Abstract: We reran the searches to December 2013 and identified three new studies. These three studies did not fulfil our inclusion criteria. Therefore, no new studies were included in this updated review. In total four randomized trials involving 210 participants were included in this review. We observed no differences in mortality (OR 1.67, 95% CI 0.38 to 7.30; P = 0.50); PHTC (OR 0.80, 95% CI 0.15 to 4.18; P = 0.79); changes in MPAP (treatment effect -2.94 mm Hg, 95% CI -9.28 to 3.40; P = 0.36), MAP (treatment effect -3.55 mm Hg, 95% CI -11.86 to 4.76; P = 0.40), HR (treatment effect 0.02 bpm, 95% CI -8.13 to 8.18; P = 1.00), or PaO2:FiO2 (mean difference 17.18, 95% CI -28.21 to 62.57; P = 0.46). There was a significant increase in the methaemoglobin level (mean difference 0.30%, 95% CI 0.24 to 0.36; P < 0.00001) in patients treated with iNO, although levels did not reach toxicity levels. Data from long-term mortality, neurodevelopmental disability, and length of stay were not available. Two trials had a low risk of bias. Very low quality of the evidence was observed considering grading of the outcomes. We observed no differences with the use of iNO in the outcomes reviewed. No data were available for several clinical outcomes including long-term mortality and neurodevelopmental outcome. We found it difficult to draw valid conclusions given concerns regarding methodologic quality, sample size, and heterogeneity.

Plain-language summary: The evidence was current to December 2013. We found four randomized clinical trials involving 210 participants aged from one day to 17 years with PH either in the preoperative (one study) or postoperative period (three studies). Control groups received conventional management therapy (two trials) or nitrogen gas as placebo (two trials). Two trials compared changes in systemic and pulmonary arterial blood pressure and heart rate (haemodynamics). The other two trials compared the number of pulmonary hypertensive crises and deaths, with changes in haemodynamic measurements as secondary outcomes. We found no differences between the groups of patients who received iNO and those that did not. Two trials reported on deaths before discharge, with none occurring in one of the trials. We observed no differences in the number of deaths (two trials); pulmonary hypertensive crises (one trial); changes in mean pulmonary arterial pressure (three trials), arterial pressure (three trials), or heart rate (HR) (three trials); or changes in oxygenation of the blood (one trial). However, no trials reported long-term deaths or neurodevelopmental disability. In addition, no data were available for analysis of length of hospital stay. Although iNO has been studied as a postsurgical therapy in children with heart disease in order to assist recovery, this review showed no benefits with its use. Two trials had a low risk of bias. The quality of the evidence was, however, very low due to the small number of participants and low event rates. All trials utilized different concentrations of iNO, different durations of administration initiated at different times after the operation, and included patients with diverse congenital heart defects necessitating repair.