Guidelines for Rational and Cost-Effective Use of iNO Therapy in Term and Preterm Infants

Abstract

Inhaled nitric oxide (iNO) is an effective but costly therapy for infants with hypoxemic respiratory failure. The approved and solidly evidence-based indication is for treatment of late preterm and term infants with persistent pulmonary hypertension of the newborn (PPHN); however, off-label use of iNO has become widespread. Although iNO treatment of infants with congenital diaphragmatic hernia constitutes one of the approved indications, available evidence from randomized trials suggests marginal if any efficacy. Rescue therapy in preterm infants with severe respiratory failure has been studied extensively and is not supported by data from a number of controlled trials. Such use is widespread, but should be discouraged. There may be a subgroup of such infants with pulmonary hypoplasia and documented PPHN who may benefit from this treatment, but the data are limited. Several studies have examined the use of iNO for prevention of chronic lung disease with inconsistent results. This promising application requires more study before it can be recommended. There may be a role of iNO in treating infants with pulmonary hypertension complicating severe bronchopulmonary dysplasia, but there are limited data on long term outcomes. Alternate therapies such as sildenafil may be beneficial in this specific population as well as in other causes of pulmonary hypertension. Rational use of this expensive treatment will maximize cost:benefit and avoid potential exposure to unknown adverse effects not balanced by documentable benefits.

Early Use of Inhaled Nitric Oxide in Preterm Infants: Is there a Rationale for Selective Approach?

“…However, a retrospective post hoc analysis of this study suggested that a subset of premature infants with preterm prolonged rupture of membranes (pPROM), oligohydramnios, and pulmonary hypoplasia may have benefitted from iNO therapy. 11 Similar conclusions were derived from other case reports/series linking pPROM to improved survival with iNO in preterm infants [12][13][14] possibly because of a transient defect in NO generation with pPROM. 15 The existence and the hemodynamic and histological features of early pulmonary hypertension (PH) and HRF in preterm infants are subjects of controversy.…”

“…Similar to these findings, other investigators have observed the beneficial effect of iNO in preterm infants with HRF and pPROM. [11][12][13][14]…”

Inhaled nitric oxide for neonates with persistent pulmonary hypertension of the newborn in the CINRGI study: time to treatment response

“…However, the mortality rate for HRF in term and late preterm patients is approximately 11% and has remained relatively constant since the FDA approval of iNO in 1999 [9]. Therefore, interest is growing in developing rational approaches to treating term and near-term infants that include defining iNO responders so that other therapies, such as ECMO, can be initiated in a timely manner [4, 10–12]. Indeed, a lack of oxygenation response within 1 h has been suggested as a criterion for discontinuing iNO [4].…”

Nitric oxide in paediatric respiratory disorders: novel interventions to address associated vascular phenomena?

“…iNO has been considered an advantage over traditional treatment measures for the above diseases due to its ability to improve oxygenation by selectively vasodilating the pulmonary vasculature [Steinhorn, 2010]. Currently, iNO is used successfully in the late preterm and term population of patients with persistent pulmonary hypertension (PPHN) [Keszler, 2012]. However, its use in other paediatric respiratory diseases has been associated with differential outcomes.…”