Therapies that enhance pulmonary vascular NO-signaling in the neonate

Abstract

There are several pulmonary hypertensive diseases that affect the neonatal population, including persistent pulmonary hypertension of the newborn (PPHN) and bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). While the indication for inhaled nitric oxide (iNO) use is for late-preterm and term neonates with PPHN, there is a suboptimal response to this pulmonary vasodilator in ~40% of patients. Additionally, there are no FDA-approved treatments for BPD-associated PH or for preterm infants with PH. Therefore, investigating mechanisms that alter the nitric oxide-signaling pathway has been at the forefront of pulmonary vascular biology research. In this review, we will discuss the various mechanistic pathways that have been targets in neonatal PH, including NO precursors, soluble guanylate cyclase modulators, phosphodiesterase inhibitors and antioxidants. We will review their role in enhancing NO-signaling at the bench, in animal models, as well as highlight their role in the treatment of neonates with PH.

Worsened short-term clinical outcomes in a cohort of patients with iNO-unresponsive PPHN: a case for improving iNO responsiveness

“…Given the large percentage of neonates with PPHN who do not respond or fail to sustain a response to iNO, there remains a need to investigate alternative treatment strategies for these groups of patients. There is emerging evidence to suggest that the PDE3 inhibitor, milrinone improves oxygenation and exhibits synergism with iNO [11,18,35,36]. PDE3 regulates vascular tone via hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), leading to vasoconstriction [9,10].…”

Successful Weaning From Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) After Initiation of Inhaled Epoprostenol in a Neonate With Refractory Persistent Pulmonary Hypertension of the Newborn (PPHN)

“…Persistent pulmonary hypertension of the newborn (PPHN) is a severe condition unique to the immediate neonatal period that occurs in approximately 10% of infants [1,2]. PPHN is characterized by failure to decrease the usually high fetal pulmonary vascular resistance (PVR) after birth, resulting in a marked decline in pulmonary blood flow (PBF) and, thus, oxygenation capacity of the lungs, leading to catastrophic clinical consequences for the neonate [3]. PPHN occurs due to birth asphyxia, meconium aspiration syndrome, respiratory distress syndrome, infections, congenital diaphragmatic hernia, and underlying heart or lung conditions [4,5].…”

Life-threatening PPHN refractory to nitric oxide: proposal for a rational therapeutic algorithm

“…Persistent pulmonary hypertension of the neonate (PPHN) is a severe clinical syndrome representing the most common form of pediatric pulmonary hypertension and is usually associated with various types of respiratory failure [1]. Refractory PPHN is defined as an acutely life-threatening condition not responding to the administration of inhaled nitric oxide (iNO Communicated by Piet Leroy at the classical dose of 20 ppm) and conventional measures (including mechanical ventilation (with alveolar recruitment, if needed) and inotropic support) with resulting hypoxemia and represents a significant proportion (up to 30-40% [2]) of PPHN patients. Refractoriness to iNO depends on many factors such as genetic background, gestational age, underlying conditions, and co-interventions; depending on these factors only some patients can be considered as candidate for extra-corporeal life support [3].…”