Biology Reference
In-Depth Information
1.2 Pathophysiology of Persistent Pulmonary Hypertension
of the Newborn
When the normal cardiopulmonary transition fails to occur, the result is PPHN.
PPHN describes a syndrome characterized by common pathophysiologic features
including sustained elevation of pulmonary vascular resistance and hypoxemia due
to right-to-left extrapulmonary shunting of blood flow across the ductus arteriosus
or foramen ovale. PPHN affects 2-6 per 1,000 live births or approximately 10% of
all infants admitted to neonatal intensive care and is accompanied by an 8-10% risk
of death and significant short-term and long-term morbidity (Walsh-Sukys et al.
2000
). The physiologic findings of PPHN may be found in association with a wide
range of cardiopulmonary disorders such as meconium aspiration, sepsis, pneumo-
nia, asphyxia, congenital diaphragmatic hernia (CDH), respiratory distress syn-
drome, and others. Pathological findings include pulmonary vascular remodeling
and smooth muscle hyperplasia, often in the absence of significant lung paren-
chyma pathology (Haworth
1988
; Murphy et al.
1981
). PPHN can largely be
thought of as one of three types: (1) the abnormally constricted pulmonary vascu-
lature, which is the most common type and includes diagnoses such as meconium
aspiration syndrome (MAS), respiratory distress syndrome, and sepsis; (2) the
structurally abnormal vasculature, which is often termed idiopathic PPHN; or (3)
the hypoplastic vasculature such as is seen in CDH or alveolar capillary dysplasia,
a rare malformation of lung development. The pathophysiology of each type
is dependent on the point in gestation when the normal transition to extrauterine
life fails. Thus, since the underlying pathophysiology differs, different pulmonary
vasodilators may be more or less successful for treatment and a thorough under-
standing of the pathways that are disrupted in each condition will be key to
determine the most appropriate therapy.
1.2.1 Meconium Aspiration Syndrome
The most common cause of PPHN is meconium aspiration syndrome (MAS), which
affects 25,000-30,000 infants with 1,000 deaths annually in the United States
(Gelfand et al.
2004
). In these cases, the infant passes meconium while still in
utero, usually in response to stressful stimuli. Affected infants aspirate the meco-
nium into their airways, where it can impede ventilation, cause severe pneumo-
nitis, and induce lung inflammatory changes. While a fair bit is known about the
parenchymal disease associated with MAS, there is much less known about the
utility of specific pulmonary vasodilators. In the NINOS trial, 51% of the infants
had MAS as the underlying cause of their PPHN. In that study, treatment with
inhaled nitric oxide (iNO) decreased the combined outcome of death or cardio-
pulmonary bypass support (known as ECMO), suggesting that modulation of
the NO-cGMP pathway may be a useful treatment modality for infants with
MAS (Group
1997
). However, little data exist to address whether the PDEs are
