TABLE 2.
Additional Details of Included Trials
| Trial | Control-Group Therapy | Randomization Method | Intervention Masking | Enrollment Criteria for Preterm Infants | Exclusion Criteria |
|---|---|---|---|---|---|
| Subhedar et al28 (1997) | Conventional management ± dexamethasone (2 × 2 factorial design) | Sealed envelopes | Unmasked | Mechanically ventilated; received surfactant therapy; considered high risk for developing BPD as defined by a modified prediction score | Major congenital anomaly, structural cardiac defect, or significant ductal shunting; culture-positive sepsis, IVH with parenchymal involvement; pulmonary or gastrointestinal hemorrhage; disordered coagulation or thrombocytopenia (platelets < 50) |
| Kinsella et al25 (1999) | No gas delivered (sham monitoring) | Sealed opaque envelopes | Masked | Severe hypoxemia defined as arterial to alveolar Po2 ratio of <0.1 on 2 successive blood gas measurements in the first 7 d of life despite mechanical ventilation and surfactant treatment | Fatal congenital anomalies or congenital heart disease (except atrial and ventricular septal defects) |
| Srisuparp et al27 (2002) | No treatment | Card-picking scheme | Unmasked | Birth weight between 500 and 2000 g; received surfactant; had clinical RDS that required mechanical ventilation; were <72 h of age with OIs that exceeded birth weight–specific criteria and had a systemic arterial catheter | Major congenital abnormalities (except PDA and/or foramen ovale) or hydrops fetalis |
| Schreiber et al26 (2003) | Oxygen | Masked | Masked | Birth weight of <2000 g; receiving ventilation for RDS | Major congenital malformations or hydrops fetalis |
| Field et al (INNOVO)23 (2005) | No treatment | Telephone | Masked | Severe respiratory failure that required assisted ventilation if the responsible physician was uncertain about whether an infant might benefit from iNO | Uncorrectable bleeding disorders; cerebral ultrasound evidence of intraparenchymal lesions (Papille grade IV); contraindication to continuation of intensive care (eg, severe congenital abnormalities or lethal chromosomal anomaly) |
| Van Meurs et al29,30 (2005 and 2007) | Placebo (simulated flow) | Telephone | Masked | Diagnosis of RDS, sepsis, or pneumonia, aspiration syndrome, idiopathic persistent pulmonary hypertension, or suspected pulmonary hypoplasia; birth weight between 401 and 1500 g29 or >1500 g30; received assisted ventilation at least 4 h after surfactant therapy and considered at high risk of death or BPD according to OI | Congenital heart disease other than ventricular septal defect, atrial level shunt, or PDA; any major congenital abnormality that involved the respiratory system, thrombocytopenia, or bleeding diathesis or a decision not to provide full treatment |
| Hascoet et al22 (2005) | Placebo | Call-in telephone system | Unmasked | Intubated with hypoxic respiratory failure criteria, defined as the need for mechanical ventilation; Fio2 > 0.4 and a/Ao2 ratio < 0.22 | Refractory hypoxemia, defined as Po2 < 50 and Pco2 < 50 mm Hg for Fio2 = 1.0, thrombocytopenia or major fetal abnormality |
| Dani et al21 (2006) | No treatment | Sealed opaque envelopes | Unmasked | Ventilated with severe respiratory distress; an Fio2 of >0.5 and an a/Ao2 ratio of <0.15 despite surfactant treatment | Major congenital anomaly; hydrops fetalis; thrombocytopenia; bleeding disorder |
| Kinsella et al24 (2006) | Nitrogen | Masked | Masked | Respiratory failure that required mechanical ventilation and birth weight between 500 and 1250 g | Lethal congenital abnormalities or congenital heart disease; active pulmonary hemorrhage; unevacuated pneumothorax; expected duration of ventilation of <48 h |
| Ballard et al19 (2006) | Nitrogen | Central randomization | Masked | Birth weight 500 to 1250 g; receiving mechanical ventilation for lung disease (not apnea) between 7 and 21 d of age; infants with a birth weight of 500–799 g who were being treated with nasal CPAP were also eligible | Life-threatening conditions such as complex congenital abnormalities, bilateral grade IV IVH, or previous iNO treatment |
| Mercier et al (EUNO)31 (2010) | Placebo | Centralized interactive Web-based randomization system | Masked | Birth weight ≥ 500 g and required surfactant within 24 h of birth or CPAP (Fio2 of ≥0.3, on mean airway pressure of at least 4 cm H2O) within 24 h of birth to maintain an oxygen saturation of ≥85% | Required Fio2 of >0.5 to maintain oxygen saturation at >85% on a sufficient mean airway pressure (eg, >8 cm H2O on intermittent mandatory ventilation) to achieve adequate lung expansion 2 h after administration of exogenous surfactant; had substantial congenital heart disease (other than PDA), lung hypoplasia, or abnormal hemostasis; had substantial congenital disorders such that full treatment was not indicated |
IVH indicates intraventricular hemorrhage; RDS, respiratory distress syndrome; PDA, patent ductus arteriosus; Fio2, fraction of inspired oxygen; a/Ao2, alveolar-arterial oxygen gradient; CPAP, continuous positive airway pressure.