Best Practice GuidelineInhaled nitric oxide in the term newborn
Introduction
Early laboratory studies demonstrated that inhaled nitric oxide (NO) therapy caused marked and sustained reduction in pulmonary vascular resistance (PVR) in newborn animal models [1], [2], [3], and it is now 16 years on from the publication of initial pilot studies showing marked improvement in oxygenation in term newborns with persistent pulmonary hypertension (PPHN) [4], [5]. Subsequent trials confirmed the safety and efficacy of inhaled NO in this population, and it is now an integral component of PPHN therapy [6], [7], [8], [9], [10], [11]. In this piece, I will provide a brief historical overview of the syndrome of PPHN, and evaluate the role of inhaled NO in the term newborn as both a therapeutic and diagnostic tool.
Section snippets
A Brief history of PPHN
In the early 1960s, the association of respiratory distress syndrome with pulmonary hypertension and right-to-left ductal shunting was shown in the landmark studies of Rudolph et al. [12] and the clinical observations of Stahlman [13]. Although it is now recognized that pulmonary hypertension with right-to-left veno-arterial admixture often complicates the course of newborns with diverse diseases, its recognition in term infants who were hypoxemic (but without significant lung disease) was
Rationale for inhaled NO therapy
As described above, the physiologic rationale for inhaled NO therapy in the treatment of PPHN is based upon its ability to achieve potent and sustained pulmonary vasodilation without decreasing systemic vascular tone [42]. As a syndrome, PPHN is associated with diverse neonatal cardiac and pulmonary disorders that are characterized by high PVR causing extrapulmonary right-to-left shunting of blood across the arterial duct and/or oval foramen. The ability of inhaled NO therapy to selectively
Nitric oxide therapy — the clinical condition
Due to its selective pulmonary vasodilator effects, inhaled NO therapy is an important adjunct to available treatments for term newborns with hypoxemic respiratory failure. However, hypoxemic respiratory failure in the term newborn represents a heterogeneous group of disorders, and disease-specific responses have clearly been described. For example, patients with extapulmonary right-to-left shunting (PPHN) show acute improvement in oxygenation when PVR becomes subsystemic during NO therapy, and
Role of echocardiography
Echocardiography has become a vital tool in the clinical management of newborns with severe hypoxemic respiratory failure. The initial echocardiographic evaluation is important to rule-out structural heart disease causing hypoxemia (e.g. coarctation of the aorta and total anomalous pulmonary venous return). Morever, it is critically important to diagnose congenital heart lesions for which inhaled NO treatment would be contraindicated. In addition to the lesions mentioned above, congenital heart
Clinical criteria for treatment with inhaled NO and treatment strategies
Available evidence from clinical trials supports the use of inhaled NO in near-term (> 34 weeks gestation) and term newborns. The use of inhaled NO in infants less than 34 weeks gestation remains investigational.
Clinical trials of inhaled NO in the newborn have incorporated ECMO treatment as an endpoint. Therefore, most patients have been enrolled in the first few days of life. Although one of the pivotal studies used to support the new drug application for inhaled NO therapy included as an
Role of lung recruitment in inhaled NO therapy
Along with inhaled NO treatment, other therapeutic strategies have emerged for the management of the term infant with hypoxemic respiratory failure. Considering the important role of parenchymal lung disease in specific disorders included in the syndrome of PPHN, pharmacologic pulmonary vasodilation alone should be expected to cause sustained clinical improvement in many cases [70]. Moreover, patients not responding to inhaled NO can show marked improvement in oxygenation with adequate lung
Inhaled NO and ECMO
In the pre-inhaled NO era, concerns were raised about delaying ECMO therapy if conventional treatment was prolonged [76]. However, these retrospective data did not account for important changes in management, including newer ventilator devices and strategies and the use of exogenous surfactant therapy in selected cases. Reports on the use of inhaled NO in ECMO centers have not substantiated early concerns that inhaled NO would adversely affect outcome by delaying ECMO utilization. In one study,
Role of inhaled NO in newborns with CDH
Congenital diaphragmatic hernia is a complex syndrome that causes severe hypoxemic respiratory failure and is associated with a high mortality rate [82]. In the most severely affected subset of newborns, CDH is characterized by pulmonary hypoplasia, pulmonary hypertension with structural and functional pulmonary vascular abnormalities, and disturbances in cardiac performance.
Inhaled NO was considered a promising therapy for the treatment of acute pulmonary hypertension in CDH, and the first
Summary
Inhaled NO improves oxygenation and decreases ECMO utilization in term newborns with PPHN. From the available information, a reasonable recommendation for the initial dose of iNO in the term infant is 20 ppm, with reductions in dose over time. Toxicity is apparent at 80 ppm, causing increases in methemoglobinemia, inspired NO2, and prolonged bleeding time. The use of iNO in non-ECMO centers must be done cautiously, with arrangements in place for transport to an ECMO center without interrupting
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