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

From: Inhaled Nitric Oxide in preterm infants: a systematic review and individual patient data meta-analysis

Study Participants Intervention Primary outcome
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
  1. a/A: arterial/alveolar oxygen ratio
  2. BPD: bronchopulmonary dysplasia
  3. CLD: chronic lung disease
  4. CMV: continuous mechanical ventilation
  5. CPAP: continuous positive airway pressure
  6. CXR: chest X ray
  7. FiO2: fraction of inspired oxygen
  8. g: grams
  9. HFOV: high-frequency oscillatory ventilation
  10. hrs: hours
  11. iNO: inhaled Nitric Oxide
  12. OI: oxygenation index
  13. pma: postmenstrual age
  14. ppm: parts per million
  15. RDS: respiratory distress syndrome
  16. SpO2: oxygen saturation
  17. wks: weeks