Inhaled nitric oxide therapy for pulmonary disorders of the term and preterm infant

Abstract

The 21st century began with the FDA approval of inhaled nitric oxide therapy for the treatment of neonatal hypoxic respiratory failure associated with pulmonary hypertension in recognition of the 2 randomized clinical trials demostrating a significant reduction in the need for extracorporeal support in the term and near-term infant. Inhaled nitric oxide is one of only a few therapeutic agents approved for use through clinical investigations primarily in the neonate. This article provides an overview of the pertinent biology and chemistry of nitric oxide, discusses potential toxicities, and reviews the results of pertinent clinical investigations and large randomized clinical trials including neurodevelopmental follow-up in term and preterm neonates. The clinical investigations conducted by the Eunice Kennedy Shriver NICHD Neonatal Research Network will be discussed and placed in context with other pertinent clinical investigations exploring the efficacy of inhaled nitric oxide therapy in neonatal hypoxic respiratory failure.

Keywords: Hypoxic respiratory failure; Inhaled nitric oxide; Newborn; Pulmonary hypertension; Surfactant.

Figure 1

The NO-cGMP pathway for initiation of pulmonary vasodilation. Nitric oxide (NO) synthase in the endothelial cell is activated by birth-related stimuli to produce NO, which then diffuses to the nearby smooth muscle cell and activates the enzyme soluble guanylate cyclase to produce cyclic GMP (cGMP). Activation of cGMP-dependent protein kinase (PKG) then initiates relaxation of vascular smooth muscle cell and vasodilation.

Figure 2

The reduced need for ECMO with inhaled nitric oxide (iNO) therapy as demonstrated in the neonatal inhaled nitric oxide study (NINOS) and the clinical inhaled nitric oxice research group investigators (CINRGI) multi-center RCTs.^,

Figure 3

The influence of early initiation of inhaled nitric oxide (iNO) compared to placebo at an oxygenation index (OI) of 15–20 on the time to discharge from NICU, plotted as a Kaplan Meir survival curve. Infants in the placebo group who progressed to an OI of ≥25 received standard iNO therapy. Early initiation of iNO was associated with earlier discharge home, with 50% of infants in the early iNO group going home by 18 days compared to 27 days for the placebo group (p=0.017 by log rank test). No difference was seen between the 2 groups when iNO was initiated at an OI≥20. Reproduced with permission from Konduri, GG et al., J Perinatol, 2013; 33: 944–949.

Figure 4

Correlation of ECMO/mortality risk with oxygenation index (OI) at the initiation of iNO in different randomized clinical trials of inhaled nitric oxide (iNO) therapy. The ECMO/mortality rate reported as primary outcome for the infants randomized to iNO in different trials was shown as bubbles whose size was shown proportional to the sample size in the trial. The ECMO/mortality rate was close to 40% for trials that enrolled infants at an average OI of 40 or above, while the rate was 10.2% when iNO was initiated at an OI of 15–20 based on post-hoc analysis of data from the trial reported by Konduri GG, et al. (Copyright for the figure: Drs. Satyan Lakshminrusimha and Girija G. Konduri. Modified from Lakshminrusimha S. The pulmonary circulation in neonatal respiratory failure. Clin Perinatol. 2012; 39(3):655–83.)

Figure 5

Meta-analysis of the effect of iNO on death or BPD at 36 weeks post-menstrual age (Adapted from Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Review Update, Neonatology 2012;102:251–3.)