When to say no to inhaled nitric oxide in neonates?

Abstract

Inhaled nitric oxide (iNO) was approved for use in critically ill term and near-term neonates (>34 weeks gestational age) in 1999 for hypoxic respiratory failure (HRF) with evidence of pulmonary hypertension. In 2011 and 2014, the National Institutes of Health and American Academy of Pediatrics respectively recommended against the use of iNO in preterm infants <34 weeks. However, these guidelines were based on trials conducted with varying inclusion criteria and outcomes. Recent guidelines from the American Thoracic Society/American Heart Association, the Pediatric Pulmonary Hypertension Network (PPHNet) and European Pediatric Pulmonary Vascular Disease Network recommend the use of iNO in preterm neonates with HRF with confirmed pulmonary hypertension. This review discusses the available evidence for off-label use of iNO. Preterm infants with prolonged rupture of membranes and pulmonary hypoplasia appear to respond to iNO. Similarly, preterm infants with physiology of pulmonary hypertension with extrapulmonary right-to-left shunts may potentially have an oxygenation response to iNO. An overview of relative and absolute contraindications for iNO use in neonates is provided. Absolute contraindications to iNO use include a ductal dependent congenital heart disease where systemic circulation is supported by a right-to-left ductal shunt, severe left ventricular dysfunction and severe congenital methemoglobinemia. In preterm infants, we do not recommend the routine use of iNO in HRF due to parenchymal lung disease without pulmonary hypertension and prophylactic use to prevent bronchopulmonary dysplasia. Future randomized trials evaluating iNO in preterm infants with pulmonary hypertension and/or pulmonary hypoplasia are warranted. (233/250 words).

Fig. 1.

Causes of hypoxemic respiratory failure (HRF) in neonates. Within the lung, alveolar lung disease, ventilation/perfusion (V/Q) mismatch and presence of intrapulmonary anastomoses between pulmonary/bronchial artery and pulmonary veins (bypassing the alveoli) contribute to hypoxemia. In addition genetic causes such as surfactant protein deficiency, T-box transcription factor 4 (TBX4) mutations, ATP-binding cassette family (ABCA-3) deficiency, thyroid transcription factor 1 (TTF1, encoded by the NKX2.1 gene), forkhead box F1 (FOXF1) associated with alveolar capillary dysplasia (ACD) or malalignment of pulmonary veins (MPV) are rare pulmonary causes of neonatal hypoxemia. Reduced pulmonary arterial flow or impaired pulmonary venous drainage are pulmonary circulatory factors contributing to hypoxemia. Right ventricular dysfunction is associated with reduced pulmonary arterial flow and left ventricular dysfunction is associated with impaired pulmonary venous drainage. Extrapulmonary shunts at patent ductus arteriosus (PDA) and patent foramen ovale (PFO) are common in pulmonary hypertension leading to hypoxemia. The factors associated with an Asterix (*) do not respond well to inhaled nitric oxide. Copyright Satyan Lakshminrusimha 2021.

Fig. 2.

Etiology of pulmonary hypertension in neonates and response to inhaled nitric oxide (iNO). Conditions that typically respond to iNO are shown in pink boxes; poor response (or contraindications for iNO) in black boxes and conditions with variable response in gray boxes. PROM – prolonged rupture of membranes, CDH – congenital diaphragmatic hernia, PPHN – persistent pulmonary hypertension of the newborn, MAS – meconium aspiration syndrome. Modified from Mathew et al. [64] – copyright Satyan Lakshminrusimha.

Fig. 3.

Use of inhaled nitric oxide (iNO) in preterm infants. (i) Early hypoxemic respiratory failure (HRF) with PPHN physiology, (ii) early HRF from respiratory distress syndrome without evidence of PPHN, (iii) prevention of bronchopulmonary dysplasia (BPD) and (iv) management of BPD with pulmonary hypertension. We recommend the use of iNO in (i) and (iv) – green boxes. RV-right ventricle, LV-left ventricle. Copyright Satyan Lakshminrusimha.

Fig. 4.

Ductal-dependent systemic circulation in (A) hypoplastic left ventricle with a narrow asending aorta (AAo) and (B) consequences of therapy with inhaled nitric oxide (iNO) leading to systemic hypoperfusion due to decreased pulmonary vascular resistance (PVR). PA – pulmonary artery, RA – right atrium, RV – right ventricle, LA – left atrium, LV – left ventricle, DAo – descending aorta, PDA – patent ductus arteriosus. Copyright Satyan Lakshminrusimha.

Fig. 5.

Reasons for poor response to inhaled nitric oxide (iNO) in congenital diaphragmatic hernia (CDH). Infants with CDH have alveolar and vascular hypoplasia with significant remodeling of pulmonary vasculature. The presence of left ventricular hypoplasia and dysfunction leads to pulmonary venous congestion and edema. Administration of an inhaled pulmonary vasodilator in these circumstances can exacerbate pulmonary edema and worsen hypoxemic respiratory failure. In addition, circulating vasoconstrictors such as endothelin [65] and oxygen free radicals generated by hyperoxic ventilation may antagonize the pulmonary vasodilatory effect of iNO [57]. The use of an inodilator such as milrinone might improve cardiac function and potentially improve response to iNO [49]. Copyright Satyan Lakshminrusimha.