Introduction
Persistent pulmonary hypertension of the newborn (PPHN) is defined as
the failure of the normal circulatory transition that occurs after
birth. It is a syndrome characterized by marked pulmonary hypertension
that causes hypoxemia secondary to right-to-left extrapulmonary shunting
of deoxygenated blood. Clinically, PPHN is most often recognized in term
or near-term neonates. The incidence of PPHN ranges from 0.4 to 6.8 per
1000 live births (1) with associated mortality of 4- 60% (2, 3). Also
significant long-term morbidities up to 25% is reported (2).
Persistent pulmonary hypertension of the newborn may be the result of
several mechanisms: 1) acute pulmonary vasoconstriction (e.g.: maternal
diabetes, antenatal exposure to non‐steroidal anti‐inflammatory
medications, elective caesarean section delivery, perinatal asphyxia,
meconium aspiration syndrome, pneumonia, sepsis, hyaline membrane
disease, metabolic acidosis), 2) pulmonary vascular remodeling (e.g.:
congenital diaphragmatic hernia (CDH), chronic intrauterine hypoxia,
antenatal ductal closure), 3) pulmonary vascular hypoplasia, (e.g.: CDH,
intrathoracic space‐occupying lesions, chronic oligohydramnios), 4)
pulmonary intravascular obstruction characterized by blood flow
restriction (polycythemia and obstructed anomalous pulmonary venous
drainage) (4, 5, 6), 5) genetic (e.g.: trisomy 21 (independent of any
cardiac lesion), genetic mutations leading to surfactant protein B
deficiency, and mutations in the ATP-binding cassette transporter 3 gene
(1).
The diagnosis of PPHN is confirmed by echocardiography. The cardinal
findings include abnormal right ventricular dilatation, leftward
deviation of the interventricular septum, tricuspid regurgitation, and
right-to-left shunting at the levels of the patent foramen ovale and
patent ductus arteriosus (7). In contrast to adult primary pulmonary
hypertension, the newborn syndrome is not defined by a specific pressure
of the pulmonary circulation. The diagnosis is confirmed regardless of
the pulmonary arterial pressure, as long as it is accompanied by a
right-to-left shunt and absence of congenital heart disease (5).
Inhaled nitric oxide (iNO) is the only approved pulmonary vasodilator
specifically for the treatment of PPHN, although it does not improve
survival and ~40% of neonates fail to respond. It is
not clear that iNO is safer and more effective than other vasodilators
delivered by inhalation such as inhaled prostacyclin (8). Therefore,
investigation of the efficacy and safety of other potential therapeutic
agents, such as pulmonary vasodilators like prostanoids,
phosphodiesterase inhibitors like sildenafil and milrinone, and
endothelin antagonists like bosentan is on-going (9, 10, 11,12).
Prostacyclin is a naturally occurring prostaglandin described more than
30 years ago (13). Prostacyclin (PGI2) and its analogues (prostanoids)
are potent vasodilators, and exhibit antithrombotic, antiproliferative
and anti-inflammatory properties. Pulmonary arterial hypertension (PAH)
is characterised by vasoconstriction, thrombosis and proliferation, and
is associated with reduced synthesis of endogenous prostacyclin. This
provides a strong rationale for the use of prostanoids to treat PAH (14,
15). Iloprost is an analogue of prostacyclin with greater chemical
stability (16). There are a number of reports which have addressed the
use of inhaled iloprost inhalation therapy for pulmonary hypertension of
the newborn in the literature (17-32). 1-2 mcg/kg/dose, every 1-4 hours
is the most used dose. Dykes et al, suggested a continuous inhalation (5
mcg/hour) to avoid swings in haemodynamics in a in a neonate with
d-transposition of the great arteries and severe PAH (30).
Hereby, 6 patients with PPHN treated with inhaled iloprost because of
lack of acessibility to iNO are presented.