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Inhaled nitric oxide (iNO) therapy had a transformational impact on the management of infants with persistent pulmonary hypertension of the newborn (PPHN). iNO remains the only approved pulmonary vasodilator for PPHN; yet 30% to 40% of patients do not respond or have incomplete response to iNO. Lung recruitment strategies with early surfactant administration and high-frequency ventilation can optimize the response to iNO in the presence of parenchymal lung diseases. Alternate pulmonary vasodilators are used commonly as rescue, life-saving measures, though there is a lack of high-quality evidence supporting their efficacy and safety. This article reviews the available evidence and future directions for research in PPHN., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The evidence for the benefits of inhaled nitric oxide (iNO) on gas exchange, cytokine-induced lung inflammation, and vascular dysfunction has been demonstrated by several animal and human studies. The use of iNO in extremely low birth weight neonates for the prevention of adverse outcomes like chronic lung disease and neurologic injury has been investigated, but the findings remain inconclusive. This review briefly outlines the biologic rationale for the use of iNO in preterm neonates and the results on the outcome measures of bronchopulmonary dysplasia and brain injury from the recent clinical trials. This article focuses on the potential toxicities, persistent controversies, and unanswered questions regarding the use of this treatment modality in this patient population at high risk for adverse outcomes.

The management of PPHN entered a new era with the development of inhaled NO therapy for the relief of pulmonary hypertension. The wider application of INO therapy and improved ventilation strategies led to a decrease in the need for invasive life-sustaining therapies such as ECMO. The remarkable advances in the understanding and treatment of PPHN were made possible by the extensive investigations in the laboratory using animal models. Further decreases in morbidity and mortality are possible with specific strategies targeted to correct the alterations in NO and prostacyclin biology and strategies to reduce lung injury. Further research is needed to understand the basis for the biologic susceptibility of some infants to environmental insults such as intra-uterine stressor exposure to NSAIDs in utero.