Nitric Oxide in Preemies

Inhaled Nitric Oxide for Preterm Infants with Severe Respiratory Failure: Van Meurs KP, Stevenson DK, Ehrenkranz RA, et al. Presented as a late breaking Platform Presentation at the 2004 PAS Meeting.

Background: Preterm infants with severe respiratory failure continue to experience significant morbidity and mortality. Inhaled nitric oxide (iNO) may benefit such infants because it causes selective pulmonary vasodilatation, improves ventilations/perfusion matching, and decreases pulmonary inflammatory response.

Objective: To determine if iNO administration to premature infants with severe respiratory failure decreases mortality or bronchopulmonary dysplasia (BPD).

Methods: Multicenter (n=16) randomized, double-masked, controlled trial in preterm infants with birth weights (BW) of 401 to 1500 grams with respiratory failure >4 hours after surfactant administration. Patients were stratified by BW and oxygenation index (OI) and randomized to receive placebo (oxygen) or iNO at 5-10 ppm. Strata 1 had oxygenation index OI>10 and Strata 2 had OI>5 followed by OI>7.5, but <10. Infants with a positive response (>10 torr increase in PaO2) were gradually weaned according to a defined protocol. Infants were monitored for signs of toxicity including methemoglobin >4% and nitrogen dioxide >3 ppm. Total exposure to study gas was limited to 14 days. A head ultrasound was required at 28 +3 days. Medical and neurodevelopmental assessment at 18 to 22 months corrected age is ongoing.

Results: 415 eligible infants were enrolled. Mean gestational age, BW and OI were 26.0 + 2.3, 840 + 265 and 23.4 + 17.1 in the iNO group (n=207) and 26.0 + 2.3, 840 + 259 and 22.5 + 17.3 in the placebo group (n=208), respectively. Baseline characteristics and status at randomization were not statistically different. Mortality was 52.7% in the iNO group vs 44.2% in the control group(p=0.08). BPD was 58.6% vs 66.9%, respectively (p=0.19). The trial was stopped 17 patients short of the sample size because of an apparent increase in severe intracranial hemorrhage (ICH) in the iNO group. Detailed analysis of trial data are underway and will be presented.

Conclusions: iNO, as delivered in this trial, was not associated with decreased mortality or BPD and was associated with an apparent increase in severe ICH in a very high risk group of preterm infants with severe respiratory failure.

Comment: This presentation of preliminary results of the NICHD’s Neonatal Network iNO trial engendered lengthy and unusually heated discussion at this year’s SPR meeting. Unfortunately for Dr. Van Meurs, this trial testified to many of the difficulties that can be encountered during execution of a complex multicenter study in a fragile premature population. The initial entry criteria defined a very small subset of infants with respiratory failure who were known to have high mortality and significant morbidity (strata 1). Enrollment lagged significantly behind projections so that entry criteria were modified mid-course (strata 2). The study was stopped early due to an interim analysis that identified an apparent increase in severe ICH in the treatment group based on individual center reports. When a greater percentage of patients was analyzed using readings made by a single neurosonologist, the difference in ICH was not significant. Multiple and sometimes conflicting criticisms were voiced. For instance, some faulted the investigators for stopping the study early while other supported the early termination but were critical that the network did not disseminate the reason for the cessation to the neonatology community at large. At the end, what more do we know about the use of iNO in preterm infants? Certainly this study should warn against using iNO as a rescue treatment for preterm infants with severe respiratory failure. It is not inconceivable that for some etiologies of respiratory failure in preterm infants, iNO may actually increase mortality. The results are consistent with those reported by the smaller study conducted by Schreiber, et al (reported in an earlier edition of NeoNotes) that found a possible benefit associated with iNO treatment but only when initiated in a more stable group of infants. MH.

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