Elsevier

Seminars in Perinatology

Volume 27, Issue 4, August 2003, Pages 311-319
Seminars in Perinatology

Inhaled nitric oxide therapy in neonatal hypoxic respiratory failure: insights beyond primary outcomes

https://doi.org/10.1016/S0146-0005(03)00043-0Get rights and content

Abstract

The Neonatal Research Network developed and initiated 3 multicenter randomized controlled clinical trials evaluating inhaled nitric oxide therapy. Additional projects evolved from these efforts including basic science research and observational investigations. This article provides a historical prospective of the Network’s investigations related to the diagnosis and management of neonatal hypoxic respiratory failure, especially those related to inhaled nitric oxide therapy. It will review the Network’s contributions toward advancing the clinical care of the newborn with severe hypoxic respiratory failure.

Section snippets

Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes

Concurrent with the development of a large, multi-center, randomized controlled-clinical trial investigating the clinical use of iNO therapy in the term and near-term neonate, the Network pursued a prospective investigation to describe the then current understanding of the disease, including its demographics, treatments, and outcomes. This prospective descriptive study was conducted between October 1993 and December 1994 at the 12 Network Centers prior to the wide spread use of iNO therapy.11

Nitrogen dioxide formation during inhaled nitric oxide therapy

Prior to the identification of an industry sponsor or a Federal Drug Administration (FDA) approved delivery system, clinical investigators faced the dilemma of developing a safe, accurate iNO delivery and monitoring system. Whenever NO and oxygen meet, a more toxic compound NO2 will be formed (see Equation 2: rate expression for NO2 formation). NO2 is a toxic gas and the Occupational Safety and Health Administration limits human peak exposure to 5 ppm.12 However, alterations in airway

Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure

In April of 1993, the National Heart, Lung, and Blood Institute (NHLBI) organized a workshop on NO.23 At this conference, basic science researchers met with clinicians and shared data about NO. The groundwork was laid for large randomized clinical trials investigating iNO therapy. Then in December 1993, the NICHD in conjunction with the NHLBI and FDA organized a second conference discussing the NO clinical trials in progress and under development. The designs of two of the investigations, the

Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia

The study design and primary hypothesis for this trial were the same as NINOS; however, the study population was limited to patients with CDH. Recruitment ceased when the main trial was terminated on May 2, 1996. With an enrollment of 53 patients, this study represents the largest controlled clinical trial conducted in the CDH population. Similar to the NINOS cohort, the mean OI in the CDH group was in excess of 45. In this cohort of acutely ill patients with CDH, there was no early improvement

Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group

Follow-up is a critical component of treatment evaluation when introducing a new treatment into the neonatal population. Of the 199 surviving infants from the NINOS trial, 86.9% were seen in follow-up at 18–24 months of age. Complete history, physical and neurodevelopmental examinations were performed, including assessments of mental and motor development as measured by the Bayley Scales of Infant Development 2nd Edition29 and of hearing. Of the infants seen at follow-up, 32% presented with one

Changes in arterial oxygen oxygen tension when weaning neonates from inhaled nitric oxide

An ancillary investigation of the NINOS trial analyzed prospectively collected data during weaning of study gas. The objective of this observational study was to provide the clinician with anticipatory guidance when weaning iNO from a responding patient. Data from 505 weaning attempts recorded from 84 patients with varying diagnoses were analyzed. Ventilator settings and FiO2 had been maintained constant over a 30-minute period in which the response to weaning iNO was measured. Weaning

A randomized trial of early versus standard inhaled nitric oxide therapy in term and near term newborn infants with hypoxic respiratory failure

Although iNO therapy reduced the need for ECMO in several large randomized clinical trials, a significant number of infants continue to require ECMO or die. The NINOS subgroup analysis suggested that patients with the lowest severity of illness (OI: 25.0–29.9) experienced the best response and outcome to iNO therapy. We hypothesized that introducing iNO therapy earlier in the disease process, before significant alveolar atelectasis or ventilator-induced lung injury occurred, would further

Inhaled nitric oxide for preterm infants with severe respiratory failure

Severe respiratory failure in the preterm infant is primarily a result of surfactant deficiency. Although surfactant therapy dramatically improves oxygenation, up to 50% of premature infants have a suboptimal response.32 Elevated pulmonary pressures with right-to-left shunting frequently complicates severe respiratory distress syndrome and is predictive of a poor outcome.33, 34, 35

The initial reports of iNO use in preterm infants suggested an improvement in oxygenation, but the coincidental

Conclusion

These investigations culminate almost a decade of investigation by the NICHD Network in neonatal hypoxic respiratory failure and iNO therapy. The PPHN observational investigation described the epidemiology, outcomes and practice variations in neonates with PPHN, and examined our pre-iNO therapy approach to this patient population. This provided a foundation from which to build further inquiry into the management of this disease process. Resolving the uncertainty of NO2 kinetics within the

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