Several cases of pulmonary hypertension after prophylactic and therapeutic use of ibuprofen for ductal closure have been reported [1-7]. In such cases, pulmonary vasodilators have been used with variable response. We report a positive response to the concomitant use of inhaled nitric oxide and oral sildenafil in an extremely premature neonate who developed severe pulmonary hypertension after ibuprofen administration.

A preterm (26 weeks) neonate, second child of triplet pregnancy, weighing 750 g was born to a 18-year-old mother who received corticosteroids and magnesium sulfate before delivery. The infant was delivered via cesarean section. He was intubated in the delivery room. The initial course involved mechanical ventilation and surfactant therapy with poor response; he was placed on high-frequency oscillatory ventilation (HFOV) on day 5 and remained stable on moderate settings.

Pulmonary hypertension is a rare but potentially lethal adverse effect of ibuprofen administration for the treatment of PDA. It may be related either to early administration of the drug, that prevents a normal drop in pulmonary vascular resistance, or to acidification of the ibuprofen solution resulting in precipitation and secondary microembolism of the lung [3]. Although this effect was initially thought to be associated with prophylactic treatment or when ibuprofen was buffered with tromethamine [1], a few cases have been observed after therapeutic use of L-lysine ibuprofen.

Most reported cases responded well to the use of iNO but some infants died despite aggressive treatment. An earlier report of the concomitant use of iNO and sildenafil in this setting reported poor outcome [5]. Our patient did not respond to iNO but pulmonary hypertension reversed with the administration of oral sildenafil. Sildenafil is a selective phosphodiesterase 5 (PDE 5) inhibitor which increases cGMP levels inducing pulmonary vascular relaxation. Oral sildenafil is the standard treatment of chronic pulmonary hypertebnsion, and is also used to aid weaning from iNO therapy in term infants. However, its use as an emergency treatment of acute pulmonary hypertension is limited and dosing regimen is not clear [8].

Studies in neonates with pulmonary hypertension have shown that sildenafil selectively reduces pulmonary vascular resistance (PVR) with few systemic effects [9]. It has been shown to have an onset of action in 30 to 120 minutes and its potential side effects include arterial hypoxemia, hypotension and retinopathy of prematurity [9]. Our patient developed stage III ROP which regressed spontaneously.

We conclude that pulmonary hypertension is a rare but potentially lethal side effect in preterm infants receiving ibuprofen for PDA closure. In case of absent or partial response to iNO, the administration of oral sildenafil may be effective.

Contributors: RC: coordinated and supervised patient management and drafted the initial manuscript.; EA: reviewed and revised the manuscript. LA: coordinated and supervised patient management and critically reviewed the manuscript. All authors approved the final version of manuscript.

Funding: None; Competing interest: None stated.

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