title: Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease.
abstract: BACKGROUND
  Nitric oxide (NO) is a prevalent molecule in humans that is responsible for many physiologic activities including pulmonary vasodilation. An exogenous, inhaled form (iNO) exists that mimics this action without affecting systemic blood pressure. This therapy has been implemented in the treatment of pulmonary hypertension. This review examines the efficacy of iNO in the postoperative management of infants and children with congenital heart disease (CHD). The original review was published in 2005, updated in 2008 and again in 2014.
  
  
  OBJECTIVE
  To compare the effects of postoperative administration of iNO versus placebo or conventional management, or both, on infants and children with CHD and pulmonary hypertension. The primary outcome was mortality. Secondary outcomes included length of hospital stay; neurodevelopmental disability; number of pulmonary hypertensive crises (PHTC); changes in mean pulmonary arterial pressure (MPAP), mean arterial pressure (MAP), and heart rate (HR); changes in oxygenation measured as the ratio of arterial oxygen tension (PaO2) to fraction of inspired oxygen (FiO2); and measurement of maximum methaemoglobin level as a marker of toxicity.
  
  
  METHODS
  In this updated version we extended the CENTRAL search to 2013, Issue 12 of The Cochrane Library, and MEDLINE and EMBASE through to 1 December 2013. The original search was performed in July 2004 and again in November 2007. We included abstracts and all languages.
  
  
  METHODS
  We included randomized and quasi-randomized controlled trials comparing iNO with placebo or conventional management, or both. Trials included only children with CHD requiring surgery complicated by pulmonary hypertension.
  
  
  METHODS
  Two authors extracted data. Data were collected on mortality; number of PHTC; changes in MPAP, MAP, HR, and PaO2:FiO2; and maximum methaemoglobin level. Data on long-term mortality, neurodevelopmental disability, and length of hospital stay were unavailable. We performed subgroup analysis by method of control (placebo or conventional management).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street WP493, P.O. Box 208064, New Haven, CT, USA, 06520-8064.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bizzarro
authors.forename: Ian
authors.initials: I
authors.lastname: Gross
authors.forename: Fabiano T
authors.initials: FT
authors.lastname: Barbosa
mesh_terms: D000280:Administration, Inhalation; D002648:Child; D002675:Child, Preschool; D006330:Heart Defects, Congenital / Q000601:surgery*; D006331:Heart Diseases / Q000151:congenital / Q000601:surgery; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality; D007223:Infant; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D011183:Postoperative Complications / Q000188:drug therapy* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic
chemical_list: D009569:Nitric Oxide