Definition And Perinatal Circulatory Transition

• Persistent pulmonary hypertension of the newborn (PPHN) presents as severe unresponsive hypoxic respiratory failure.
• It reflects the failure of the transition of fetal to neonatal circulation.
• Normal perinatal transition requires a rapid fall in pulmonary vascular resistance (PVR).
• It also requires a marked increase in systemic vascular resistance (SVR) after umbilical cord clamping.
• If PVR remains high and does not fall below SVR, blood flows from right to left.
• This abnormal shunting occurs across the patent foramen ovale (PFO) and patent ductus arteriosus (PDA).
• This right-to-left shunting results in severe systemic hypoxia.

Epidemiology And Etiology

• PPHN occurs at a rate of 1 to 2 per 1,000 live births.
• It is most common among full-term and post-term infants.
• Mortality associated with PPHN ranges from 5% to 30%.

Pathophysiology

• Pulmonary vascular remodeling is pathognomonic of idiopathic PPHN.
• Abnormal muscularization of normally non-muscular intra-acinar arteries occurs.
• This leads to increased medial thickness of the larger muscular arteries.
• It results in a decreased cross-sectional area of the pulmonary vascular bed and elevated PVR.
• Reversible pulmonary vasospasm is often the mechanism in non-fatal PPHN.
• Hypoxia induces profound pulmonary vasoconstriction.
• This vasoconstriction response is exaggerated by acidemia.
• Right ventricular (RV) failure alters diastolic compliance.
• This causes right-to-left atrial shunting, even in the absence of elevated PVR.
• Left ventricular (LV) dysfunction causes pulmonary venous hypertension.
• This contributes to secondary pulmonary arterial hypertension.

Clinical Presentation

History And Risk Factors

• Severe or prolonged oligohydramnios indicates potential pulmonary hypoplasia.
• Absent or decreased fetal movements suggest fetal hypoxia or acidosis.
• Maternal intake of aspirin, NSAIDs, SSRIs, and lithium are known risk factors.
• Meconium-stained amniotic fluid or perinatal asphyxia are strong indicators.

Physical Examination

• Infants typically present with severe hypoxia and cyanosis.
• They exhibit labile oxygen saturations that fluctuate with handling or agitation.
• The oxygen requirement is often out of proportion to the parenchymal lung disease.
• Differential cyanosis is a hallmark feature of PPHN.
• The preductal oxygen saturation (right arm) is 5% to 10% higher than post-ductal limbs (lower limbs).
• Tachypnea with cyanosis without retractions points to idiopathic PPHN or cyanotic heart disease.
• The presence of retractions, grunting, or nasal flaring suggests secondary parenchymal disease.
• Cardiovascular examination may reveal a single, loud S2.
• A systolic murmur of tricuspid regurgitation may be heard.

Diagnostic Evaluation

Bedside Tests And Imaging

Echocardiography

• Echocardiography is the gold standard diagnostic tool for PPHN.
• The first step is ruling out congenital heart disease by confirming situs and venous return.
• It confirms PPHN by documenting increased pulmonary artery pressure.
• Pulmonary pressures of 30 to 60 mm Hg are calculated from the tricuspid regurgitation (TR) jet.
• It assesses the direction of the shunt through the PDA and PFO.
• It helps evaluate right and left ventricular function.
• Fractional shortening or ejection fraction are used for LV assessment.

Differential Diagnosis

• Conditions associated with secondary pulmonary hypertension may be misdiagnosed as PPHN.
• Obstructed total anomalous pulmonary venous connections (TAPVC) presents with refractory hypoxemia and white out of the lungs.
• Left ventricular outflow obstruction, including aortic stenosis and coarctation of aorta, must be excluded.
• Primary LV myocardial diseases like myocarditis and cardiomyopathies cause secondary PAH from venous hypertension.

Management Strategies

General And Supportive Care

• PPHN is a medical emergency where immediate intervention is critical.
• Maintain normothermia and avoid stress through minimal and gentle handling.
• Nurse the neonate in quiet surroundings with low noise and direct lighting.
• Sedation and analgesia may be used, as agitation can aggravate hypoxia.
• Fentanyl or midazolam are useful adjuncts to minimize pain and agitation.
• Correct metabolic abnormalities such as hypoglycemia, hypocalcemia, and acidosis.
• Correct polycythemia, as hyperviscosity increases pulmonary vascular resistance.

Respiratory Management

• Hypoxia is a powerful pulmonary vasoconstrictor, making oxygen a primary therapy.
• Administer supplemental oxygen to maintain adequate PaO2 (50 to 80 mm Hg).
• Maintain a preductal saturation target of 91% to 95%.
• Hyperoxia must be avoided as it inactivates surfactant and increases PVR through free radicals.
• Gentle ventilation strategies with optimal positive end-expiratory pressure (PEEP) are required.
• Practice permissive hypercapnia with a target pCO2 of 40 to 50 mm Hg.
• Hyperventilation and alkalosis are harmful and increase the risk of mortality.
• High-frequency ventilation (HFV) achieves better lung recruitment in parenchymal lung disease.
• Surfactant replacement improves oxygenation when PPHN is secondary to parenchymal lung disease like MAS.

Hemodynamic Support

• Optimal cardiac output is necessary to maximize tissue perfusion and oxygenation.
• Maintain adequate intravascular volume using fluid boluses of 10 mL/kg normal saline.
• Avoid excessive volume expansion as myocardial activity may be compromised.
• Maintain blood pressures in the normal range, as the right-to-left shunt size depends partly on systemic BP.
• Dopamine is the primary inotrope used to augment cardiac output.
• Norepinephrine or epinephrine may be utilized if systemic blood pressure remains low.
• Milrinone is a phosphodiesterase-3 inhibitor used for ventricular dysfunction.
• Milrinone functions as a pulmonary vasodilator and inotrope but can cause systemic hypotension.

Specific Pulmonary Vasodilator Therapy

• iNO response is defined by the 20-20-20 rule: an increase in PaO2 by 20 mm Hg within 20 minutes of starting 20 ppm iNO.
• Nearly 40% of infants may fail to sustain a response to iNO and require evaluation for LV dysfunction.

Advanced Therapies

• Extracorporeal membrane oxygenation (ECMO) is a lifesaving rescue therapy.
• It is indicated for refractory PPHN that fails conventional management and iNO treatment.
• Glucocorticoids (hydrocortisone) may be beneficial in restoring normal pulmonary vasculature.
• Hydrocortisone increases cGMP, attenuates oxidative stress, and improves systemic pressure.

Prognosis And Follow-Up

• With improved therapy including iNO and ECMO, mortality has reduced to less than 10% in tertiary care centers.
• Survivors of PPHN remain at a significant risk for medical and neurodevelopmental sequelae.
• Approximately 24% to 26% of survivors have hearing and neurodevelopmental impairments at 18 to 24 months.
• Infants who develop PPHN are at a higher risk of rehospitalization within 1 year of discharge.
• Pulmonary hypertension may persist in some infants.
• Echocardiography must be repeated at 3 to 6 months of age to look for unresolved pulmonary hypertension.