{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T10:30:23Z","timestamp":1775817023890,"version":"3.50.1"},"reference-count":39,"publisher":"Georg Thieme Verlag KG","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Am J Perinatol"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:p>\n            Objective\u2003An alternative therapy for preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA) is needed when cyclooxygenase inhibitors fail or where treatment is contraindicated due to coexisting renal failure, necrotizing enterocolitis, and\/or intestinal perforation. No studies have evaluated the efficacy of per rectum (PR) acetaminophen. The study aimed to evaluate the efficacy of PR acetaminophen in modulating the risk of PDA ligation.<\/jats:p><jats:p>\n            Study Design\u2003A retrospective matched case\u2013control study was conducted to compare neonates born &lt;29 weeks' gestation with evidence of hsDA, in an era when rescue rectal acetaminophen was used (January 2014\u2013March 2018) as a treatment strategy, versus historical controls (July 2006\u2013August 2012). All patients underwent comprehensive echocardiography assessment of ductal shunt volume according to a standardized protocol. Acetaminophen treated neonates were matched according to demographics, gestation, preintervention echocardiography features, and comorbidities. Control patients were selected when an echocardiography was performed at an equivalent postnatal age. Infants with a genetic syndrome, severe congenital malformation, or major forms of congenital heart disease excluding small atrial septal defect or ventricular septal defect, PDA, or patent formale ovale were excluded. The primary outcome was surgical ligation of the PDA. Secondary outcomes included echocardiography indices of hemodynamic significance, the composite of death, or severe BPD (defined by ventilator dependence at 36 weeks postmenstrual age). Descriptive statistics and univariate (t-tests, Fisher's exact test, and Mann\u2013Whitney U test) analyses were used to evaluate clinical and echocardiography characteristics of the groups and compare outcomes.<\/jats:p><jats:p>\n            Results\u2003Forty infants (20 cases and 20 controls), with similar demographic and echocardiography features, were compared. Cases received 6.8\u2009\u00b1\u20090.7 days (60\u2009mg\/kg\/day) of PR acetaminophen. Responders (n\u2009=\u200912, 60%) had echocardiography evidence of reduced ductal diameter (2.2\u2009mm [1.9\u20132.6] to 1.1\u2009mm [0\u20131.7], p\u2009=\u20090.002), left ventricular output (363\u2009\u00b1\u2009108\u2013249\u2009\u00b1\u200961\u2009mL\/min\/kg; p\u2009=\u20090.002) and left atrium to aortic root ratio (1.7\u2009\u00b1\u20090.3\u20131.3\u2009\u00b1\u20090.2; p\u2009=\u20090.002) following treatment. The rate of PDA ligation was 50% lower (p\u2009=\u20090.02) and composite outcome of death or severe bronchopulmonary dysplasia was reduced (p\u2009=\u20090.04) in the acetaminophen group.<\/jats:p><jats:p>\n            Conclusion\u2003Rectal acetaminophen was associated with improvement in echocardiography indices of PDA shunt volume, a 50% reduction in PDA ligation rates and a reduction in the composite outcome of death or severe BPD. Pharmacologic and further prospective clinical studies are needed.<\/jats:p><jats:p>\n            Key Points\n          <\/jats:p>","DOI":"10.1055\/s-0041-1735214","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T22:49:28Z","timestamp":1632869368000},"page":"1223-1231","source":"Crossref","is-referenced-by-count":3,"title":["Rectal Acetaminophen Improves Shunt Volume and Reduces Patent Ductus Arteriosus Ligation in Extremely Preterm Infants"],"prefix":"10.1055","volume":"40","author":[{"given":"Michael P.","family":"Castaldo","sequence":"additional","affiliation":[{"name":"Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaine","family":"Neary","sequence":"additional","affiliation":[{"name":"Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrianne R.","family":"Bischoff","sequence":"additional","affiliation":[{"name":"Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maura H.F.","family":"Resende","sequence":"additional","affiliation":[{"name":"Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dany E.","family":"Weisz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada"},{"name":"Newborn and Developmental Pediatrics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amish","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada"},{"name":"Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6227-6761","authenticated-orcid":false,"given":"Regan E.","family":"Giesinger","sequence":"additional","affiliation":[{"name":"Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada"},{"name":"Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick J.","family":"McNamara","sequence":"additional","affiliation":[{"name":"Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada"},{"name":"Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"issue":"05","key":"ref1","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1542\/peds.2009-3506","article-title":"Patent ductus arteriosus of the preterm infant","volume":"125","author":"S E Hamrick","year":"2010","journal-title":"Pediatrics"},{"issue":"06","key":"ref2","doi-asserted-by":"crossref","first-page":"F505","DOI":"10.1136\/archdischild-2013-303816","article-title":"Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3","volume":"98","author":"A Sellmer","year":"2013","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"issue":"04","key":"ref3","doi-asserted-by":"crossref","first-page":"F279","DOI":"10.1136\/archdischild-2011-300532","article-title":"Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants","volume":"97","author":"O Erdeve","year":"2012","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"issue":"04","key":"ref4","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jpeds.2010.10.008","article-title":"Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus","volume":"158","author":"T Gokmen","year":"2011","journal-title":"J Pediatr"},{"issue":"10","key":"ref5","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1056\/NEJM200009073431001","article-title":"A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus","volume":"343","author":"B Van Overmeire","year":"2000","journal-title":"N Engl J Med"},{"issue":"02","key":"ref6","first-page":"CD003481","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":"ref7","doi-asserted-by":"crossref","first-page":"423","DOI":"10.3109\/14767058.2012.733775","article-title":"Treatment of patent ductus arteriosus (PDA) using ibuprofen: renal side-effects in VLBW and ELBW newborns","volume":"26","author":"F Bagnoli","year":"2013","journal-title":"J Matern Fetal Neonatal Med"},{"issue":"09","key":"ref8","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1007\/s00467-008-0835-9","article-title":"Oral-ibuprofen-induced acute renal failure in a preterm infant","volume":"23","author":"O Erdeve","year":"2008","journal-title":"Pediatr Nephrol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/sj.jp.7210795","article-title":"Neonatal necrotizing enterocolitis with intestinal perforation in extremely premature infants receiving early indomethacin treatment for patent ductus arteriosus","volume":"22","author":"A M Fujii","year":"2002","journal-title":"J Perinatol"},{"issue":"03","key":"ref10","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/S0022-3468(99)90495-5","article-title":"Indomethacin-associated bowel perforations: a study of possible risk factors","volume":"34","author":"N A Shorter","year":"1999","journal-title":"J Pediatr Surg"},{"issue":"05","key":"ref11","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1007\/s00467-003-1402-z","article-title":"Indomethacin and renal impairment in neonates","volume":"19","author":"S Akima","year":"2004","journal-title":"Pediatr Nephrol"},{"issue":"04","key":"ref12","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1159\/000092870","article-title":"Mechanisms regulating the ductus arteriosus","volume":"89","author":"R I Clyman","year":"2006","journal-title":"Biol Neonate"},{"issue":"03","key":"ref13","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s10787-013-0172-x","article-title":"The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings","volume":"21","author":"G G Graham","year":"2013","journal-title":"Inflammopharmacology"},{"issue":"11","key":"ref14","doi-asserted-by":"crossref","first-page":"e77888","DOI":"10.1371\/journal.pone.0077888","article-title":"Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial","volume":"8","author":"D Dang","year":"2013","journal-title":"PLoS One"},{"issue":"03","key":"ref15","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.jpeds.2013.11.008","article-title":"Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial","volume":"164","author":"M Y Oncel","year":"2014","journal-title":"J Pediatr"},{"issue":"01","key":"ref16","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1159\/000355146","article-title":"Effect of positive end-expiratory pressure on ductal shunting and systemic blood flow in preterm infants with patent ductus arteriosus","volume":"105","author":"M F Fajardo","year":"2014","journal-title":"Neonatology"},{"issue":"06","key":"ref17","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/jp.2015.213","article-title":"The impact of a dedicated patent ductus arteriosus ligation team on neonatal health-care outcomes","volume":"36","author":"M H Resende","year":"2016","journal-title":"J Perinatol"},{"issue":"06","key":"ref18","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.jpeds.2009.01.005","article-title":"The role of patent ductus arteriosus ligation in bronchopulmonary dysplasia: reexamining a randomized controlled trial","volume":"154","author":"R Clyman","year":"2009","journal-title":"J Pediatr"},{"issue":"01","key":"ref19","doi-asserted-by":"crossref","first-page":"e138","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"},{"issue":"06","key":"ref20","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1016\/j.jpeds.2015.03.012","article-title":"Association between hemodynamically significant patent ductus arteriosus and bronchopulmonary dysplasia","volume":"166","author":"F Schena","year":"2015","journal-title":"J Pediatr"},{"issue":"06","key":"ref21","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/j.jpeds.2012.05.062","article-title":"Neurodevelopmental outcomes following two different treatment approaches (early ligation and selective ligation) for patent ductus arteriosus","volume":"161","author":"A C Wickremasinghe","year":"2012","journal-title":"J Pediatr"},{"issue":"06","key":"ref22","doi-asserted-by":"crossref","first-page":"F498","DOI":"10.1136\/adc.2005.092734","article-title":"Patent ductus arteriosus: lack of evidence for common treatments","volume":"92","author":"C L Bose","year":"2007","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"issue":"04","key":"ref23","doi-asserted-by":"crossref","first-page":"e1024","DOI":"10.1542\/peds.2013-3431","article-title":"PDA ligation and health outcomes: a meta-analysis","volume":"133","author":"D E Weisz","year":"2014","journal-title":"Pediatrics"},{"issue":"05","key":"ref24","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1001\/jamapediatrics.2016.5143","article-title":"Association of patent ductus arteriosus ligation with death or neurodevelopmental impairment among extremely preterm infants","volume":"171","author":"D E Weisz","year":"2017","journal-title":"JAMA Pediatr"},{"issue":"06","key":"ref25","doi-asserted-by":"crossref","first-page":"1100","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 F El-Khuffash","year":"2013","journal-title":"J Pediatr"},{"issue":"05","key":"ref26","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/s41372-018-0056-4","article-title":"Post-ligation cardiac syndrome is associated with increased morbidity in preterm infants","volume":"38","author":"T JB Ulrich","year":"2018","journal-title":"J Perinatol"},{"issue":"12","key":"ref27","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/jp.2008.101","article-title":"Postoperative cardiorespiratory instability following ligation of the preterm ductus arteriosus is related to early need for intervention","volume":"28","author":"L S Teixeira","year":"2008","journal-title":"J Perinatol"},{"issue":"08","key":"ref28","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/jp.2016.60","article-title":"Acetaminophen to avoid surgical ligation in extremely low gestational age neonates with persistent hemodynamically significant patent ductus arteriosus","volume":"36","author":"D E Weisz","year":"2016","journal-title":"J Perinatol"},{"issue":"06","key":"ref29","doi-asserted-by":"crossref","first-page":"e1618","DOI":"10.1542\/peds.2011-0359","article-title":"Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment","volume":"128","author":"C Hammerman","year":"2011","journal-title":"Pediatrics"},{"issue":"01","key":"ref30","doi-asserted-by":"crossref","first-page":"F94","DOI":"10.1136\/archdischild-2012-302044","article-title":"An alternative drug (paracetamol) in the management of patent ductus arteriosus in ibuprofen-resistant or contraindicated preterm infants","volume":"98","author":"M Y Oncel","year":"2013","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"issue":"04","key":"ref31","doi-asserted-by":"crossref","first-page":"312","DOI":"10.4103\/0022-3859.123164","article-title":"Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates","volume":"59","author":"B Jasani","year":"2013","journal-title":"J Postgrad Med"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"F253","DOI":"10.1136\/archdischild-2014-307930","article-title":"Late medical therapy of patent ductus arteriosus using intravenous paracetamol","volume":"100","author":"A T James","year":"2015","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"issue":"03","key":"ref33","first-page":"238","article-title":"Intravenous versus oral acetaminophen for pain: systematic review of current evidence to support clinical decision-making","volume":"68","author":"F Jibril","year":"2015","journal-title":"Can J Hosp Pharm"},{"issue":"01","key":"ref34","doi-asserted-by":"crossref","first-page":"F59","DOI":"10.1136\/fn.80.1.F59","article-title":"Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates","volume":"80","author":"R A van Lingen","year":"1999","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"issue":"06","key":"ref35","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1542\/peds.55.6.818","article-title":"Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion","volume":"55","author":"G Levy","year":"1975","journal-title":"Pediatrics"},{"issue":"03","key":"ref36","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/cpt1976193284","article-title":"Acetaminophen elimination kinetics in neonates, children, and adults","volume":"19","author":"R P Miller","year":"1976","journal-title":"Clin Pharmacol Ther"},{"issue":"08","key":"ref37","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1136\/adc.58.8.631","article-title":"Neonatal paracetamol poisoning: treatment by exchange transfusion","volume":"58","author":"S Lederman","year":"1983","journal-title":"Arch Dis Child"},{"issue":"02","key":"ref38","doi-asserted-by":"crossref","first-page":"F127","DOI":"10.1136\/archdischild-2014-307312","article-title":"Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis","volume":"101","author":"G Terrin","year":"2016","journal-title":"Arch Dis Child Fetal Neonatal Ed"},{"issue":"06","key":"ref39","doi-asserted-by":"crossref","first-page":"485","DOI":"10.2165\/00003088-198005060-00001","article-title":"Clinical pharmacokinetics in newborns and infants. Age-related differences and therapeutic implications","volume":"5","author":"P L Morselli","year":"1980","journal-title":"Clin Pharmacokinet"}],"container-title":["American Journal of Perinatology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/s-0041-1735214.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T11:08:13Z","timestamp":1730804893000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/s-0041-1735214"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,28]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,7,29]]},"published-print":{"date-parts":[[2023,8]]}},"URL":"https:\/\/doi.org\/10.1055\/s-0041-1735214","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0735-1631","1098-8785"],"issn-type":[{"value":"0735-1631","type":"print"},{"value":"1098-8785","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,28]]}}}