Table 2 MAPPiNO Collaboration: description of eligible trials as at October 2009

Ballard 2006

582 infants <1250 g and <32 wks on assisted ventilation at 7-21 days (or, if <800 g, on CPAP)

Inhaled NO at 20 ppm initial dose for 48 to 96 hours, then dose subsequently decreased to 10, 5, and 2 ppm at weekly intervals, with a minimum treatment duration of 24 days

Survival without BPD at 36 wks postmenstrual age

Dani 2006

40 infants <30 wks ventilated with severe RDS: FiO₂ >0.5 and arterial-alveolar oxygen ratio < 0.15 despite surfactant treatment

Inhaled NO at 10 ppm for 4 hours followed by 6 ppm. Weaning (decrease by 2 ppm every 3 hrs) started at 72 hrs or when the infant was extubated or when the FiO₂ <0.3 with a mean airway pressure <8 cmH₂O

Death or BPD (oxygen requirement at 36 weeks postconceptional age) in survivors

Hascoet 2005

860 infants <32 wk enrolled at birth; n = 145 infants were eligible for study gas as had hypoxic respiratory failure (defined as need for mechanical ventilation, FiO₂>0.40 and arterio-alveolar O₂ ratio <0.22) at 6-48 hrs age

Inhaled NO was administered starting at 5 ppm, with adjustments allowed depending on response up to a maximum of 10 ppm.

Subjects were allowed to receive (unblinded) iNO in either group if they developed refractory hypoxemia.

Intact survival at 28 days (defined as alive without need for oxygen supplementation or IVH >grade 1 or refractory hypoxaemia (need for 100% oxygen with PaO₂<50 mmHg) and PCO₂ <50 mmHg)

INNOVO 2005

108 preterm infants (<34 wks) less than 28 days of age with severe respiratory failure requiring ventilator support and have had surfactant when appropriate

Inhaled NO usually at 5 ppm, up to 40 ppm based on response criteria (satisfactory response: increase in PaO₂ >22.5 mmHg after 15 minutes iNO)

1) Death or severe disability at 1 year corrected age; and

2) Death before discharge or continued oxygen need at 36 wks pma and/or at expected date of delivery

Kinsella 1999

80 preterm infants (</= 34 weeks) aged 7 days or less, with a/A ratio <0.1 on two sequential arterial blood measurements despite mechanical ventilation and surfactant treatment

Inhaled NO at 5 ppm for 7 days after which periods of no study gas were tried; threshold criteria for gas re-start was an increase of >/=15% in OI; maximum treatment duration was 14 days

Survival to discharge

Kinsella 2006

793 preterm infants < 34 wks, with respiratory failure needing assisted ventilation in first 48 hours of life

Inhaled NO at 5 ppm for 21 days or until extubation

Death or BPD (need for supplemental oxygen or mechanical ventilation at 36 wks pma and abnormal CXR)

Schreiber 2003

207 infants < 34 wks and < 2000 g birth weight, < 72 hours of age, and intubated/ventilated for RDS, having had exogenous surfactant

Inhaled NO starting at 10 ppm for 12-24 hrs, then 5 ppm for 6 days, then weaned by 1 ppm every 6 hrs if PaO₂ did not decrease by more than 15% until extubation; 2 × 2 factorial trial of iNO vs control gas and HFOV vs CMV

Death or CLD (supplemental oxygen and CXR showing persistent parenchymal lung disease at 36 weeks pma) among surviving infants

Srisuparp 2002

34 infants < 2000 g, ventilated after surfactant with an arterial catheter and less than 72 hours of age + satisfying severity of illness criterion: OI >4 if birthweight<1000 g; >6 if 1001-1250 g; >8 if 1251-1500 g; >10 if 1501-1750 g; and >12 if 1751-2000 g birthweight

Inhaled NO at 20 ppm for 6-12 hrs, then reduced to 10 ppm, and weaned to 5 ppm in the next 12 hrs; weaning tolerated if PaO₂did not decrease by more than 15%; once 5 ppm achieved, weaning was attempted at 1 ppm a time as tolerated until gas discontinued; maximum duration allowed was 7 days

Severe intraventricular hemorrhage (grade 3 or 4)

Subhedar 1997

42 preterm infants, < 32 wks, assessed at 96 hrs age for: mechanical ventilation since birth, had received surfactant, and high risk of developing CLD using a modified prediction score

Inhaled Nitric Oxide at 20 ppm for 2 hrs then weaned according to response criteria (positive response: decrease in OI by >=25% or reduction in FiO₂ of >=0.10) by 5 ppm increments every 15 mins until 5 ppm level for further 72 hrs, then weaned off; 2 × 2 factorial trial of iNO vs control and IV dexamethasone vs control

Death before discharge or CLD (oxygen dependency for at least 28 days and beyond 36 wks pma with abnormal CXR)

Van Meurs 2005

420 preterm infants, < 34 weeks, 401-1500 g birthweight, assisted ventilation, OI >=10 on two consecutive blood gases 30 min -12 hrs apart at least 4 hrs after surfactant

Inhaled Nitric Oxide initially at 5-10 ppm; weaning commenced 10-14 hrs after initiation according to response criteria (change in PaO₂); at 30 min intervals; maximum duration was 336 hours

Death or BPD at 36 wks in survivors

EUNO 2008

800 preterm infants <29 wks, birthweight >=500 g requiring either surfactant or CPAP >4 cmH₂O with FiO₂ >0.3 to maintain SpO₂ ≥ 85%

Inhaled NO 5 ppm for minimum 7 to maximum of 21 days if still requiring respiratory support (including CPAP use)

Survival without BPD at 36 wks post conceptional age