Description of the condition
Persistent pulmonary hypertension of the newborn (PPHN)
Persistent pulmonary hypertension of the newborn (PPHN) or persistent fetal circulation (PFC) is a clinical syndrome characterised by failure of the lung circulation to achieve or sustain the normal drop in pulmonary vascular resistance (PVR) at birth (Gersony 1984). Incidence of PPHN is estimated at two per 1000 live births and is associated with substantial morbidity and mortality (Steinhorn 2010). PPHN represents a failure of the unique adaptations that occur in the pulmonary circulation at birth (Konduri 2009). The fetal lung is a fluid filled organ that does not participate in gas exchange and offers high resistance to blood flow. Low oxygen tension present during fetal life and high levels of endogenous vasoconstrictors like endothelin-1 and thromboxane facilitate the maintenance of high PVR (Lakshminrusimha 1999). A dramatic decrease in PVR occurs immediately after birth as the lungs take over the gas exchange function. Several mechanisms contribute to the normal fall in PVR at birth, including increased oxygen tension, ventilation and shear stress. These physiological stimuli lower the PVR through increased release of potent endogenous vasodilators, such as nitric oxide (NO) and prostacyclin (PGI2), and decreased activity of vasoconstrictors such as endothelin (ET)-1 (Levy 2005; Levy 2005a). Some neonates fail to achieve the normal decrease in PVR at birth, resulting in PPHN (Rao 2010). Affected neonates are hypoxaemic because of right-to-left shunt through the ductus arteriosus and foramen ovale leading to a vicious cycle of hypoxaemia, acidosis and further pulmonary vasoconstriction (Greenough 2005). In advanced stages of PPHN, progressive pulmonary vascular functional and structural changes ultimately cause increased pulmonary vascular impedance, right-ventricular failure and death.
Echocardiography is an important tool in the diagnosis of PPHN. The main findings are presence of right to left shunting at the atrial level or via the patent ductus arteriosus, near or suprasystemic pulmonary pressures and the presence of tricuspid regurgitation (Rao 2010; Stayer 2010; Dhillon 2012).
Management of PPHN includes prevention and/or treatment of active pulmonary vasoconstriction, support of right-ventricle function, treatment of the underlying disease and promotion of regressive remodelling of structural pulmonary vascular changes (Oishi 2011). The vital role of nitric oxide (NO)-cGMP signalling in the regulation of the perinatal lung circulation, leading to the development and successful application of inhaled nitric oxide (iNO) therapy for PPHN is now well established (Abman 2007). Approximately 40% of patients will not respond or sustain a response to iNO (Steinhorn 2010) and hence newer alternatives or adjuncts to iNO are being explored.
Description of the intervention
Endothelin receptor antagonists (ETRAs)
Endothelin-1 was discovered by Japanese scientists, Yanagisawa and co-workers, in 1988 (Yanagisawa 1988); they described it as one of the most potent vasoconstrictors. It was subsequently characterised as the most potent vasoconstrictor ever identified, being 100 times more potent than noradrenaline (Barton 2008). Endothelins are a family of 21 aminoacid peptides that are secreted mainly by the systemic and pulmonary vascular endothelial cells. To a lesser degree, they are also secreted by other cell types including smooth muscle cells of the pulmonary artery and fibroblasts. There are three isoforms, ET-1, ET-2 and ET-3, of which ET-1 is biologically the most active. ET-1 is produced in response to various stimuli such as hypoxia, hyperoxia, reactive oxygen species, cytokines, catecholamine stress etc. (Abman 2009). It is synthesised from its biologically inactive precursor by the endothelin-converting enzyme (Davenport 2006). ET-1 is also a smooth muscle mutagen (Abman 2009; Galie 2004).
ET-1 acts via two G protein coupled receptors: ETA receptors which are located primarily on the vascular smooth muscle cells and ETB receptors which are expressed both on vascular endothelium and vascular smooth muscle cells. They are present in both pulmonary as well as systemic vasculature. The activation of ETA receptors mediates vasoconstriction, smooth muscle proliferation, hypertrophy, cell migration and fibrosis, whereas the activation of ETB receptors stimulates the release of potent vasodilators (NO and PGI2), which also exhibit anti-proliferative properties and prevent apoptosis (La 1995; Dakshinamurti 2005; Abman 2009; Rao 2010).
ET-1 plays an important role in the pathogenesis of pulmonary arterial hypertension in adult and paediatric populations. In a very important study in this field, Giaid and co-workers (Giaid 1993) studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridisation) in the lung specimens of 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (out of which seven had primary pulmonary hypertension) and 17 patients with secondary pulmonary hypertension. In the controls, endothelin-1-like immunoreactivity was rarely seen in the pulmonary vascular endothelial cells. In patients with pulmonary hypertension, endothelin-1-like immunoreactivity was abundant, predominantly in endothelial cells of pulmonary arteries with medial thickening and intimal fibrosis. Likewise endothelin-1 messenger RNA was increased in patients with pulmonary hypertension and was expressed primarily at sites of endothelin-1-like immunoreactivity. They concluded that pulmonary hypertension is associated with increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endothelin-1 may contribute to the vascular abnormalities associated with this disorder (Giaid 1993). Plasma ET-1 are known to be elevated in adults and children with pulmonary hypertension and correlate with increased morbidity and mortality (Allen 1993; Shao 2011).
ET-1 is also known to play an important role in the pathogenesis of PPHN in newborn infants. During fetal life, ET-1 and its receptors are strongly expressed in the pulmonary circulation early during lung development. Basal ET-1 activity contributes to the high pulmonary vascular resistance in utero (Abman 2009) via predominant action on the ETA receptors. Activation of the ETB receptor causes vasodilatation by release of nitric oxide and partly contributes to pulmonary vasodilatation that occurs at birth. In PPHN, the balance is in favour of ETA receptor activation leading to increased pulmonary vascular resistance. In a case control study, Rosenberg and co-workers (Rosenberg 1993) found that plasma ET-1 concentrations were significantly higher in neonates with PPHN compared to those with hyaline membrane disease or cord blood of healthy newborn infants. They also reported that plasma ET-1 levels correlated with disease severity in PPHN. In another case control study Endo and co-workers also found that plasma ET-1 concentrations were significantly higher in the PPHN group than in the control group at < 12 hours and 24 hours of age (Endo 2001). de Lagausie and co-workers (de Lagausie 2005) studied the ETA and ETB receptor protein expression using immunohistochemistry in 10 lung specimens obtained from newborns with congenital diaphragmatic hernia (CDH) and four normal lung specimens. ETA and ETB mRNAs were quantified using real-time RT-PCR in laser-micro-dissected pulmonary resistive arteries. In the lungs of newborns with CDH, immunohistochemistry of both ETA and ETB receptors demonstrated over-expression in the thickened media of pulmonary arteries. Using laser micro-dissection and real-time RT-PCR, higher levels of ETA and ETB mRNA were found in CDH pulmonary arteries than in controls: this increase was more pronounced for ETA mRNA.They concluded that dysregulation of ET-1 receptors may contribute to PPHN associated with CDH (de Lagausie 2005).
Hence blocking the ET receptors using endothelin receptor antagonists (ETRA) may be of benefit in the treatment of PPHN. Bosentan and tezosentan are non-selective ETRAs because they block both the ETA and ETB receptors, whereas sitaxentan and ambisentran are selective ETA receptor inhibitors (Luscher 2000; Geiger 2006; O'Callaghan 2011). The ETRAs are administered either orally or intravenously (Torre Amione 2003). The inhalation route has also been tried in animal models of pulmonary hypertension (Persson 2009).
How the intervention might work
The biology of ET receptors is complex and incompletely understood (Abman 2009). ETRAs appear to work by blocking the endothelin receptors thereby leading to decreased pulmonary vascular resistance and decreased medial hypertrophy of pulmonary vasculature. Newborn animal studies have shown that ETRAs reduce pulmonary hypertension secondary to sepsis (Peng 2003) and meconium aspiration syndrome (Kuo 2001). Ambalavanan and co-workers studied hypoxia-induced pulmonary vascular remodeling (HPVR) leading to PPHN or cor pulmonale in a newborn mouse model. They demonstrated that HPVR secondary to chronic hypoxia can be completely prevented and partially reversed by ET(A) blockade (Ambalavanan 2005).
The most important potential adverse effect of ETRA is hypotension because ETRAs block the endothelin receptors not only in the pulmonary circulation, but also in the systemic circulation. Other potential adverse effects of ETRA are liver dysfunction, cardiac arrhythmias and hypoxaemia. However, a systematic review of observational studies of bosentan in a paediatric population concluded that it is a well tolerated and effective therapy for paediatric pulmonary hypertension (Beghetti 2009).
Why it is important to do this review
The current treatment for PPHN involves conventional/high-frequency ventilation, administration of oxygen, sedation, iNO and the phosphodiesterase 5 (PDE) inhibitor, sildenafil (Rao 2010; Shah 2011). Approximately 40% of patients do not respond or will not sustain a response to iNO (Steinhorn 2010); iNO is also very expensive. Hence, alternatives to iNO in the management of PPHN are being explored.
Experience with the use of ETRA in adult patients with pulmonary arterial hypertension
A recently published Cochrane review in adult patients with pulmonary hypertension included 12 randomised controlled trials involving 1471 patients (Liu 2013). They concluded that ETRAs can increase exercise capacity, improve World Health Organization (WHO)/New York Heart Association (NYHA) functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III (Liu 2013).
Experience with the use of ETRA in paediatric patients with pulmonary arterial hypertension
Observational studies have shown that ETRAs may improve the outcomes of children with pulmonary hypertension associated with congenital heart disease (Nemoto 2007; Goissen 2008; Hirono 2010 ), congenital diaphragmatic hernia (Stathopoulos 2011) and bronchopulmonary dysplasia (Krishnan 2008). A systematic review of observational studies also suggested a beneficial effect of ETRA in paediatric pulmonary hypertension (Beghetti 2009). The details of these studies are given below.
Goissen and co-workers (Goissen 2008) reported two cases of PPHN complicating transposition of great arteries with intact ventricular septum that were refractory to multiple therapies and resolved 48 hours after initiation of bosentan therapy.
Nemoto and co-workers (Nemoto 2007) reported on successful application of bosentan in the treatment of pulmonary hypertension early after surgical correction of congenital heart disease. Two infants (five and nine-month old girls who underwent repair of complete atrioventricular septal defect and closure of ventricular septal defect, respectively) suffered from pulmonary hypertension-related symptoms after extubation despite oral sildenafil treatment. After administration of bosentan, the symptoms were dramatically relieved. Bosentan caused a transient increment of liver transaminase in the five-month old girl.
Hirono and co-workers (Hirono 2010) investigated the efficacy of bosentan in patients with single-ventricle physiology who were unable to undergo right-sided heart bypass surgery because of high pulmonary vascular resistance and pulmonary artery pressure. Eight patients with single-ventricle physiology (two male and six female; aged seven months to five years, median one year) were enrolled. Right-sided heart bypass surgery was contraindicated for all patients because of high pulmonary vascular resistance and pulmonary artery pressure. Bosentan therapy successfully reduced pulmonary artery pressure and pulmonary vascular resistance in all patients. All patients had improved clinical symptoms and underwent successful Fontan operations.
Stathopoulos and co-workers (Stathopoulos 2011) studied the effects of tezosentan, a non-selective ETA and ETB receptor antagonist on the cardiopulmonary profile in a fetal lamb model of CDH in utero. A diaphragmatic hernia was surgically created at day 75 of gestation. During 45 minutes of tezosentan perfusion at 135 days of gestation, cardiopulmonary haemodynamic parameters were measured. Age-matched fetal lambs served as controls. In the CDH group, pulmonary artery pressures decreased in the tezosentan group but not in controls.
Krishnan and co-workers (Krishnan 2008) reported a series of six children with chronic lung disease (CLD) and severe pulmonary hypertension treated with bosentan (six of six) and sildenafil (four of six). Vascular reactivity was assessed by cardiac catheterisation prior to and after six months of therapy. Serial echocardiography was also used to assess response. Patients were treated for 2.1 to 2.9 years. They found improvement in oxygenation, symptoms, echocardiographic parameters and haemodynamics by cardiac catheterisation. Transiently elevated liver enzymes were noted, associated with viral respiratory infections in two subjects; no other adverse effects were noted.
Beghetti and coworkers (Beghetti 2009) conducted a systematic review to evaluate the safety and effectiveness of bosentan in paediatric pulmonary arterial hypertension. Twenty-one clinical studies (2000 to 2007) were selected: one interventional prospective, six prospective observational, five retrospective and nine case reports/case series. They concluded that experience from observational studies suggests that bosentan is a well-tolerated and effective therapy for paediatric pulmonary hypertension. Bosentan appeared to improve long-term functional status and haemodynamics in children with pulmonary arterial hypertension. Adverse events, including liver enzyme elevations, also appeared to be less frequent than reported in the adult clinical trials.
Experience with the use of ETRA in animal models of PPHN
Pearl and co-workers showed that bosentan prevents hypoxia-reoxygenation-induced pulmonary hypertension and improves pulmonary function in neonatal piglets (Pearl 1999).
Clinical experience with the use of ETRA in neonatal population
Clinical experience with ET-1 receptor antagonists in the neonatal population is limited. Nakwan et al have reported the benefits of bosentan in a neonate with PPHN (Nakwan 2009). Radicioni and co-workers reported the use of oral bosentan as adjunct therapy to iNO and oral sildenafil in a preterm infant with PPHN after preterm rupture of membranes (PPROM) (Radicioni 2011). Goissen and co-workers have also reported the benefits of bosentan in PPHN associated with congenital heart disease (Goissen 2008).
Considering that ETRAs have shown to be of benefit in adult and paediatric patients with pulmonary arterial hypertension and animal models of PPHN, there may be a role for them in the management of PPHN. Hence, we will conduct this systematic review.