Sildenafil for pulmonary hypertension in neonates.

BACKGROUND: Persistent pulmonary hypertension in neonates (PPHN) is associated with high mortality. Currently, the therapeutic mainstay for PPHN is assisted ventilation and administration of inhaled nitric oxide (iNO). However, nitric oxide is costly and 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 has led to the use of phosphodiesterase inhibitors such as sildenafil or milrinone.

OBJECTIVES: To assess the efficacy and safety of sildenafil in the treatment of persistent pulmonary hypertension in neonates.

SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL databases were searched from their inception until December 2010; Clinicaltrials.gov web site, the reference lists of identified trials, and abstracts of meetings were searched without any language restriction.

SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of sildenafil compared with placebo or other pulmonary vasodilators, irrespective of dose, route and duration of administration in neonates with PPHN, were included if the trial reported any of the pre-specified outcomes.

DATA COLLECTION AND ANALYSIS: The methodological quality of the trials was assessed regarding how bias was minimized at study entry, during study intervention and at outcomes measurement. Data on relevant outcomes were extracted and the effect size was estimated and reported as relative risk (RR), risk difference (RD) and weighted mean difference (MD) as appropriate. The I-squared (I(2)) test of heterogeneity was applied.

MAIN RESULTS: Three eligible trials that enrolled 77 infants were identified. The methodological quality of the studies indicated low-moderate risk of bias. All studies were performed in resource-limited settings where iNO and high frequency ventilation were not available at the time of study. There was significant reduction in mortality in the sildenafil group (typical RR 0.20, 95% CI 0.07 to 0.57; typical RD -0.38, 95% CI -0.60 to -0.16; Number needed to treat to benefit 3, 95% CI 2 to 6). Physiological parameters of oxygenation (oxygenation index, PaO(2)) suggested a steady improvement after the first dose of sildenafil. No clinically important side effects were identified.

AUTHORS' CONCLUSIONS: Sildenafil in the treatment of PPHN has significant potential especially in resource limited settings. However, a large scale randomised trial comparing sildenafil with the currently used vasodilator, inhaled nitric oxide, is needed to assess efficacy and safety.