3.50.1"},"reference-count":44,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T00:00:00Z","timestamp":1606262400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010414","name":"Health Research Board","doi-asserted-by":"publisher","award":["NCHF-2017-005"],"award-info":[{"award-number":["NCHF-2017-005"]}],"id":[{"id":"10.13039\/100010414","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Temple Street Hospital Foundation","award":["RPAC 16-03"],"award-info":[{"award-number":["RPAC 16-03"]}]},{"DOI":"10.13039\/100014364","name":"National Children\u2019s Research Centre","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014364","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["hrbopenresearch.org"],"crossmark-restriction":false},"short-container-title":["HRB Open Res"],"abstract":"<ns3:p>A patent ductus arteriosus (PDA) in preterm infants is associated with increased ventilator dependence and chronic lung disease, necrotizing enterocolitis, intraventricular haemorrhage, and poor neurodevelopmental outcome. Randomised controlled trials of early PDA treatment have not established a drop in the aforementioned morbidities. Those trials did not physiologically categorise PDA severity. Incorporating the specific physiological features of a haemodynamic significant PDA may evolve our understanding of this phenomenon, allowing accurate triaging using echocardiography and targeted treatment.\u00a0 Our group has recently demonstrated that a PDA severity score (PDAsc) derived at 36-48 hours of age can accurately predict the later occurrence of chronic lung disease or death (CLD\/Death). Using echocardiography, we assessed PDA characteristics, as well as left ventricular diastolic function and markers of pulmonary overcirculation, and from this formulated a PDAsc. Gestation was also incorporated into the score. We hypothesise that in preterm infants at high risk of developing CLD\/Death based on a PDAsc, early treatment with Ibuprofen compared with placebo will result in a reduction in CLD\/Death. This is a single centre double-blind two arm randomised controlled trial conducted in the neonatal intensive care unit in the Rotunda Hospital, Dublin. Echocardiogram is carried out in the first 36-48 hours of life to identify preterm infants with a PDAsc \u2265 5.0 and these infants are randomised to Ibuprofen or placebo. Primary outcomes are assessed at 36 weeks post menstrual age. This pilot study\u2019s purpose is to assess the feasibility of performing the trial and to obtain preliminary data to calculate a sample size for a definitive multi-centre trial of early PDA treatment using a PDAsc. We aim to recruit a total of 60 infants with a high risk PDA over three years.<\/ns3:p>\n                  <ns3:p>\n                    <ns3:bold>Trial Registration:<\/ns3:bold>\n                    ISRCTN\n                    <ns3:ext-link xmlns:ns4=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns4:href=\"https:\/\/doi.org\/10.1186\/ISRCTN13281214\">ISRCTN13281214<\/ns3:ext-link>\n                    (26\/07\/2016) and the European Union Drug Regulating Authorities Clinical Trials Database\n                    <ns3:ext-link xmlns:ns4=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns4:href=\"https:\/\/www.clinicaltrialsregister.eu\/ctr-search\/search?query=eudract_number:2015-004526-33\">2015-004526-33<\/ns3:ext-link>\n                    (03\/12\/2015).\n                  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R.","family":"Breatnach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4778-3888","authenticated-orcid":false,"given":"Aisling","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Tully","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"McCallion","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John David","family":"Corcoran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Looi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Cleary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orla","family":"Franklin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7648-8872","authenticated-orcid":false,"given":"Patrick J.","family":"McNamara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2020,11,25]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"177-184","DOI":"10.1016\/j.siny.2004.10.003","article-title":"The pharmacologic closure of the patent ductus arteriosus.","volume":"10","author":"B Van Overmeire","year":"2005","journal-title":"Semin Fetal Neonatal Med."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"e138-44","DOI":"10.1542\/peds.2008-2418","article-title":"Failure of ductus arteriosus closure is associated with increased mortality in preterm infants.","volume":"123","author":"S Noori","year":"2009","journal-title":"Pediatrics."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"F183-6","DOI":"10.1136\/fn.75.3.f183","article-title":"Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants.","volume":"75","author":"N Evans","year":"1996","journal-title":"Arch Dis Child Fetal Neonatal Ed."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"184-8","DOI":"10.1097\/00005176-200502000-00019","article-title":"Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study.","volume":"40","author":"S Dollberg","year":"2005","journal-title":"J Pediatr Gastroenterol Nutr."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"88-92","DOI":"10.3928\/01913913-20130108-03","article-title":"Patent ductus arteriosus and indomethacin treatment as independent risk factors for plus disease in retinopathy of prematurity.","volume":"50","author":"I Tsui","year":"2013","journal-title":"J Pediatr Ophthalmol Strabismus."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"605-10","DOI":"10.1016\/s0022-3476(95)70362-4","article-title":"Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease.","volume":"126","author":"M Rojas","year":"1995","journal-title":"J Pediatr."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"674-81","DOI":"10.1542\/peds.2007-2781","article-title":"Patent ductus arteriosus therapy: impact on neonatal and 18-month outcome.","volume":"123","author":"J Madan","year":"2009","journal-title":"Pediatrics."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"272-7","DOI":"10.1016\/j.siny.2015.03.004","article-title":"Preterm patent ductus arteriosus: A continuing conundrum for the neonatologist?","volume":"20","author":"N Evans","year":"2015","journal-title":"Semin Fetal Neonatal Med."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"CD003745","DOI":"10.1002\/14651858.CD003745","article-title":"Indomethacin for asymptomatic patent ductus arteriosus in preterm infants.","author":"L Cooke","year":"2003","journal-title":"Cochrane Database Syst 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Pediatr."},{"key":"ref-30","doi-asserted-by":"publisher","first-page":"317-323","DOI":"10.1136\/thorax.56.4.317","article-title":"Long term sequelae of bronchopulmonary dysplasia (chronic lung disease of infancy).","volume":"56","author":"E Eber","year":"2001","journal-title":"Thorax."},{"key":"ref-31","doi-asserted-by":"publisher","first-page":"F318-F322","DOI":"10.1136\/fetalneonatal-2011-300244","article-title":"Outcomes at 7 years for babies who developed neonatal necrotising enterocolitis: the ORACLE Children Study.","volume":"97","author":"K Pike","year":"2012","journal-title":"Arch Dis Child Fetal Neonatal Ed."},{"key":"ref-32","doi-asserted-by":"publisher","first-page":"733-738","DOI":"10.1016\/s0022-3476(99)70093-4","article-title":"Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus.","volume":"135","author":"M Pezzati","year":"1999","journal-title":"J Pediatr."},{"key":"ref-33","doi-asserted-by":"publisher","first-page":"1672-1678","DOI":"10.1152\/jappl.1993.74.4.1672","article-title":"Indomethacin compromises hemodynamics during positive-pressure ventilation, independently of prostanoids.","volume":"74","author":"D Malcolm","year":"1993","journal-title":"J Appl Physiol (1985)."},{"key":"ref-34","doi-asserted-by":"publisher","first-page":"534-539","DOI":"10.1159\/000088046","article-title":"Effects of ibuprofen and indomethacin on urinary antidiuretic hormone excretion in preterm infants treated for patent ductus arteriosus.","volume":"20","author":"V Zanardo","year":"2005","journal-title":"Fetal Diagn Ther."},{"key":"ref-35","doi-asserted-by":"publisher","first-page":"CD003481","DOI":"10.1002\/14651858.CD003481.pub6","article-title":"Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants.","author":"A Ohlsson","year":"2015","journal-title":"Cochrane Database Syst Rev."},{"key":"ref-36","doi-asserted-by":"publisher","first-page":"529-534","DOI":"10.1016\/s0022-3476(78)80282-0","article-title":"Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.","volume":"92","author":"L Papile","year":"1978","journal-title":"J Pediatr."},{"key":"ref-37","doi-asserted-by":"publisher","first-page":"1100-1106","DOI":"10.1016\/j.jpeds.2012.12.094","article-title":"Ligation of the patent ductus arteriosus in preterm infants: understanding the physiology.","volume":"162","author":"A El-Khuffash","year":"2013","journal-title":"J Pediatr."},{"key":"ref-38","doi-asserted-by":"publisher","first-page":"164-70","DOI":"10.1053\/j.semperi.2006.05.002","article-title":"Definitions and diagnostic criteria for bronchopulmonary dysplasia.","volume":"30","author":"E Bancalari","year":"2006","journal-title":"Semin Perinatol."},{"key":"ref-39","doi-asserted-by":"publisher","first-page":"3-16","DOI":"10.1053\/siny.1999.0112","article-title":"Mechanisms of perinatal brain injury.","volume":"5","author":"T Inder","year":"2000","journal-title":"Semin Neonatol."},{"key":"ref-40","doi-asserted-by":"publisher","first-page":"1057-1078","DOI":"10.1016\/j.echo.2011.07.014","article-title":"Targeted Neonatal Echocardiography in the Neonatal Intensive Care Unit: Practice Guidelines and Recommendations for Training Writing group of the American Society of Echocardiography (ASE) in collaboration with the European Association of Echocardiography (EAE) and the Association for European Pediatric Cardiologists (AEPC).","volume":"24","author":"L Mertens","year":"2011","journal-title":"J Am Soc Echocardiogr."},{"key":"ref-41","doi-asserted-by":"publisher","first-page":"50-60","DOI":"10.1016\/j.siny.2010.05.001","article-title":"Neonatologist-performed functional echocardiography in the neonatal intensive care unit.","volume":"16","author":"A El-Khuffash","year":"2011","journal-title":"Semin Fetal Neonatal Med."},{"key":"ref-42","doi-asserted-by":"publisher","first-page":"829-835","DOI":"10.1016\/j.earlhumdev.2014.09.004","article-title":"Assessment of myocardial performance in preterm infants less than 29 weeks gestation during the transitional period.","volume":"90","author":"A James","year":"2014","journal-title":"Early Hum Dev."},{"key":"ref-43","article-title":"Early Targeted Patent Ductus Arteriosus Treatment in Premature Neonates Using a Risk Based Severity Score: Appendices.docx.","author":"N Bussmann","year":"2020","journal-title":"figshare."},{"key":"ref-44","first-page":"121-30","article-title":"ICH Harmonised Tripartite Guideline: guideline for good clinical practice.","volume":"47","year":"2001","journal-title":"J Postgrad Med."}],"container-title":["HRB Open 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/hrbopenres.14253.r29120, Sanket Shah, Department of Pediatrics, Division of Neonatology, University of Florida College of Medicine, Jacksonville, FL, USA, 04 May 2021, version 1, indexed","URL":"https:\/\/hrbopenresearch.org\/articles\/3-87\/v1#referee-response-29120","order":0,"name":"referee-response-29120","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/hrbopenres.14253.r30183, Yung-Chieh Lin, Jieh-Neng Wang, Department of Pediatrics, National Cheng Kung University, Tainan, 70457, Taiwan, 06 Sep 2021, version 1, indexed","URL":"https:\/\/hrbopenresearch.org\/articles\/3-87\/v1#referee-response-30183","order":1,"name":"referee-response-30183","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Health Research Board Ireland [NCHF-2017-005].\n\nThis study was funded by a Research Grant from the Temple Street Hospital Foundation [RPAC 16-03]. The National Children\u2019s Research Centre funded PhD fees associated with this project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":2,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}