International Journal of Clinical Pediatrics, ISSN 1927-1255 print, 1927-1263 online, Open Access
Article copyright, the authors; Journal compilation copyright, Int J Clin Pediatr and Elmer Press Inc
Journal website http://www.theijcp.org

Review

Volume 2, Number 1, June 2013, pages 1-11

Persistent Pulmonary Hypertension of the Newborn: Recent Advances in the Management

Figure

Figure 1.
Figure 1. Role of nitric oxide (NO) and prostacyclin (PGI2) signaling pathways in the regulation of pulmonary vascular tone and mechanism of action of different pharmacologic agents. Endothelial NO synthase (eNOS) enzyme stimulates the synthesis of NO by stimulating the conversion of L-arginine to L-citrulline. NO increases intracellular cyclic guanosine monophosphate (cGMP) levels by stimulating soluble guanylate cyclase (sGC) enzyme. PGI2 is an arachidonic acid (AA) metabolite formed by cyclooxygenase (COX) and prostacyclin synthase (PGIS) enzymes in the vascular endothelium. PGI2 stimulates adenylate cyclase in vascular smooth muscle cells, which increases intracellular cyclic adenosine monophosphate (cAMP) levels. Both cGMP and cAMP mediate smooth muscle relaxation by decreasing free cytosolic calcium levels. These cyclic nucleotides are degraded by type 5 and type 3 phosphodiesterase (PDE) respectively thus limiting the duration of vasodilation. Sildenafil and milrinone inhibits PDE-5 and PDE-3 respectively and enhance pulmonary vasodilation. NO levels are decreased by endogenous NO antagonist asymmetric dimethyl arginine (ADMA), superoxide (O2─), and endothelin (ET-1). Exogenous NO administration, endothelin receptor antagonist (bosentan) and rhSOD (recombinant human superoxide dismutase) treatment may promote vasodilation in PPHN by increasing NO levels. Antenatal exposure to non-steroidal anti-inflammatory drugs (NSAIDs) may cause PPHN by interfering with prostacyclin pathway through inhibition of COX. Prostacyclin analogues (PGI2, beraprost sodium, iloprost) may help in PPHN by promoting vasodilation mediated via stimulation of adenylate cyclase. GTP: guanosine triphosphate; ATP: adenosine triphosphate.

Table

Table 1. Drugs Used for Management of PPHN
 
TherapyMechanism of ActionDosesSide Effects
NO: nitric oxide; sGC: soluble guanylate cyclase; PDE: phosphodiesterase; SMC: smooth muscle cell; cGMP: cyclic guanosine monophosphate; cAMP: cyclic adenosine monophosphate; IV: intravenous; PO: per oral.
Inhaled NO [46]Increased cGMP levels via stimulation of sGC activity5 -20 ppm through ventilatorMethemoglobinemia, formation of NO2 and peroxinitrite, inhibition of platelet aggregation
Dipyridamole [47]Increased cGMP levels via non-specific PDE inhibitionIV 0.3 - 0.6 mg/kgSystemic vasodilation and hypotension
Sildenafil [50, 51]Increased cGMP levels via specific PDE-5 inhibitionPO 0.5 - 2 mg/kg/dose every 6 hours IV 0.4 mg/kg over 3 hr loading f/b infusion 1.6 mg/kg/dHypotension especially with NO, impaired retinal vascular growth, thrombocytopenia is a relative contraindication
Milrinone [53]Increased cAMP levels via specific PDE-3 inhibition0.33 - 0.99 µg/kg/min IV infusionSystemic hypotension, Intraventricular hemorrhage (IVH)
Prostacyclin (PGI2) [54, 55]Increased cAMP levels via adenylate cyclase enzyme5 - 40 ng/kg/min IV infusionHypotension
Iloprost [56]Increased cAMP levels via adenylate cyclase enzyme20 µg/kg/dose every 90 min inhalationNone reported
Beraprost sodium [57]Increased cAMP levels via adenylate cyclase enzyme0.5 - 1.0 µg/kg/dose 12 hourlyWatery diarrhoea, flushing, headache
Magnesium Sulphate [59]Modulates vascular contraction by affecting calcium influx thereby inhibits SMC depolarization and promotes vasodilationIV 200 mg/kg loading over 20 min f/b 20 - 150 mg/kg/h infusionBradycardia, hypotension, respiratory depression
Adenosine [60, 61]Release of endogenous NO, stimulation of K+-ATP channels, and decreased calcium influx30-90 µg/kg/min IV infusion
Bosentan [62, 63]Increased cGMP levels via ET-1 receptor antagonismPO 1 mg/kg/dose 12 hourlySystemic hypotension