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Meta-Analysis
. 2017 Aug 4;8(8):CD005494.
doi: 10.1002/14651858.CD005494.pub4.

Sildenafil for pulmonary hypertension in neonates

Lauren E Kelly  1 , Arne Ohlsson, Prakeshkumar S Shah
Affiliations
Meta-Analysis

Sildenafil for pulmonary hypertension in neonates

Lauren E Kelly et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: To assess the efficacy and safety of sildenafil for treatment of pulmonary hypertension in neonates.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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 I2 test of heterogeneity and used GRADE to assess the quality of evidence.

Main results: 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; I2 = 0% - none; typical RR -0.36, 95% CI -0.53 to -0.18; number needed to treat for an additional beneficial outcome 3, 95% CI 2 to 6; I2 = 39% - low). Trials reported no significant differences in mortality upon comparison of the sildenafil group versus the active control group (one study, 65 participants; typical RR 0.55, 95% CI 0.05 to 5.75), or when iNO was administered to both groups (one study, 24 participants; typical RR 1.27, 95% CI 0.26 to 6.28). Physiological parameters of oxygenation (oxygenation index, partial pressure of oxygen in arterial blood (PaO2)) suggested steady improvement after the first dose of sildenafil. None of the included trials identified any clinically important side effects. We rated the quality of evidence as low to very low owing to imprecision related to small sample size and unclear methodological features.

Authors' conclusions: Sildenafil used for treatment of pulmonary hypertension has potential for reducing mortality and improving oxygenation in neonates, especially in resource-limited settings where iNO is not available. However, large-scale randomised trials comparing sildenafil versus active controls (other pulmonary vasodilators) and providing follow-up for survivors are needed to assess the comparative effectiveness and long-term safety of sildenafil versus other pulmonary vasodilators.

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Conflict of interest statement

The review authors have no conflicts of interest to declare.

Figures

1
1
Study flow diagram: review update.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Sildenafil versus placebo, Outcome 1 Pulmonary arterial pressure.
1.2
1.2. Analysis
Comparison 1 Sildenafil versus placebo, Outcome 2 PaO2 in mmHg (absolute values).
1.3
1.3. Analysis
Comparison 1 Sildenafil versus placebo, Outcome 3 Mean arterial blood pressure in mmHg.
1.4
1.4. Analysis
Comparison 1 Sildenafil versus placebo, Outcome 4 All‐cause mortality.
1.5
1.5. Analysis
Comparison 1 Sildenafil versus placebo, Outcome 5 Oxygenation index (absolute values).
1.6
1.6. Analysis
Comparison 1 Sildenafil versus placebo, Outcome 6 Change in oxygenation index.
1.7
1.7. Analysis
Comparison 1 Sildenafil versus placebo, Outcome 7 A‐a DO2 difference.
1.8
1.8. Analysis
Comparison 1 Sildenafil versus placebo, Outcome 8 Mean airway pressure.
2.1
2.1. Analysis
Comparison 2 Sildenafil versus active control, Outcome 1 All‐cause mortality.
2.2
2.2. Analysis
Comparison 2 Sildenafil versus active control, Outcome 2 Time to adequate response (days).
2.3
2.3. Analysis
Comparison 2 Sildenafil versus active control, Outcome 3 Duration of ventilation (days).
2.4
2.4. Analysis
Comparison 2 Sildenafil versus active control, Outcome 4 Inotropic agent.
3.1
3.1. Analysis
Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 1 All‐cause mortality.
3.2
3.2. Analysis
Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 2 Length of stay in hospital (days).
3.3
3.3. Analysis
Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 3 Inotropic agent.
3.4
3.4. Analysis
Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 4 Duration of ventilation (days).
3.5
3.5. Analysis
Comparison 3 Sildenafil plus iNO versus placebo plus iNO, Outcome 5 Retinopathy of prematurity.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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