Neonatology on the Web

Inhaled Nitric Oxide for PPHN

www.neonatology.net

Inhaled Nitric Oxide for PPHN

Persistent pulmonary hypertension of the newborn: a brief review

In fetal life, pulmonary vascular resistance (PVR) is high and most right ventricular output bypasses the lungs through the ductus arteriosus and foramen ovale. At birth, lung inflation and rising oxygen tension normally trigger a rapid fall in PVR, allowing pulmonary blood flow to increase several-fold. PPHN is the failure of this transition: PVR remains suprasystemic, sustaining right-to-left shunting across the ductus and foramen ovale, which produces profound, often labile hypoxemia that is disproportionate to the degree of parenchymal lung disease.

The physiology comes in a few recognizable patterns: a maladapted vascular bed (normal anatomy that fails to relax, as in meconium aspiration, sepsis/pneumonia, or perinatal asphyxia), a maldeveloped bed (remodeled, hypertrophied vasculature, as in idiopathic PPHN), and a hypoplastic bed (reduced cross-sectional area, as in congenital diaphragmatic hernia or oligohydramnios-related pulmonary hypoplasia).

The most common clinical settings are meconium aspiration syndrome (the single largest group), pneumonia and sepsis (notably group B streptococcus), perinatal asphyxia, respiratory distress syndrome, congenital diaphragmatic hernia, and idiopathic (“black-lung”) PPHN with no parenchymal disease. It is predominantly a disease of term and near-term infants. The diagnostic hallmark is a pre-/post-ductal saturation gradient with echocardiographic confirmation of elevated pulmonary pressures and right-to-left shunting in a structurally normal heart. That echocardiogram is also what distinguishes PPHN from ductal-dependent congenital heart disease—a distinction that directly determines whether iNO will help or harm.

From signaling molecule to bedside therapy

For a therapy now considered routine in the NICU, inhaled nitric oxide (iNO) has a remarkably compressed history—roughly a decade from basic pharmacology to FDA approval. Its story begins not in neonatology but in vascular biology.

In 1980, Robert Furchgott demonstrated that vascular relaxation depended on an intact endothelium, and proposed that endothelial cells released an unidentified “endothelium-derived relaxing factor” (EDRF). Over the following years, work by Furchgott, Louis Ignarro, and Ferid Murad—building on Murad’s 1977 finding that nitroglycerin acts by releasing nitric oxide—converged on the identification of EDRF as nitric oxide itself, established around 1986–1987. Furchgott, Ignarro, and Murad received the 1998 Nobel Prize in Physiology or Medicine for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system. (Salvador Moncada, whose group published foundational EDRF/NO work in 1987, was a notable omission that drew comment at the time.)

The key insight for neonatology was that NO, when inhaled, acts as a selective pulmonary vasodilator: it dilates the pulmonary vasculature adjacent to ventilated alveoli, then is rapidly inactivated by hemoglobin before reaching the systemic circulation. This selectivity is exactly what PPHN demands—lowering pulmonary pressures without causing systemic hypotension, the fatal flaw of intravenous vasodilators like tolazoline.

The pivotal neonatal trials

The clinical translation moved quickly. In 1992, two pilot reports published back-to-back in The Lancet—one from Jesse Roberts and colleagues (with Warren Zapol’s group at Massachusetts General), and one from John Kinsella, Steven Neish, and colleagues in Colorado—showed that low-dose iNO improved oxygenation in term infants with PPHN. Kinsella and Steven Abman at the University of Colorado became central figures in the subsequent neonatal iNO program.

Two randomized controlled trials then established efficacy:

  • NINOS (1997) — The Neonatal Inhaled Nitric Oxide Study Group conducted a double-blind, placebo-controlled multicenter trial in 235 term and near-term infants with hypoxic respiratory failure. iNO reduced the combined endpoint of death or ECMO from 64% in the control group to 46%. Notably, it reduced the need for ECMO without reducing mortality alone. A parallel NINOS substudy in congenital diaphragmatic hernia (CDH) showed no benefit—an important early signal that CDH physiology responds differently.
  • Roberts et al. (1997, NEJM) — In 58 term infants, inhaled nitric oxide doubled systemic oxygenation in 53% of treated infants versus 7% with conventional therapy.

Numerous other randomized controlled trials and outcome studies followed. The trials rapidly led to FDA approval of iNO in 1999 for term and near-term (≥34 weeks) neonates with hypoxic respiratory failure associated with pulmonary hypertension. It remains one of the few drugs approved primarily through neonatal clinical investigation, and the only FDA-approved pulmonary vasodilator for PPHN.

The preterm question

Enthusiasm drove substantial off-label use in preterm infants—for hypoxic respiratory failure and for prevention of bronchopulmonary dysplasia (BPD). The evidence did not support it.

The 2011 NIH Consensus Development Conference and the 2014 AAP Committee on Fetus and Newborn clinical report both concluded that available data do not support routine use of iNO in preterm infants. The AAP statement recommended against both rescue and routine use to improve survival, and against use to prevent or ameliorate BPD. Following the NIH conference, iNO use in extremely preterm infants dropped markedly, and network data found no associated improvement in death or severe BPD.

The nuance that persists in practice: many clinicians and pediatric PH experts still consider iNO reasonable in selected preterm infants—those with pulmonary hypoplasia from prolonged rupture of membranes/oligohydramnios, or with echocardiographically confirmed BPD-associated pulmonary hypertension and right ventricular dysfunction—after optimizing ventilation and hemodynamics. This is off-label, echocardiography-guided, individualized use, not routine practice.

Current standards of practice

Contemporary guidance (AAP, Canadian Paediatric Society, and European Pediatric Pulmonary Vascular Disease Network) converges on several points:

Indication. iNO is recommended in late-preterm and term infants with hypoxic respiratory failure and PPHN who remain hypoxemic despite optimal oxygenation and ventilation. It should ideally be started after echocardiographic confirmation of PPHN—both to confirm suprasystemic pulmonary pressures and to exclude conditions where iNO is harmful.

Prior Echocardiography is mandatory. iNO can be detrimental in infants with severe left ventricular dysfunction and in ductal-dependent congenital heart disease with a right-to-left ductal shunt supporting systemic flow. These, along with severe congenital methemoglobinemia, are the principal contraindications.

Dosing and monitoring. The standard starting dose is 20 ppm. Response is typically assessed by an increase in post-ductal PaO₂ or SpO₂ after a defined interval; roughly a quarter to a third of neonates are non-responders. Higher doses generally add toxicity without benefit. Monitoring includes methemoglobin levels and inspired NO₂ concentration. iNO must be weaned rather than stopped abruptly—sudden discontinuation can precipitate rebound pulmonary hypertension.

Adjuncts and alternatives. iNO is layered onto lung recruitment (often high-frequency oscillatory ventilation), surfactant where indicated, and hemodynamic support. When iNO fails or is unavailable, alternatives include milrinone, sildenafil, and inhaled prostacyclin; ECMO remains the rescue for refractory cases.

A practical caveat on CDH: the response is inconsistent, and iNO in CDH should be guided by echocardiographic assessment of pulmonary pressures and left heart function rather than applied reflexively.

References
  1. The Nobel Prize in Physiology or Medicine 1998 (Furchgott, Ignarro, Murad). NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1998/press-release/
  2. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526. PMID: 3495737 DOI: 10.1038/327524a0
  3. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet. 1992;340:818–819. PMID: 1357245 DOI: 10.1016/0140-6736(92)92686-a
  4. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn. Lancet. 1992;340:819–820. PMID: 1357246 DOI: 10.1016/0140-6736(92)92687-b
  5. Roberts JD Jr, Fineman JR, Morin FC 3rd, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med. 1997;336(9):605–610. PMID: 9032045 DOI: 10.1056/NEJM199702273360902
  6. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997 Feb. 27;336:597–604. PMID: 9036320 DOI: 10.1056/NEJM19970227336090
  7. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics. 1997 June;99(6):838–845. PMID: 9190553 DOI: 10.1542/peds.99.6.838
  8. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up (NINOS). J Pediatr. 2000 May;136(5):611–617. PMID: 10802492 DOI: 10.1067/mpd.2000.104826
  9. Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference Statement: Inhaled nitric oxide therapy for premature infants. Pediatrics. 2011;127:363–369. Epub 2011 Jan 10 (Conference held 2010.) PMID: 21220405 DOI: 10.1542/peds.2010-3507
  10. Kumar P; AAP Committee on Fetus and Newborn. Use of inhaled nitric oxide in preterm infants. Pediatrics. 2014;133(1):164–170. PMID: 24379225 DOI: 10.1542/peds.2013-3444
  11. Canadian Paediatric Society, Fetus and Newborn Committee. Inhaled nitric oxide use in newborns. https://cps.ca/en/documents/position/inhaled-nitric-oxide
  12. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000 Jan;105:14–20. PMID: 10617698 DOI: 10.1542/peds.105.1.14
  13. Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term (Review). Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD000399. DOI: 10.1002/14651858.CD000399.pub3.

Last Updated on 07/04/26