Pulmonary vasodilator therapy in the NICU: inhaled nitric oxide, sildenafil, and other pulmonary vasodilating agents

Abstract

The perinatal transition from fetal to extrauterine life requires a dramatic change in the circulatory pattern as the organ of gas exchange switches from the placenta to the lungs. Pulmonary hypertension can occur during early newborn life, and present as early respiratory failure or as a complication of more chronic diseases, such as bronchopulmonary dysplasia. The most effective pharmacotherapeutic strategies for infants with persistent pulmonary hypertension of the newborn are directed at selective reduction of pulmonary vascular resistance. This article discusses currently available therapies for pulmonary hypertension, their biologic rationales, and evidence for their clinical effectiveness.

Fig. 1

Nitric oxide (NO) and prostacyclin (PGI₂) signaling pathways in the regulation of pulmonary vascular tone. NO is synthesized by NO synthase (NOS) from the terminal nitrogen of l-arginine. NO stimulates soluble guanylate cyclase (sGC) to increase intracellular cGMP. PGI₂ is an arachidonic acid (AA) metabolite formed by cyclooxygenase (COX-1) and prostacyclin synthase (PGIS) in the vascular endothelium. PGI₂ stimulates adenylate cyclase in vascular smooth muscle cells, which increases intracellular cAMP. Both cGMP and cAMP indirectly decrease free cytosolic calcium, resulting in smooth muscle relaxation. Specific phosphodiesterases (PDE) hydrolyze cGMP and cAMP, thus regulating the intensity and duration of their vascular effects. Inhibition of these PDE with such agents as sildenafil and milrinone may enhance pulmonary vasodilation. (From Steinhorn RH. Lamb models of pulmonary hypertension. Drug Discov Today Dis Models 2010;7:99–105; with permission.)

Fig. 2

Endothelin (ET)-1 signaling pathway in the regulation of pulmonary vascular tone. Big ET-1 is cleaved to ET-1 by endothelin converting enzyme (ECE) in endothelial cells. ET-1 binds its specific receptors ETA and ETB with differential effects. Binding of ET-1 to ETA or ETB on smooth muscle cells leads to vasoconstrictive and proliferative effects. ETB are transiently expressed on endothelial cells after birth; binding of ET-1 to ETB on endothelial cells leads to downregulation of ECE activity and increased production of nitric oxide (NO) and prostacyclin (PGI₂), which led to vasodilation and antiproliferation.

Fig. 3

Response to intravenous sildenafil. Seven infants were treated with open-label intravenous sildenafil before initiation of iNO. Oxygenation index was improved by 1 hour (24.6 ± 4.6 to 16.1 ± 9.9; *P = .0502), with significant and sustained improvement by 4 hours after initiation of sildenafil (14.7 ± 6.4; ^†P = .0088). Only one infant went on to require therapy with iNO. (From Steinhorn RH, Kinsella JP, Butrous G, et al. Open-label, multicentre, pharmacokinetic study of iv sildenafil in the treatment of neonates with persistent pulmonary hypertension of the newborn (PPHN). Circulation 2007;116:II-614; with permission.)