Sildenafil for pulmonary hypertension in neonates

• Published in: Cochrane database of systematic reviews 2017-08, Vol.8 (8), p.CD005494
• Main Authors: Kelly, Lauren E, Ohlsson, Arne, Shah, Prakeshkumar S
• Format: Article
• Language: English
• Subjects: Bronchodilator Agents - therapeutic use; Cause of Death; Child health; Humans; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - mortality; Infant, Newborn; Neonatal care; Nitric Oxide - therapeutic use; Randomized Controlled Trials as Topic; Respiratory Disorders; Sildenafil Citrate - therapeutic use; Vasodilator Agents - therapeutic use
• ISSN: 1469-493X; 1469-493X
• DOI: 10.1002/14651858.CD005494.pub4

Persistent pulmonary hypertension in the neonate (PPHN) is associated with high mortality. Currently, the therapeutic mainstay for PPHN consists of assisted ventilation and administration of inhaled nitric oxide (iNO). However, nitric oxide is costly, and its use may not be appropriate in resource-poor settings. Approximately 30% of patients fail to respond to iNO. High concentrations of phosphodiesterases in the pulmonary vasculature have led to the use of phosphodiesterase inhibitors such as sildenafil or milrinone. To assess the efficacy and safety of sildenafil for treatment of pulmonary hypertension in neonates. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 3), MEDLINE via PubMed (1966 to 18 April 2017), Embase (1980 to 18 April 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 18 April 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We included randomised and quasi-randomised controlled trials of sildenafil compared with placebo or other pulmonary vasodilators, irrespective of dose, route, and duration of administration, in neonates with pulmonary hypertension, if investigators reported any of the prespecified outcomes. We assessed the methodological quality of trials regarding how bias was minimised at study entry, during study intervention, and at outcomes measurement. We extracted data on relevant outcomes; we estimated the effect size and reported it as risk ratio (RR), risk difference (RD), or mean difference (MD), as appropriate. We applied the I test of heterogeneity and used GRADE to assess the quality of evidence. For this update, we identified two additional studies, for a total of five eligible trials that enrolled 166 infants. The methodological quality of these studies ranged from low to high risk of bias. Three studies were performed in resource-limited settings, where iNO and high-frequency ventilation were not available at the time of the study. One study compared sildenafil versus active controls, and another study evaluated sildenafil as adjuvant therapy to iNO. When comparing sildenafil with placebo, investigators noted significant reduction in mortality in the sildenafil alone group (three studies, 77 participants; typical RR 0.20, 95% confidence interval (CI) 0.07 to 0.56; I