P S Shah1, A Ohlsson. 1. University of Toronto, Department of Paediatrics, Rm 775A, 600 University Avenue, Toronto, Ontario, Canada, M5G 1XB. pshah@mtsinai.on.ca
Abstract
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: MEDLINE, EMBASE, CINAHL databases were searched from their inception until March 2007; the Cochrane Central Register of Controlled Trials, the Cochrane Library, the reference lists of identified trials, and abstracts of meetings were searched without any language restriction. SELECTION CRITERIA: Randomized or quasi-randomized 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 at study entry, study intervention and outcomes measurement was minimized. 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: Two small eligible trials (one full article and one abstract) were identified. The methodological quality of the trial presented in the full article was good. Information provided in the abstract was limited. The total number of enrolled patients in the two studies was 37. Both studies were performed in resource-limited settings where iNO and high frequency ventilation are not available. Both studies reported statistically significant improvement in oxygenation (reduction in oxygenation index) in the Sildenafil group. One study reported what would be, if replicated, a strongly protective effect on mortality (RR 0.17, 95% CI 0.03, 1.09) favoring the Sildenafil group. However, this result needs to be replicated in larger studies. No clinically important side effects were reported. AUTHORS' CONCLUSIONS: The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials. Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN.
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: MEDLINE, EMBASE, CINAHL databases were searched from their inception until March 2007; the Cochrane Central Register of Controlled Trials, the Cochrane Library, the reference lists of identified trials, and abstracts of meetings were searched without any language restriction. SELECTION CRITERIA: Randomized or quasi-randomized 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 at study entry, study intervention and outcomes measurement was minimized. 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: Two small eligible trials (one full article and one abstract) were identified. The methodological quality of the trial presented in the full article was good. Information provided in the abstract was limited. The total number of enrolled patients in the two studies was 37. Both studies were performed in resource-limited settings where iNO and high frequency ventilation are not available. Both studies reported statistically significant improvement in oxygenation (reduction in oxygenation index) in the Sildenafil group. One study reported what would be, if replicated, a strongly protective effect on mortality (RR 0.17, 95% CI 0.03, 1.09) favoring the Sildenafil group. However, this result needs to be replicated in larger studies. No clinically important side effects were reported. AUTHORS' CONCLUSIONS: The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials. Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN.