Neonatal pulmonary hypertension

Abstract

When the normal cardiopulmonary transition fails to occur, the result is persistent pulmonary hypertension of the newborn. Severe persistent pulmonary hypertension of the newborn is estimated to occur in 2 per 1000 live-born term infants, and some degree of pulmonary hypertension complicates the course of >10% of all neonates with respiratory failure. This review article discusses the vascular abnormalities that are associated with neonatal pulmonary hypertension, including recognition of its role in severe bronchopulmonary dysplasia in preterm infants. A systematic review of the evidence for common therapies including inhaled nitric oxide, high-frequency ventilation, surfactant, and extracorporeal life support is included. Finally, this field is rapidly evolving, and the rationale for promising new treatment approaches is reviewed, including inhibition of phosphodiesterases and scavengers of reactive oxygen species.

Figure 1

Nitric oxide (NO) and prostacyclin (PGI₂) signaling pathways in the regulation of pulmonary vascular tone. NO is synthesized by nitric oxide 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 hydrolyze cGMP and cAMP, thus regulating the intensity and duration of their vascular effects. Inhibition of these phosphodiesterases with agents such as sildenafil and milrinone may enhance pulmonary vasodilation.

Figure 2

Increased reactive oxygen species (ROS) such as superoxide and hydrogen peroxide are produced in the vascular wall of pulmonary vessels affected by persistent pulmonary hypertension of the newborn (PPHN). In addition, even brief exposures to hyperoxia elevate cellular levels of ROS in the neonatal pulmonary vasculature. Increased ROS diminish nitric oxide synthase (NOS) activity and increase type 5 phosphodiesterase (PDE5) activity, both of which blunt the normal production of cGMP.

Figure 3

Normal lambs were ventilated with 21% or 100% oxygen for 30 minutes at the time of birth. After recovery, pulmonary vascular tone was increased with a thromboxane analog, and the lambs received 20 ppm inhaled NO or an infusion of acetylcholine (1 μg/kg/min) to stimulate endogenous nitric oxide synthase (NOS) activity. Exposure to 30 minutes of hyperoxia blunted the responses to both exogenous and endogenous NO (43).