{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T01:52:35Z","timestamp":1785289955772,"version":"3.55.0"},"reference-count":47,"publisher":"American Academy of Pediatrics (AAP)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1997,6,1]]},"abstract":"<jats:p>Objective.\u2003We designed and conducted a randomized, double-masked, controlled multicenter study to determine whether inhaled nitric oxide (INO) in term and near-term infants with congenital diaphragmatic hernia (CDH) would reduce the occurrence of death and\/or the initiation of extracorporeal membrane oxygenation (ECMO).<\/jats:p><jats:p>Patients and Methods.\u2003Infants of 34 weeks gestation or more, &amp;lt;14 days of age with CDH, without known structural heart disease, requiring assisted ventilation for hypoxemic respiratory failure with two oxygenation indices (OIs) of 25 or more at least 15 minutes apart, were eligible for this trial. Infants were centrally randomized and then received masked treatment with 20 ppm NO or 100% oxygen as control. Infants with less than a full response to 20 ppm NO (increase in Pao2 &amp;gt;20 Torr) after 30 minutes were evaluated at 80 ppm NO\/control study gas.<\/jats:p><jats:p>Results.\u2003The 28 control and 25 treated infants enrolled by the 13 participating centers were not significantly different at randomization for any of the measured variables including prerandomization therapies and initial OIs (45.8 \u00b1 16.3 for controls, 44.5 \u00b1 14.5 for INO). Death at &amp;lt;120 days of age or the need for ECMO occurred in 82% of control infants compared with 96% of INO infants (ns). Death occurred in 43% of controls and 48% of the INO group (ns), and ECMO treatment was used for 54% of control and 80% of INO-treated infants. There was no significant improvement in Pao2 (\u0394 Pao2 7.8 \u00b1 19.8 vs 1.1 \u00b1 7.6 Torr, ns) nor significant reduction in OI (-2.7 \u00b1 23.4 vs 4.0 \u00b1 14.8, ns) associated with INO treatment. Mean peak nitrogen dioxide (NO2) concentration was 1.9 \u00b1 1.3 ppm and the mean peak methemoglobin was 1.6 \u00b1 0.8 mg\/dL. No infant had study gas discontinued for toxicity. There were no differences between the control and INO groups for the occurrence of intracranial hemorrhage, specific grades of intracranial hemorrhage, periventricular leukomalacia, brain infarction, and pulmonary or gastrointestinal hemorrhages.<\/jats:p><jats:p>Conclusions.\u2003Although the immediate short-term improvements in oxygenation seen in some treated infants may be of benefit in stabilizing responding infants for transport and initiation of ECMO, we conclude that for term and near-term infants with CDH and hypoxemic respiratory failure unresponsive to conventional therapy, inhaled NO therapy as used in this trial did not reduce the need for ECMO or death.<\/jats:p>","DOI":"10.1542\/peds.99.6.838","type":"journal-article","created":{"date-parts":[[2004,8,13]],"date-time":"2004-08-13T23:40:17Z","timestamp":1092440417000},"page":"838-845","source":"Crossref","is-referenced-by-count":402,"title":["Inhaled Nitric Oxide and Hypoxic Respiratory Failure in Infants With Congenital Diaphragmatic Hernia"],"prefix":"10.1542","volume":"99","author":[{"name":"The Neonatal Inhaled Nitric Oxide Study Group (NINOS)","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[1997,6,1]]},"reference":[{"key":"2021121023201895400_B1","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/0022-3468(95)90565-0","article-title":"Cost per anomaly: what does a diaphragmatic hernia cost?","volume":"30","author":"Metkus","year":"1995","journal-title":"J Pediatr Surg."},{"key":"2021121023201895400_B2","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1001\/jama.1994.03510290064038","article-title":"A prospective study of the outcome for fetuses with diaphragmatic hernia.","volume":"271","author":"Harrison","year":"1994","journal-title":"JAMA."},{"key":"2021121023201895400_B3","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0022-3476(96)70218-4","article-title":"You gotta have heart.","volume":"129","author":"Irish","year":"1996","journal-title":"J Pediatr."},{"key":"2021121023201895400_B4","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0022-3476(05)83293-7","article-title":"Evaluation of left ventricular mass in children with left-sided congenital diaphragmatic hernia.","volume":"125","author":"Schwartz","year":"1994","journal-title":"J Pediatr."},{"key":"2021121023201895400_B5"},{"key":"2021121023201895400_B6","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0140-6736(05)65240-3","article-title":"UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation.","volume":"348","author":"Field","year":"1996","journal-title":"Lancet."},{"key":"2021121023201895400_B7","first-page":"694","volume":"44","author":"Economic costs of birth defects and cerebral palsy\u2014United States, 1992","year":"1995","journal-title":"MMWR."},{"key":"2021121023201895400_B8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1161\/01.RES.65.1.1","article-title":"Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein.","volume":"65","author":"Ignarro","year":"1989","journal-title":"Circ Res."},{"key":"2021121023201895400_B9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1096\/fasebj.3.1.2642868","article-title":"Endothelium-derived nitric oxide: actions and properties.","volume":"3","author":"Ignarro","year":"1989","journal-title":"FASEB J."},{"key":"2021121023201895400_B10","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1152\/jappl.1990.68.2.735","article-title":"Comparison of the hemodynamic effects of nitric oxide and endothelium-dependent vasodilators in intact lungs.","volume":"68","author":"Archer","year":"1990","journal-title":"J Appl Physiol."},{"key":"2021121023201895400_B11","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1096\/fasebj.3.9.2545495","article-title":"Endothelium-derived relaxing and contracting factors.","volume":"3","author":"Furchgott","year":"1989","journal-title":"FASEB J."},{"key":"2021121023201895400_B12","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/327524a0","article-title":"Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.","volume":"327","author":"Palmer","year":"1987","journal-title":"Nature."},{"key":"2021121023201895400_B13","doi-asserted-by":"crossref","first-page":"9265","DOI":"10.1073\/pnas.84.24.9265","article-title":"Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.","volume":"84","author":"Ignarro","year":"1987","journal-title":"Proc Natl Acad Sci USA."},{"key":"2021121023201895400_B14","first-page":"211","article-title":"Relaxation of bovine coronary artery and activation of coronary arterial guanylate cyclase by nitric oxide, nitroprusside, and a carcinogenic nitrosoamine.","volume":"5","author":"Gruetter","year":"1979","journal-title":"J Cyclic Nucleotide Res."},{"key":"2021121023201895400_B15","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1016\/S0006-291X(88)81362-7","article-title":"L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation.","volume":"153","author":"Palmer","year":"1988","journal-title":"Biochem Biophys Res Commun."},{"key":"2021121023201895400_B16","doi-asserted-by":"crossref","first-page":"4997","DOI":"10.1016\/S0021-9258(19)89205-0","article-title":"Activation of soluble guanylate cyclase by NO-hemoproteins involves NO-heme exchange.","volume":"261","author":"Ignarro","year":"1986","journal-title":"J Biol Chem."},{"key":"2021121023201895400_B17","first-page":"L393","article-title":"Hydrogen peroxide-induced pulmonary vasodilation: role of guanosine 3\u2032,5\u2032-cyclic monophosphate.","volume":"261","author":"Burke-Wolin","year":"1991","journal-title":"Am J Physiol."},{"key":"2021121023201895400_B18","first-page":"42","article-title":"Physiological role of cGMP and cGMP-dependent protein kinase in the cardiovascular system.","volume":"113","author":"Walter","year":"1989","journal-title":"Rev Physiol Biochem Pharmacol."},{"key":"2021121023201895400_B19","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1161\/01.CIR.83.6.2038","article-title":"Inhaled nitric oxide\u2013a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction.","volume":"83","author":"Frostell","year":"1991","journal-title":"Circulation."},{"key":"2021121023201895400_B20","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1097\/00000542-199112000-00011","article-title":"Inhaled nitric oxide: a selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep.","volume":"75","author":"Fratacci","year":"1991","journal-title":"Anesthesiology."},{"key":"2021121023201895400_B21","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1161\/01.RES.72.2.246","article-title":"Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb.","volume":"72","author":"Roberts","year":"1993","journal-title":"Circ Res."},{"key":"2021121023201895400_B22","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S0022-3476(06)80020-X","article-title":"Treatment of persistent pulmonary hypertension in the newborn lamb by inhaled nitric oxide.","volume":"122","author":"Zayek","year":"1993","journal-title":"J Pediatr."},{"key":"2021121023201895400_B23","first-page":"A107","article-title":"Wallwork J. Inhaled \u201cendothelium-derived relaxing factor\u201d (EDRF) in primary hypertension (PPH).","volume":"137","author":"Higenbottam","year":"1988","journal-title":"Am Rev Respir Dis."},{"key":"2021121023201895400_B24","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/0140-6736(91)92033-X","article-title":"Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension.","volume":"338","author":"Pepke-Zaba","year":"1991","journal-title":"Lancet."},{"key":"2021121023201895400_B25","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1056\/NEJM199302113280605","article-title":"Inhaled nitric oxide for the adult respiratory distress syndrome.","volume":"328","author":"Rossaint","year":"1993","journal-title":"N Engl J Med."},{"key":"2021121023201895400_B26","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":"2021121023201895400_B27","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":"2021121023201895400_B28","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0022-3476(05)81551-3","article-title":"Shaffer E, Abman SH. 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":"2021121023201895400_B29","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":"2021121023201895400_B30","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1542\/peds.94.5.715","article-title":"Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios.","volume":"94","author":"Karamanoukian","year":"1994","journal-title":"Pediatrics."},{"key":"2021121023201895400_B31","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/0022-3468(94)90269-0","article-title":"Inhaled nitric oxide in congenital diaphragmatic hernia.","volume":"29","author":"Shah","year":"1994","journal-title":"J Pediatr Surg."},{"key":"2021121023201895400_B32","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/j.1365-2044.1993.tb07179.x","article-title":"Near fatal pulmonary hypertension after surgical repair of congenital diaphragmatic hernia.","volume":"48","author":"Frostell","year":"1993","journal-title":"Anesthesia."},{"key":"2021121023201895400_B33","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":"2021121023201895400_B34","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/0022-3468(95)90763-7","article-title":"Inhalation of nitric oxide as a treatment of pulmonary hypertension in congenital diaphragmatic hernia.","volume":"30","author":"Henneberg","year":"1995","journal-title":"J Pediatr Surg."},{"key":"2021121023201895400_B35","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":"2021121023201895400_B36","doi-asserted-by":"crossref","first-page":"353A","DOI":"10.1203\/00006450-199604001-02129","article-title":"Minimizing nitrogen dioxide exposure during inhaled nitric oxide therapy.","volume":"39","author":"Van Meurs","year":"1996","journal-title":"Pediatr Res."},{"key":"2021121023201895400_B37","doi-asserted-by":"crossref","first-page":"350A","DOI":"10.1203\/00006450-199604001-02108","article-title":"Nitrogen dioxide kinetics in a neonatal continuous flow ventilatory circuit.","volume":"39","author":"Sokol","year":"1996","journal-title":"Pediatr Res."},{"key":"2021121023201895400_B38","doi-asserted-by":"crossref","first-page":"529","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 1500 gm.","volume":"92","author":"Papile","year":"1978","journal-title":"J Pediatr."},{"key":"2021121023201895400_B39","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/0022-3468(95)90597-9","article-title":"Pathophysiology of congenital diaphragmatic hernia X: localization of nitric oxide synthase in the intima of pulmonary artery trunks of lambs with surgically created congenital diaphragmatic hernia.","volume":"30","author":"Karamanoukian","year":"1995","journal-title":"J Pediatr Surg."},{"key":"2021121023201895400_B40","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1165\/ajrcmb.13.6.7576705","article-title":"Pulmonary endothelial nitric oxide synthase gene expression is decreased in a rat model of congenital diaphragmatic hernia.","volume":"13","author":"North","year":"1995","journal-title":"Am J Respir Cell Mol Biol."},{"key":"2021121023201895400_B41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0022-3468(95)90596-0","article-title":"Pathophysiology of congenital diaphragmatic hernia VIII: inhaled nitric oxide requires exogenous surfactant therapy in the lamb model of congenital diaphragmatic hernia.","volume":"30","author":"Karamanoukian","year":"1995","journal-title":"J Pediatr Surg."},{"key":"2021121023201895400_B42","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/S0022-3468(96)90097-4","article-title":"Surfactant rescue in the fetal lamb model of congenital diaphragmatic hernia.","volume":"31","author":"O'Toole","year":"1996","journal-title":"J Pediatr Surg."},{"key":"2021121023201895400_B43","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/0022-3468(94)90580-0","article-title":"Surfactant (Beractant) therapy for infants with congenital diaphragmatic hernia on ECMO. Evidence of persistent surfactant deficiency.","volume":"29","author":"Lotze","year":"1994","journal-title":"J Pediatr Surg."},{"key":"2021121023201895400_B44","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/0022-3468(94)90725-0","article-title":"A prospective randomized trial of delayed vs immediate repair of congenital diaphragmatic hernia.","volume":"29","author":"Nio","year":"1994","journal-title":"J Pediatr Surg."},{"key":"2021121023201895400_B45","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/0022-3468(93)90431-J","article-title":"Persistent pulmonary hypertension in high-risk congenital diaphragmatic hernia patients: incidence and vasodilator therapy.","volume":"28","author":"Bos","year":"1993","journal-title":"J Pediatr Surg."},{"key":"2021121023201895400_B46","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1001\/archinte.1985.00360040141030","article-title":"When was a \u201cnegative\u201d clinical trial big enough?","volume":"145","author":"Detsky","year":"1985","journal-title":"Arch Intern Med."},{"key":"2021121023201895400_B47","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1097\/00003246-199511000-00012","article-title":"Perfluorocarbon-associated gas exchange improves pulmonary mechanics, oxygenation, ventilation, and allows nitric oxide delivery in the hypoplastic lung congenital diaphragmatic hernia lamb model.","volume":"23","author":"Wilcox","year":"1995","journal-title":"Crit Care Med."}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/99\/6\/838\/1001550\/pe069700838o.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/99\/6\/838\/1001550\/pe069700838o.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T07:33:06Z","timestamp":1734507186000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/99\/6\/838\/75407\/Inhaled-Nitric-Oxide-and-Hypoxic-Respiratory"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,6,1]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[1997,6,1]]},"published-print":{"date-parts":[[1997,6,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.99.6.838","relation":{},"ISSN":["1098-4275","0031-4005"],"issn-type":[{"value":"1098-4275","type":"electronic"},{"value":"0031-4005","type":"print"}],"subject":[],"published":{"date-parts":[[1997,6,1]]}}}