Persistent Pulmonary Hypertension in the Newborn (PPHN) is the clinical manifestation of deficient oxygen supply in the newborn with high pulmonary arterial pressure, as a result of failure of normal circulatory transition during or after delivery. It is a rare but severe condition when detected (affecting 2 out of every 1,000 newborns), and can have fatal consequences if not treated immediately.
In general terms, the lungs are responsible for converting the deoxygenated (oxygen deficient) blood into oxygenated blood (oxygen rich blood) to be transported to the rest of the body through the aorta. In PPHN, this does not happen because shunting between the right and left ventricles leads to the mixing of deoxygenated and oxygenated blood, creating pressure inside the lungs and imminent shortness of breath.
During the gestational period, when the lungs are not fully developed in the fetus, the umbilical cord and the placenta serve as the media for gas exchange between the mother and the child. In this state, most of the right ventricular output is carried through to the aorta via the ductus arterioles. The ductus arterioles is a blood vessel connecting the pulmonary artery to the descending aorta, which allows most of the blood from the right ventricle to bypass the fetus’s fluid-filled non-functioning lungs. In this process, only 5-10 % of the blood is transported to the lung’s vasculature.
As a result, the pulmonary arterial pressure (PAP) and vascular resistance (PVR) is normally high during this time, with not enough oxygenated blood in the lungs. PVR increases with the gradual expansion of the vascular bed in the growing fetus, along with gestational age. Vasoconstrictors like Rho-kinase, endothelin-1, and leukotrienes are responsible for maintenance of high PVR during gestational period. Low synthesis of vasodilators like prostacyclin and nitric oxide (NO) also contribute.
At the time of birth for normally healthy newborns, a drastic change in the circulatory dynamics occurs. The development of the lungs and closing of the fossa ovals and ductus arterioles, allows proper blood flow through the heart into the infant’s lungs. This action causes a decrease in PAP and PVP, and increases the pulmonary blood flow up to 10 times, all while reducing carbon dioxide tension and increasing the oxygen supply.
During late gestational period to the time of birth, there is an increase in the amount of vasodilators that synthesize guanylate cycles and cyclooxygenase I (COX-1) and prostacyclin, which in turn is responsible for the synthesis of adenylate cycles – all of which are responsible for relaxation of blood vessels and vasodilation. They do so by decreasing the concentration of intracellular calcium (controllers of calcium ion channels).
However, in newborns with PPHN, there is a shunting of blood between the two ventricles (because of an open fossa ovals) between the pulmonary artery and aorta (because of an open ductus arterioles). The shunting makes it difficult for the correct amount of oxygen rich blood to reach the desired organs after passing though the lungs. It exerts pressure on the lungs and leads to refractory hypoxemia and related breathing abnormalities.
Mortalities associated with PPHN range between 5-10% with 25% of those cases having neurodevelopmental abnormalities as well.
PPHN is a rare syndrome and is most often associated with other congenital conditions than can include: lung parenchymal diseases; alveolar cardiac dysplasia (misalignment of the pulmonary blood vessels); pulmonary hypoplasia (incomplete development of the lungs); and congenital heart diseases.
Meconium Aspiration Syndrome (MAS is intrauterine gasping of the first stool of the infant) has also been associated with PPHN and pediatric pulmonary hypertension. It occurs with PPHN in 1 or 2 cases per 1,000 births.
Disruption of the NO-cGMP (cyclic guanyl monophosphate) pathway also leads to vasoconstriction. Pulmonary arterial and ventricular pressure rise as a consequence.
Recent studies have pointed to the use of anti-depressants (like Selective Serotonin Reuptake Inhibitors; SSRI) and non-steroidal anti-inflammatory drugs (NSAIDs) during the third trimester of pregnancy as a risk factor of PPHN.
Sepsis, low blood sugar, low body temperature and low levels of amniotic fluid within the amniotal sac in the womb, may also contribute to the development of PPHN.
Persistent Pulmonary Hypertension in Newborns (PPHN) is often associated with several congenital heart diseases that can include anomalous venous connection and tricuspid atresia (absence of a tricuspid valve, which causes mixing of blood between the left and right ventricle, similar to the pathophysiology of PPHN).
Primary parenchymal lung diseases such as bronchopulmonary dysplasia (BPD), a chronic lung condition injuring alveolar passages and airways in newborns); neonatal pneumonia; and respiratory distress syndrome with sepsis due to infection with streptococcus pneumonia may also be reasons for lung infections.
All of these conditions have similar symptoms making confirmation by a phsycian necessary to continue with specific medication and therapy.
Cyanosis (when body parts of the infant turn blue) is an indicator for oxygen deficiency in the newborn and demands further physical examination. Tachycardia (rapid heartbeats), tachypnea (rapid breathing), and a deep second heart sound on cardiac examination also point toward PPHN.
Monitoring serum electrolyte and glucose levels may indicate the degree of vasoconstriction, which is dependent on levels of intracellular calcium and glucose. Determining the amount of oxygen dissolved in blood can give an idea of hypoxia. Also, blood tests assessing degree of coagulation and differential leukocyte counts to determine underlying sepsis or pneumonia, also help zero in on PPHN.
Chest radiography helps check for parenchymal lung disorders. Echocardiography is the most important technique used in this regard, which can determine the shunt formed due to open fossa ovalis and ductus arteriosus. It aids in measuring the systolic and diastolic pressure. It is the most effective way to rule out heart diseases and detect pulmonary insufficiency.
Ultrasonography, magnetic resonance testing and computed tomography scanning might be necessary in order to check for internal hemorrhage or bleeding when extracorporeal membrane oxygen is necessary.
To increase the efficiency of the heart, the general line of treatment that follows after diagnosis of PPHN includes administration of cardiotonic drugs (such as dopamine or milrinone) and maintenance of proper levels of glucose and electrolytes, as a supportive therapy. Cardiotonic therapy helps increase the pumping efficiency of the heart, with sufficient amounts of blood pumped out and ensuring proper oxygen transport throughout the body.
After specifically zeroing in on PPHN, ECMO (external supply of oxygen to the body when needed) or high frequency oscillatory ventilation might be necessary depending on the severity of the condition.
Surfactants may help in lung expansion and subsequent vasodilation and muscle relaxation, releasing pressure off the lungs.
Inhaled nitric oxide (iNO) is one of the most selective and potent vasodilators. As small molecules, they can diffuse easily to the pulmonary vascular beds and help synthesize guanylate cycles. This i helps reduce blood pressure. The iNO-cGMP (cyclic guanyl monophosphate) pathway is the most sought-after topic of research in the therapeutic department as far as pulmonary hypertension is concerned.
A second messenger, phosphodiesterase 5 (PDE5) inhibitors, have also shown potential in terms of relaxing smooth muscles of the lungs and the heart. The downstream signaling processes of both iNO and PDE5 are similar, as both of them help in restoring cyclic guanyl monophosphate (cGMP) and cyclic adenyl monophosphate (cAMP) levels that help in vasodialtion. Hence PDE5 inhibitors can also be used as substitutes for iNO.
Pulmonary sildenafil is also a proven vasodilator.
Another mechanism which is thought to be a contributor to increased pulmonary arterial and ventricular pressure is formation of free radicals that cause oxidative stress. Superoxide dismutase (SOD) is a potent quencher of free radicals, which helps in the catalysis of hydrogen peroxide to water and release of free oxygen. The free oxygen then reduces pulmonary pressure and enhances normal breathing. However, it been demonstrated in animal models; human trials are still needed to prescribe the same for PPHN treatment.
PPHN, though a rare condition, can be fatal if not treated immediately. Breathing problems in a newborn could lead to chocking and ultimate death. Much research is being carried on to determine causes for conditions with varied severities and making it easier to distinguish between other similar co-morbidities. More research into the condition could help formulate more and better therapies.
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