Description of the condition

Pulmonary hypertension (PH) in neonates, or persistent pulmonary hypertension of newborns (PPHN), is a serious disorder of the pulmonary vasculature that results from failure of successful postnatal transition of faetal pulmonary circulation. A normal transition includes a decrease in pulmonary vascular resistance (PVR) to 50% of systemic vascular resistance (SVR), a 10‐fold increase in pulmonary blood flow due to expansion and oxygenation of the alveoli, a decrease in the ratio of pulmonary vasoconstrictors to vasodilators, and clamping of the umbilical cord (Teitel 1990; Cornfield 1992; Cabral 2013). In PPHN, the PVR is elevated compared to the SVR; this may be due to low oxygen tension in the lung and an increased ratio of pulmonary vasoconstrictors to vasodilators, or to abnormal function and/or anatomy of the musculature of lung blood vessels, independent of the mechanism(s) for high PVR, blood shunts away from the lungs through a right‐left shunt through the ductus arteriosus or foramen ovale, or both (Lakshminrusimha 1999). PPHN is confirmed by the presence of a right‐left shunt through the ductus arteriosus or foramen ovale, or both, without accompanying heart disease, irrespective of pulmonary artery pressure (Lakshminrusimha 2012; Porta 2012; Cabral 2013; Ivy 2013).

The incidence of PPHN ranges from 0.4 to 2 per 1000 live births, with associated mortality of around 11% (Walsh‐Sukys 2000; Cabral 2013). Several mechanisms for PPHN may be divided into the following categories.

• Acute pulmonary vasoconstriction as a result of abundance of endogenous pulmonary vasoconstrictors compared to vasodilators; this may be associated with maternal diabetes, antenatal exposure to non‐steroidal anti‐inflammatory medications, elective caesarean section delivery, perinatal asphyxia, meconium aspiration syndrome, pneumonia, sepsis, hyaline membrane disease, or metabolic acidosis.

• Pulmonary vascular remodeling, which is characterized by pulmonary artery smooth muscle hyperplasia, adventitial thickening, and muscularization of intra‐acinar arteries (e.g. congenital diaphragmatic hernia (CDH), chronic intrauterine hypoxia, antenatal ductal closure).

• Pulmonary vascular hypoplasia, a condition characterized by decreased pulmonary blood vessels and cross‐sectional area of the pulmonary vascular bed, thereby elevating PVR and causing flow restriction (e.g. CDH, intrathoracic space‐occupying lesions, chronic oligohydramnios).

• Pulmonary intravascular obstruction characterized by blood flow restriction from conditions such as polycythemia and obstructed anomalous pulmonary venous drainage (Lakshminrusimha 2012; Cabral 2013; Storme 2013).

The gold standard for the diagnosis of PH is cardiac catheterization. However, this invasive procedure is not performed in most patients suspected to have PH, and the diagnosis is based on one or more of the following echocardiographic (Echo) findings: right ventricular systolic pressure/systemic systolic blood pressure ratio > 0.5 ascertained via assessment, interventricular septal flattening, cardiac shunt with bidirectional or right‐to‐left blood flow, and right ventricular hypertrophy in the absence of congenital heart disease (Mourani 2008; Bhat 2012; Mourani 2015).

The only intervention proven to improve clinical outcomes in PPHN is inhaled nitric oxide (iNO), a selective pulmonary vasodilator. Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor that causes vasodilatation by preventing cyclic guanosine monophosphate (GMP) breakdown in smooth muscle cells. It is commonly used as add‐on therapy to iNO for infants with iNO‐refractory PH, for weaning off iNO therapy, or as primary therapy for PPHN in resource‐limited places where iNO is not available (Lakshminrusimha 2016). However, evidence is insufficient to support recommending this as first‐line or sole therapy for infants with PH (Kelly 2017). This review is focused mainly on prostanoids and their analogues for the treatment of pulmonary hypertension in neonates. Other therapeutic measures for PH in neonates include optimizing lung volumes, providing adequate alveolar recruitment, and optimizing cardiac function. These supportive measures provide the context for treatment with other pulmonary vasodilators such as inhaled nitric oxide (iNO), prostanoids, phosphodiesterase inhibitors such as sildenafil and milrinone, and endothelin antagonists such as bosentan, in addition to general supportive care such as maintenance of temperature and correction of electrolyte and metabolic derangements (Porta 2012; Steinhorn 2012; Cabral 2013; Storme 2013).

Description of the intervention

Prostanoids are metabolites of arachidonic acid that include prostaglandins, prostacyclin (also called prostaglandin I₂, or PGI₂), and thromboxanes. The enzyme cyclo‐oxygenase converts arachidonic acid to an unstable intermediate, prostaglandin G, and various synthase enzymes catalyze reactions leading to the production of various prostanoids including prostacyclin and prostaglandin E (PGE) (Ivy 2010). The prostanoids have numerous biological functions, and many are vasodilators, whereas thromboxanes are vasoconstrictors and are not useful in the treatment of PH. In addition to being a potent pulmonary vasodilator, PGI₂ exerts antithrombotic, antiproliferative, antimitogenic, and immunomodulatory activities (Read 1985; Jones 1997; Wharton 2000; Vane 2003). Prostanoids and their analogues that can be administered by various routes (e.g. intravenous, subcutaneous, by inhalation, by nebulization) are available for clinical use (Keller 2016).

Epoprostenol (Flolan) is the most commonly administered synthetic PGI₂ analogue used to treat pulmonary arterial hypertension in adults (Dorris 2012). Epoprostenol has a very short half‐life (< 5 minutes) that requires stable vascular access for administration as a continuous infusion. Evidence in children and adults with PH suggests that epoprostenol improves pulmonary hemodynamics, exercise capacity, quality of life, and survival (Barst 1994; Barst 1996; Barst 1999; Rosenzweig 1999; Sitbon 2002; Yung 2004). Children usually require a higher dose of epoprostenol than adults to obtain beneficial vasodilatory effects (Ivy 2010; Steinhorn 2012). Intravenous epoprostenol is initiated at a dose of 1 ng/kg/min and is gradually titrated to a dose of up to 50 to 100 ng/kg/min (Ivy 2010; Porta 2012). The most common side effects of intravenous prostacyclin are secondary to systemic vasodilation that leads to systemic hypotension, flushing, diarrhea, headache, jaw pain, alterations in hepatic enzymes, and an erythematous blotchy skin rash (Ivy 2010; Steinhorn 2012). Any interruption of its infusion can result in severe rebound PH and even death (Rubin 1990; Barst 1994; Doran 2008).

Iloprost is a prostacyclin analogue with a half‐life of 20 to 30 minutes, which can be administered intravenously or by inhalation or nebulization (Ewert 2009). Administration by inhalation or nebulization results in selective pulmonary vasodilation and improved ventilation/perfusion mismatch, and limits systemic side effects. However, the need for repeated nebulizations and side effects such as development of reactive airway disease limit its use (Ivy 2008; Ivy 2010; Dorris 2012). The main side effects are increased need for inotropic support among infants, as reported in Janjindamal 2013, and headache and cough in adults (Saji 2016).

Treprostinil is a long‐acting tricyclic benzindene prostacyclin analogue with a half‐life of about three hours that can be administered subcutaneously, intravenously, orally, or by inhalation (McNulty 1993). It is most commonly administered subcutaneously via a microinfusion pump. The main side effect is pain at the site of subcutaneous administration. However, treprostinil has fewer side effects when compared to epoprostenol (Ivy 2007; Doran 2008; Ivy 2010). Common side effects of this medication used in adults are headache, diarrhea, flushing, and jaw pain (Tapson 2013).

Beraprost, an oral prostacyclin analogue that is readily absorbed from the small intestine, is rapidly and almost completely excreted in the urine and the faeces after oral dosing (Olschewski 2004). A retrospective study reports its use in neonates with PH (Nakwan 2011). Hypotension is a common side effect of this medication in infants (Nakwan 2011).

The optimal dose of iloprost and treprostinil for treatment of neonates and infants with PH remains to be determined.

PGE₁ is used widely in neonatology to maintain patency of the ductus arteriosus in cases of duct‐dependent congenital heart disease. Compared to PGI₂, PGE₁ has a shorter half‐life; in addition, PGE₁ exerts bronchodilatory action and anti‐inflammatory effects on the lung. Inhaled PGE₁ has been shown to be a selective pulmonary vasodilator in neonates with hypoxic respiratory failure (Sood 2004), as well as in adults with acute lung injury and pulmonary hypertension (Putensen 1998). In adults, the side effects of PGE₁ include hypotension, nausea, vomiting, and fatigue (Koch 2000).

How the intervention might work

Prostacyclins signal via G‐protein‐coupled cell surface receptors (Gomberg‐Maitland 2008), which when activated stimulate the enzyme adenylate cyclase. The resulting increase in intracellular cyclic AMP (cAMP), opening of Ca²⁺‐activated K⁺ channels, and membrane hyperpolarization lead to relaxation of vascular smooth muscle and vasodilatation (Vane 1995). Pulmonary hypertensive disorders of neonates, children, and adults are associated with a PGI₂‐deficient state, which forms the basis for PGI₂ therapy in PH (Christman 1992; Majed 2012). Among infants, prostacyclins are comparable to iNO in decreasing pulmonary artery pressure and improving oxygenation (Bos 1993; Nakayama 2007). PGE₁ is an effective pulmonary vasodilator in adults with acute respiratory distress syndrome (ARDS), with an action similar to that of iNO (Putensen 1998). Currently, prostacyclin and its analogues and PGE₁ are increasingly used as 'add‐on' therapy for iNO‐refractory PH (Kelly 2002; Ehlen 2003; Chotigeat 2007; De Luca 2007; Levy 2011).

Why it is important to do this review

Pulmonary hypertension is a serious debilitating illness that is associated with high neonatal mortality and may require extracorporeal membrane oxygenation (ECMO) for survival. Hence, optimal management of PH is critical for improving outcomes in high‐risk neonates. Inhaled NO is the only FDA‐approved pulmonary vasodilator for treating PH in infants, but 30% to 50% of neonates with severe PH have a suboptimal response to iNO (Lakshminrusimha 2016;Pedersen 2018). Therefore, systematically analyzing the efficacy and safety of treatment with other pulmonary vasodilators such as prostanoids, phosphodiesterase inhibitors such as sildenafil and milrinone, and endothelin antagonists such as bosentan is necessary to generate an evidence‐based consensus and to inform clinicians of appropriate therapeutic interventions for iNO‐resistant PH. Failure to do such analyses may lead to suboptimal management and increased mortality among these critically ill infants. We aimed to systematically review evidence for the use of prostanoids and their analogues in the treatment of PH in neonates and to identify gaps in knowledge that will inform future clinical trials.