{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T14:46:10Z","timestamp":1785249970046,"version":"3.55.0"},"reference-count":34,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Reports"],"abstract":"<jats:p>Background: Persistent pulmonary hypertension of the newborn (PPHN) remains a life-threatening condition resulting from failure of postnatal circulatory adaptation. Inhaled nitric oxide (iNO) is the standard first-line therapy; however, limited access or inadequate response highlight the need for alternative treatments. Milrinone, a selective phosphodiesterase-3 inhibitor with nitric oxide-independent vasodilatory and inotropic properties, has been proposed as one such option. Methods: In this study we present a case series of three neonates with PPHN\u2014term (41 weeks), late preterm (35 weeks), and extremely preterm (23 weeks)\u2014treated with intravenous milrinone in a neonatal unit without immediate access to iNO. A narrative literature review was also conducted, focusing on clinical outcomes, safety, and therapeutic applicability. Results: Milrinone was initiated within the first 24 h of life. In the term and late-preterm infants, oxygenation and echocardiographic parameters improved within 48 h, with normalization of shunt direction and successful extubation by days 4\u201310. Transient systemic hypotension occurred in both cases and required dose adjustment or vasoactive support. In the extremely preterm neonate, only temporary hemodynamic improvement was achieved, followed by severe intraventricular hemorrhage and coagulopathy, possibly exacerbated by vasodilatory and antiplatelet effects of milrinone. Conclusions: Milrinone may serve as a feasible adjunct or bridging therapy for PPHN when iNO is unavailable. However, its use requires careful hemodynamic and neurological monitoring, particularly in very preterm infants. Further studies are needed to confirm safety and define optimal dosing across gestational ages.<\/jats:p>","DOI":"10.3390\/pediatric17060116","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:15:14Z","timestamp":1762175714000},"page":"116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Can Milrinone Be a Therapeutic Alternative in Persistent Pulmonary Hypertension of the Newborn? A Case Series and Narrative Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5288-0586","authenticated-orcid":false,"given":"Eliza","family":"Wasilewska","sequence":"first","affiliation":[{"name":"Department of Allergology, Medical University of Gda\u0144sk, 80-211 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9250-0517","authenticated-orcid":false,"given":"Norbert","family":"Dera","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Perinatology and Neonatology, Center of Postgraduate Medical Education, 01-809 Warsaw, Poland"},{"name":"Warsaw Institute of Women\u2019s Health, 00-189 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2536-3508","authenticated-orcid":false,"given":"\u0141ukasz","family":"Minarowski","sequence":"additional","affiliation":[{"name":"Head of Department of Respiratory Pathophysiology, Faculty of Health Sciences, Medical University of Bialystok, 15-540 Bia\u0142ystok, Poland"},{"name":"2nd Department of Lung Diseases, Lung Cancer and Internal Diseases, University Teaching Hospital, 15-540 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0141ukasz","family":"Osi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Neonatal Intensive Care, Regional Specialist Hospital in Olsztyn, 10-452 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Doboszynska","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, School of Public Health, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6556-5008","authenticated-orcid":false,"given":"S\u0142awomir","family":"Szajda","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, University of Warmia and Mazury, 10-719 Olszty, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9595-0628","authenticated-orcid":false,"given":"Alina","family":"Minarowska","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, School of Public Health, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland"},{"name":"Outpatient Cystic Fibrosis Clinic, Department of Pediatrics, Gastroenterology, Hepatology, Nutrition, Allergology and Pulmonology, Children\u2019s University Hospital in Bialystok, 15-274 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1161\/CIR.0000000000000329","article-title":"Pediatric Pulmonary Hypertension: Guidelines from the American Heart Association and American Thoracic Society","volume":"132","author":"Abman","year":"2015","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1055\/a-1711-0778","article-title":"Evidence-Based Guidelines for Acute Stabilization and Management of Neonates with Persistent Pulmonary Hypertension of the Newborn","volume":"40","author":"Ball","year":"2023","journal-title":"Am. J. Perinatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1002\/j.2040-4603.2021.tb00176.x","article-title":"Pediatric Pulmonary Hypertension: Definitions, Mechanisms, Diagnosis, and Treatment","volume":"11","author":"Mukherjee","year":"2021","journal-title":"Compr. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"ii49","DOI":"10.1136\/heartjnl-2015-308591","article-title":"Pulmonary hypertension associated with acute or chronic lung diseases in the preterm and term neonate and infant. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK","volume":"102","author":"Hilgendorff","year":"2016","journal-title":"Heart"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e680","DOI":"10.1542\/neo.16-12-e680","article-title":"Persistent Pulmonary Hypertension of the Newborn","volume":"16","author":"Lakshminrusimha","year":"2015","journal-title":"Neoreviews"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0022-3476(97)70124-0","article-title":"Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn","volume":"131","author":"Kinsella","year":"1997","journal-title":"J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Nelin, L.D., and Potenziano, J.L. (2019). Inhaled nitric oxide for neonates with persistent pulmonary hypertension of the newborn in the CINRGI study: Time to treatment response. BMC Pediatr., 19.","DOI":"10.1186\/s12887-018-1368-4"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.clp.2023.11.001","article-title":"Inhaled Nitric Oxide in Neonatal Pulmonary Hypertension","volume":"51","author":"Cookson","year":"2024","journal-title":"Clin. Perinatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e17139","DOI":"10.1097\/MD.0000000000017139","article-title":"Effect of NO inhalation on ECMO use rate and mortality in infants born at or near term with respiratory failure","volume":"98","author":"Wang","year":"2019","journal-title":"Medicine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1590\/S0041-87812000000400006","article-title":"Inhaled nitric oxide in the management of persistent pulmonary hypertension of the newborn: A meta-analysis","volume":"55","author":"Oliveira","year":"2000","journal-title":"Rev. Hosp. Clin."},{"key":"ref_11","first-page":"CD000399","article-title":"Nitric oxide for respiratory failure in infants born at or near term","volume":"1","author":"Barrington","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1055\/a-2419-0021","article-title":"Clinical Analysis of Inhaled Nitric Oxide Therapy in Preterm Infants at Different Gestational Ages: A National Retrospective Multicenter Study","volume":"42","author":"Liang","year":"2025","journal-title":"Am. J. Perinatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1007\/s00431-021-04138-4","article-title":"Life-threatening PPHN refractory to nitric oxide: Proposal for a rational therapeutic algorithm","volume":"180","author":"Fortas","year":"2021","journal-title":"Eur. J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1053\/j.semperi.2015.12.004","article-title":"Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide","volume":"40","author":"Lakshminrusimha","year":"2016","journal-title":"Semin. Perinatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1017\/S1047951114002698","article-title":"The effect of milrinone on right and left ventricular function when used as a rescue therapy for term infants with pulmonary hypertension","volume":"26","author":"James","year":"2016","journal-title":"Cardiol. Young"},{"key":"ref_16","unstructured":"(2025, August 24). Australian Neonatal Medicines Formulary (ANMF) Guidelines. Milrinone Dosing in Neonates. 2021. Milrinone, Newborn Use Only. Available online: https:\/\/www.anmfonline.org\/wp-content\/uploads\/2021\/06\/milrinone-18022021-3.0.pdf."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jclinepi.2013.08.003","article-title":"The CARE guidelines: Consensus-based clinical case report guideline development","volume":"67","author":"Gagnier","year":"2014","journal-title":"J. Clin. Epidemiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bassler, D., Kreutzer, K., McNamara, P., and Kirpalani, H. (2010). Milrinone for persistent pulmonary hypertension of the newborn. Cochrane Database Syst. Rev., CD007802.","DOI":"10.1002\/14651858.CD007802.pub2"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.jcrc.2006.01.001","article-title":"Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn","volume":"21","author":"McNamara","year":"2006","journal-title":"J. Crit. Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000088192","article-title":"Neonatal persistent pulmonary hypertension treated with milrinone: Four case reports","volume":"89","author":"Bassler","year":"2006","journal-title":"Biol. Neonate"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1097\/PCC.0b013e31824ea2cd","article-title":"Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxide","volume":"14","author":"McNamara","year":"2013","journal-title":"Pediatr. Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.1002\/ppul.26451","article-title":"Comparison of the efficacy of inhaled versus infused milrinone in the management of persistent pulmonary hypertension of the newborn in resource-limited settings: A randomized clinical trial","volume":"58","author":"Choobdar","year":"2023","journal-title":"Pediatr. Pulmonol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s40748-018-0093-1","article-title":"The use of milrinone in neonates with persistent pulmonary hypertension of the newborn\u2014A randomised controlled trial pilot study (MINT 1): Study protocol and review of literature","volume":"4","author":"McNamara","year":"2018","journal-title":"Matern. Health Neonatol. Perinatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1055\/s-0036-1597996","article-title":"Pharmacokinetics and Pharmacodynamics in Neonates with Persistent Pulmonary Hypertension of the Newborn","volume":"34","author":"Giaccone","year":"2017","journal-title":"Am. J. Perinatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41372-021-01228-x","article-title":"Worsened short-term clinical outcomes in a cohort of patients with iNO-unresponsive PPHN: A case for improving iNO responsiveness","volume":"42","author":"Dillard","year":"2022","journal-title":"J. Perinatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s40272-020-00412-4","article-title":"Efficacy of Milrinone Plus Sildenafil in the Treatment of Neonates with Persistent Pulmonary Hypertension in Resource-Limited Settings: Results of a Randomized, Double-Blind Trial","volume":"22","author":"Hammad","year":"2020","journal-title":"Paediatr. Drugs."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1097\/FJC.0000000000001332","article-title":"Milrinone Versus Sildenafil in Treatment of Neonatal Persistent Pulmonary Hypertension: A Randomized Control Trial","volume":"80","author":"Imam","year":"2022","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e165","DOI":"10.1542\/neo.21-3-e165","article-title":"Milrinone Use in Persistent Pulmonary Hypertension of the Newborn","volume":"21","author":"Qasim","year":"2020","journal-title":"Neoreviews"},{"key":"ref_29","first-page":"1","article-title":"Persistent Pulmonary Hypertension of the Newborn: Recent Advances in the Management","volume":"2","author":"Agrawal","year":"2013","journal-title":"Int. J. Clin. Pediatr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1080\/21678707.2024.2383172","article-title":"Management of pulmonary hypertension in infants","volume":"12","author":"Darren","year":"2024","journal-title":"Expert Opin. Orphan Drugs"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1038\/s41390-024-03234-z","article-title":"Milrinone in persistent pulmonary hypertension of newborn: A scoping review","volume":"96","author":"Galis","year":"2024","journal-title":"Pediatr. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s00431-023-05342-0","article-title":"Reassessing the role of milrinone in the treatment of heart failure and pulmonary hypertension in neonates and children: A systematic review and meta-analysis","volume":"183","author":"Matsushita","year":"2024","journal-title":"Eur. J. Pediatr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e314","DOI":"10.1097\/CCM.0000000000006227","article-title":"Comparison of Different Treatments of Persistent Pulmonary Hypertension of the Newborn: A Systematic Review and Network Meta-Analysis","volume":"52","author":"Fei","year":"2024","journal-title":"Crit. Care Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.clp.2020.05.006","article-title":"Updates on Management for Acute and Chronic Phenotypes of Neonatal Pulmonary Hypertension","volume":"47","author":"Ruoss","year":"2020","journal-title":"Clin. Perinatol."}],"container-title":["Pediatric Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2036-7503\/17\/6\/116\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T13:45:25Z","timestamp":1762263925000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2036-7503\/17\/6\/116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,3]]},"references-count":34,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["pediatric17060116"],"URL":"https:\/\/doi.org\/10.3390\/pediatric17060116","relation":{},"ISSN":["2036-7503"],"issn-type":[{"value":"2036-7503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,3]]}}}