{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:31:42Z","timestamp":1787697102282,"version":"build-2784847793"},"reference-count":35,"publisher":"American Academy of Pediatrics (AAP)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1998,3,1]]},"abstract":"<jats:p>Objectives.\u2003To assess the dose-related effects of inhaled nitric oxide (I-NO) as a specific adjunct to early conventional therapy for term infants with persistent pulmonary hypertension (PPHN), with regard to neonatal outcome, oxygenation, and safety.<\/jats:p><jats:p>Methods.\u2003Randomized, placebo-controlled, double-masked, dose-response, clinical trial at 25 tertiary centers from April 1994 to June 1996. The primary endpoint was the PPHN Major Sequelae Index ([MSI], including the incidence of death, extracorporeal membrane oxygenation (ECMO), neurologic injury, or bronchopulmonary dysplasia [BPD]). Patients required a fraction of inspired oxygen [Fio2] of 1.0, a mean airway pressure \u226510 cm H2O on a conventional ventilator, and echocardiographic evidence of PPHN. Exogenous surfactant, concomitant high-frequency ventilation, and lung hypoplasia were exclusion factors. Control (0 ppm) or nitric oxide (NO) (5, 20, or 80 ppm) treatments were administered until success or failure criteria were met. Due to slowing recruitment, the trial was stopped at N = 155 (320 planned).<\/jats:p><jats:p>Results.\u2003The baseline oxygenation index (OI) was 24 \u00b1 9 at 25 \u00b1 17 hours old (mean \u00b1 SD). Efficacy results were similar among NO doses. By 30 minutes (no ventilator changes) the Pao2 for only the NO groups increased significantly from 64 \u00b1 39 to 109 \u00b1 78 Torr (pooled) and systemic arterial pressure remained unchanged. The baseline adjusted time-weighted OI was also significantly reduced in the NO groups (-5 \u00b1 8) for the first 24 hours of treatment. The MSI rate was 59% for the control and 50% for the NO doses (P = .36). The ECMO rate was 34% for control and 22% for the NO doses (P = .12). Elevated methemoglobin (&amp;gt;7%) and nitrogen dioxide (NO2) (&amp;gt;3 ppm) were observed only in the 80 ppm NO group, otherwise no adverse events could be attributed to I-NO, including BPD.<\/jats:p><jats:p>Conclusion.\u2003For term infants with PPHN, early I-NO as the sole adjunct to conventional management produced an acute and sustained improvement in oxygenation for 24 hours without short-term side effects (5 and 20 ppm doses), and the suggestion that ECMO use may be reduced.<\/jats:p>","DOI":"10.1542\/peds.101.3.325","type":"journal-article","created":{"date-parts":[[2004,8,13]],"date-time":"2004-08-13T23:44:32Z","timestamp":1092440672000},"page":"325-334","source":"Crossref","is-referenced-by-count":288,"title":["Inhaled Nitric Oxide for the Early Treatment of Persistent Pulmonary Hypertension of the Term Newborn: A Randomized, Double-Masked, Placebo-Controlled, Dose-Response, Multicenter Study"],"prefix":"10.1542","volume":"101","author":[{"given":"Dennis","family":"Davidson","sequence":"first","affiliation":[{"name":"From the Departments of Pediatrics,"},{"name":"Schneider Children's Hospital, Long Island Jewish Medical Center, Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York; the"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine S.","family":"Barefield","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics,"},{"name":"University of Alabama, Birmingham, Alabama; the"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Kattwinkel","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics,"},{"name":"University of Virginia, Charlottesville, Virginia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Golde","family":"Dudell","sequence":"additional","affiliation":[{"name":"From the Departments of Pediatrics,"},{"name":"San Diego Children's Hospital, San Diego, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Damask","sequence":"additional","affiliation":[{"name":"Ohmeda, PPD, Liberty Corner, New Jersey."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Straube","sequence":"additional","affiliation":[{"name":"Ohmeda, PPD, Liberty Corner, New Jersey."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared","family":"Rhines","sequence":"additional","affiliation":[{"name":"Ohmeda, PPD, Liberty Corner, New Jersey."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Tao","family":"Chang","sequence":"additional","affiliation":[{"name":"Ohmeda, PPD, Liberty Corner, New Jersey."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the I-NO\/PPHN Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[1998,3,1]]},"reference":[{"key":"2021121000254701100_B1","first-page":"87","article-title":"\u2018PFC\u2019 Syndrome (Persistence of the fetal circulation).","volume":"40(suppl 3)","author":"Gersony","year":"1969","journal-title":"Circulation."},{"key":"2021121000254701100_B2","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1164\/ajrccm.151.6.7767553","article-title":"Persistent pulmonary hypertension of the newborn: state of the art.","volume":"151","author":"Morin","year":"1995","journal-title":"Am J Resp Crit Car Med."},{"key":"2021121000254701100_B3","doi-asserted-by":"crossref","first-page":"202A","DOI":"10.1203\/00006450-199704001-01218","article-title":"Diagnoses associated with the delivery of mechanical ventilation in the newborn.","volume":"41","author":"Linde-Zwirble","year":"1997","journal-title":"Pediatr Res."},{"key":"2021121000254701100_B4","first-page":"244A","article-title":"Persistent pulmonary hypertension of the newborn (PPHN): prospective, multicenter study of treatments and outcome.","volume":"37","author":"Walsh-Sukys","year":"1995","journal-title":"Pediatr Res."},{"key":"2021121000254701100_B5","first-page":"369","article-title":"National survey of diagnosis and management of persistent pulmonary hypertension of the newborn.","volume":"10","author":"Weigel","year":"1990","journal-title":"J Perinatol."},{"key":"2021121000254701100_B6","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0022-3476(94)70354-X","article-title":"A decade of experience with neonatal extracorporeal membrane oxygenation.","volume":"124","author":"Kanto","year":"1994","journal-title":"J Pediatr."},{"key":"2021121000254701100_B7","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1097\/00000658-199409000-00004","article-title":"Extracorporeal life support for neonatal respiratory failure\u2014a 20-year experience.","volume":"220","author":"Shanley","year":"1994","journal-title":"Ann Surg."},{"key":"2021121000254701100_B8","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/0140-6736(92)92686-A","article-title":"Inhaled nitric oxide in persistent pulmonary hypertension of the newborn.","volume":"340","author":"Roberts","year":"1992","journal-title":"Lancet."},{"key":"2021121000254701100_B9","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/0140-6736(92)92687-B","article-title":"Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn.","volume":"340","author":"Kinsella","year":"1992","journal-title":"Lancet."},{"key":"2021121000254701100_B10","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1164\/ajrccm.149.4.8143049","article-title":"Eicosanoids decrease with successful extracorporeal membrane oxygenation therapy in neonatal pulmonary hypertension.","volume":"149","author":"Dobyns","year":"1994","journal-title":"Am J Respir Crit Care Med."},{"key":"2021121000254701100_B11","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1152\/jappl.1992.72.4.1320","article-title":"Prophylactic effects of dexamethasone in lung injury caused by hyperoxia and hyperventilation.","volume":"72","author":"Davis","year":"1992","journal-title":"J Appl Physiol."},{"key":"2021121000254701100_B12","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1161\/01.RES.72.2.246","article-title":"Inhaled nitric oxide reverse pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb.","volume":"72","author":"Roberts","year":"1993","journal-title":"Circ Res."},{"key":"2021121000254701100_B13","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0022-3476(05)81551-3","article-title":"Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide.","volume":"123","author":"Kinsella","year":"1993","journal-title":"J Pediatr."},{"key":"2021121000254701100_B14","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/S0022-3476(94)70324-8","article-title":"Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response.","volume":"124","author":"Finer","year":"1994","journal-title":"J Pediatr."},{"key":"2021121000254701100_B15","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0140-6736(94)91341-2","article-title":"Echocardiographic investigation of inhaled nitric oxide in newborns with severe hypoxemia.","volume":"344","author":"Roze\u0301","year":"1994","journal-title":"Lancet."},{"key":"2021121000254701100_B16","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1164\/ajrccm\/147.5.1078","article-title":"NO bandwagon, yet: Inhaled nitric oxide (NO) for neonatal pulmonary hypertension.","volume":"147","author":"Davidson","year":"1993","journal-title":"Am Rev Respir Dis."},{"key":"2021121000254701100_B17","first-page":"A103","article-title":"Monitoring accuracy for the measurement of nitric oxide in the 0 to 80 ppm range.","volume":"24","author":"Bathe","year":"1996","journal-title":"Crit Care Med."},{"key":"2021121000254701100_B18"},{"key":"2021121000254701100_B19","first-page":"21","article-title":"Recommendations for occupational safety and health standards.","volume":"37(suppl)","author":"Centers for Disease Control","year":"1988","journal-title":"MMWR."},{"key":"2021121000254701100_B20"},{"key":"2021121000254701100_B21","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1056\/NEJM199702273360901","article-title":"Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure.","volume":"336","author":"The Neonatal Inhaled Nitric Oxide Study Group","year":"1997","journal-title":"N Engl J Med."},{"key":"2021121000254701100_B22","doi-asserted-by":"crossref","first-page":"226A","DOI":"10.1203\/00006450-199604001-01364","article-title":"Survanta pre-ECMO trial: multicenter evaluation of Survanta in treatment of term infants with severe respiratory failure.","volume":"39","author":"Lotze","year":"1996","journal-title":"Pediatr Res."},{"key":"2021121000254701100_B23","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1542\/peds.97.1.48","article-title":"Surfactant replacement therapy for meconium aspiration syndrome.","volume":"97","author":"Findlay","year":"1996","journal-title":"Pediatrics."},{"key":"2021121000254701100_B24","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0022-3476(94)70374-4","article-title":"Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in candidates for extracorporeal membrane oxygenation.","volume":"124","author":"Clark","year":"1994","journal-title":"J Pediatr."},{"key":"2021121000254701100_B25","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":"2021121000254701100_B26","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1542\/peds.98.6.1035","article-title":"High-frequency jet ventilation in the early management of respiratory distress syndrome is associated with a greater risk of adverse outcomes.","volume":"98","author":"Wiswell","year":"1996","journal-title":"Pediatrics."},{"key":"2021121000254701100_B27","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1542\/peds.96.6.1147","article-title":"Inhaled nitric oxide for persistent pulmonary hypertension of the newborn: implications and strategy for future \u201chigh-tech\u201d neonatal clinical trials.","volume":"96","author":"Stark","year":"1995","journal-title":"Pediatrics."},{"key":"2021121000254701100_B28","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0140-6736(96)04100-1","article-title":"UK collaborative randomized trial of neonatal extracorporeal membrane oxygenation.","volume":"348","author":"UK Collaborative ECMO Trial Group","year":"1996","journal-title":"Lancet."},{"key":"2021121000254701100_B29","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1056\/NEJM199702273360902","article-title":"Inhaled nitric oxide and persistent pulmonary hypertension of the newborn.","volume":"336","author":"Roberts","year":"1997","journal-title":"N Engl J Med."},{"key":"2021121000254701100_B30","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1016\/0140-6736(93)90802-N","article-title":"Bleeding time prolongation and NO inhalation.","volume":"341","author":"Ho\u0308gman","year":"1993","journal-title":"Lancet."},{"key":"2021121000254701100_B31","doi-asserted-by":"crossref","first-page":"79S","DOI":"10.1378\/chest.105.3_Supplement.79S","article-title":"Free radical chemistry of nitric oxide.","volume":"105","author":"Freeman","year":"1994","journal-title":"Chest."},{"key":"2021121000254701100_B32","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1097\/00003246-199406000-00009","article-title":"Delivery and monitoring of inhaled nitric oxide in patients with pulmonary hypertension.","volume":"22","author":"Wessel","year":"1994","journal-title":"Crit Care Med."},{"key":"2021121000254701100_B33","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1016\/0140-6736(92)91886-D","article-title":"Safety guidelines for use of nitric oxide.","volume":"339","author":"Foubert","year":"1992","journal-title":"Lancet."},{"key":"2021121000254701100_B34","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0140-6736(95)92681-X","article-title":"Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide.","volume":"346","author":"Miller","year":"1995","journal-title":"Lancet."},{"key":"2021121000254701100_B35","doi-asserted-by":"crossref","first-page":"F118","DOI":"10.1136\/fn.76.2.F118","article-title":"Weaning strategy with inhaled nitric oxide treatment in persistent pulmonary hypertension of the newborn.","volume":"76","author":"Aly","year":"1997","journal-title":"Arch Dis Child."}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/101\/3\/325\/828304\/325.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/101\/3\/325\/828304\/325.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T05:32:33Z","timestamp":1682746353000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/101\/3\/325\/61929\/Inhaled-Nitric-Oxide-for-the-Early-Treatment-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,3,1]]},"references-count":35,"journal-issue":{"issue":"3","published-online":{"date-parts":[[1998,3,1]]},"published-print":{"date-parts":[[1998,3,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.101.3.325","relation":{},"ISSN":["1098-4275","0031-4005"],"issn-type":[{"value":"1098-4275","type":"electronic"},{"value":"0031-4005","type":"print"}],"subject":[],"published":{"date-parts":[[1998,3,1]]}}}