What is the role of sildenafil in the treatment of persistent pulmonary hypertension of the newborn (PPHN)?

Updated: Sep 03, 2019
  • Author: Kate A Tauber, MD; Chief Editor: Howard S Weber, MD, FSCAI  more...
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Among the 11 isoforms of phosphodiesterases (PDEs), the most important are the PDE3 and PDE5 isoforms, which degrade cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), respectively.

Sildenafil, a PDE5 inhibitor was shown to selectively reduce pulmonary vascular resistance in both animal models and adult humans. It also has been reported to be successful in the treatment of infants with PPHN. [50]  It is presently available in both oral and intravenous forms; however, the intravenous form increases the possible side effect of systemic vasodilation. Intravenous administration was shown in one study to improve oxygenation in patients with PPHN with and without prior exposure to iNO. [51]

In a Cochrane meta-analysis with 37 newborns from centers that did not have access to iNO and HFV, significant improvement in oxygenation was observed in the group receiving sildenafil. [52] This study noted that sildenafil may be a treatment option for PPHN.

Additional studies are needed to assess the safety and efficacy of sildenafil compared with treatment with the more costly iNO. [53]

Abmen et al reported on the FDA's recent warning against using sildenafil for pediatric pulmonary hypotension in patients aged 1-17 years because of an apparent increase in mortality if used in high doses for long-term therapy. This warning, which is based on extremely limited data, indicates the need for further assessment of the efficacy and safety of sildenafil, especially with long-term treatment. [54]

A more recent systematic review of off-label use of sildenafil in premature infants at risk for bronchopulmonary dysplasia (BPD) or BPD-associated pulmonary hypertension as well as term or near-term infants with pulmonary hypertension reported little evidence to support the use of sildenafil in term or near-term infants with PPHN in areas where iNO is available. [55] The investigators also noted the need for more data regarding sildenafil dosing, safety, and efficacy in premature, term, and near-term infants with pulmonary hypertension. [55]

Milrinone is an ionotropic vasodilator which inhibits PDE3 and has been shown to relax pulmonary arteries in lamb models of PPHN. [51]   Although not widely used, it has been reported in a case series to be effective in treating infants with severe PPHN. [56]

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