Inhaled nitric oxide in preterm infants undergoing mechanical ventilation

STUDY DESIGN Randomized, stratified, double-blind, placebo-controlled trial of inhaled nitric oxide at 21 centers. Population Inclusion ≤32 weeks of GA with BW of 500 to 1250g and were receiving mechanical ventilation (MV) for lung disease (not apnea) between 7 and 21 days of age including re-intubated infants Infants with BW of 500 to 799 g being treated with nasal CPAP. Exclusion Life-threatening conditions Pre-existing bilateral grade four intraventricular hemorrhage (IVH) Previous receipt of iNO therapy. Research hypothesis Administration of iNO to infants would increase survival without BPD at 36 weeks PMA. Intervention Inhaled nitric oxide (INOmax, INO Therapeutics) and the delivery system (INOvent, Datex-Ohmeda). METHOD The trial was conducted at 21 infant Intensive Care Units. General guidelines for MV, the treatment of patent ductus arteriosus (PDA), and criteria for administration of postnatal corticosteroids were set. Randomization of infants occurred at the data coordinating center in Philadelphia and was stratified according to birth weight (500-799 g and 800-1250 g) and site with the use of permuted blocks, with equal assignment to the group receiving nitric oxide or the placebo group within blocks. iNO (INOmax, INO Therapeutics) and the delivery system (INOvent, Datex-Ohmeda) were provided to all sites. Except respiratory therapist who administered the study gas was aware of infants' gas assignment all other health care providers are unaware of the therapeutic assignment. The software and hardware labels were hided form the managing team. Infants initially received 20 ppm of study gas for 48-96 hours, and the doses were subsequently decreased to doses of 10, 5, and 2 ppm at weekly intervals, with minimum treatment duration of 24 days. For practicality (not all infants have arterial line); a simplified severity score consisting of the mean airway pressure multiplied by the FiO 2 was used. Infants were treated with an oxygen saturation goal of 88-94% and were expected to have a PaO 2 range of 40-70 mmHg. Accordingly, a severity score of 3.5 was equivalent to an oxygenation index between 5 and 9. All complications were monitored like; sepsis, PDA, IVH, periventricularleukomalacia (PVL), Necrotizing Enterocolitis (NEC), Retinopathy of prematurity (ROP). Adverse events occurring during their hospitalization were assessed. Blood methemoglobin concentrations were measured at baseline and within the first 24 hours after the initiation of study gas. Primary outcome BPD at 36 weeks of postmenstrual age. Secondary outcome Duration of oxygen therapy Duration of hospitalization Duration of ventilation, CPAP. RESULT There were no significant differences between groups in gestational age, BW, sex, race or ethnic group, or incidence of pre-existing conditions, including pneumothorax, pulmonary hemorrhage, sepsis, NEC, PDA, or unilateral grade 3 or 4 IVH. There was no significant difference between groups in the number of infants receiving nasal CPPV, as compared with MV. In iNO group; 129 of 294 infants survived to 36 weeks of postmenstrual age without BPD (43.9 percent), as compared with 106 of 288 infants in the placebo group (36.8 percent) (relative benefit, 1.23; 95% confidence interval, 1.01 to 1.51; P=0.04). NNT for one improved outcome was 14. The rate of survival without BPD was similar in both birth-weight strata. Infants treated with iNO were discharged sooner (P=0.04) and received supplemental oxygen therapy for a shorter period (P=0.006) than did the controls. At 40 and 44 weeks postmenstrual age, a significantly lower proportion of infants receiving iNO than of infants in the placebo group remained in the hospital and required MV, nasal CPPV, or supplemental oxygen (P=0.01 at 40 weeks and P=0.03 at 44 weeks); BPD, when it occurred, was less severe among infants receiving iNO. A total of 21 infants (9 who received iNO and 12 who received placebo) died while receiving study gas. None had significant elevations of methemoglobin. No significant differences between groups in the incidence of complications of prematurity; sepsis, NEC, PDA requiring therapy, ROP, or the evolution of neurologic findings on ultrasonography either during or after the administration of study gas. iNO treatment yielded a significant benefit in the group of infants between the ages of 7 and 14 days at enrollment, but not in the group of infants between the ages of 15 and 21 days. CONCLUSIONS Prolonged iNO therapy that is initiated between 7 and 21 days of age in preterm infants undergoing MV significantly improved survival without BPD without short-term adverse effects. COMMENTARY This trial differed in design from previously reported trials of iNO which focused on preterm infants with respiratory failure shortly after birth with the intention of treating pulmonary hypertension or reducing inflammation (during the first 24-48 hours after birth) instead; the therapy was started later (between 7 and 21 days. The early starting point might help exclude all infants with brain injury which usually happen during 1 st week of life that might be attributed to iNO and start before the lung injury started (before 14 days). The use of prolonged iNO therapy might be needed to prevent increased airway resistance and muscularity, to attenuate hyperoxic injury, and to improve surfactant function, lung growth, angiogenesis and alveolarization. In addition to earlier starts; infants treated with high dose of iNO (started with 20 ppm) and for longer duration than other studies which might be the reasons for better outcome. However, the long-term outcome especially on neurodevelopment complication was not assessed, neither the cost of giving higher dose of iNO for longer duration was assessed yet. Abstracted from Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 2006;355:343-53.

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