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Persistent Pulmonary Hypertension of the Newborn
Introduction
The placenta functions as the primary organ for air exchange in the fetus. The lungs have to rapidly assume this role after birth. Persistent pulmonary hypertension occurs due to failure of normal transition from intrauterine circulation. It is characterized by persistently elevated pulmonary vascular resistance (PVR), resulting in decreased pulmonary blood flow (PBF).
Symptoms range from mild respiratory distress to severe hypoxic respiratory failure requiring mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Persistent pulmonary hypertension in the newborn is a potentially life-threatening condition in the early neonatal phase. It is essential for the healthcare provider to promptly identify and provide appropriate care to neonates.[1]
Etiology
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Etiology
Persistent pulmonary hypertension in the newborn can occur due to several reasons. Lung parenchymal conditions such as meconium aspiration syndrome (MAS), pneumonia, respiratory distress syndrome (RDS), and sepsis contribute to persistent pulmonary hypertension in the newborn.[2]
Other etiological factors include oligohydramnios, pulmonary hypoplasia, infants of diabetic mothers, in utero closure of ductus arteriosus, small and large for gestational age status.[3]
Maternal risk factors such as obesity, diabetes, pre-eclampsia, chorioamnionitis, smoking, selective serotonin reuptake inhibitors (SSRI), and NSAID use during pregnancy can also contribute to persistent pulmonary hypertension in the newborn.[4][5] [Level 4]
Congenital anomalies such as transposition of great arteries (TGA) and congenital diaphragmatic hernia (CDH) are also associated with persistent fetal circulation in the immediate neonatal period.
Epidemiology
The overall incidence of persistent pulmonary hypertension in newborns is 1.8 per 1000 live births.[6][7] However, contrary to popular belief, the incidence of persistent pulmonary hypertension in newborns is higher in late preterm infants at 5.4 per 1000 live births. In term infants, the incidence is 1.6 per 1000 live births.[8]
Mortality ranges from 7.6 to 10.7%, depending on the severity of the condition. Boys had a higher risk than girls with an adjusted risk ratio of 0.8, 95% CI 0.7-0.8. African American babies had the highest risk, followed closely by Hispanic and Asian infants.
Pathophysiology
High PVR relative to systemic vascular resistance is essential to normal intrauterine fetal circulation. Fluid-filled alveoli and hypoxia-induced pulmonary vasoconstriction in the presence of circulating vasoconstrictors such as endothelin-1 and thromboxane maintain high PVR in the fetal phase Lak. Conversely, circulating levels of vasodilators such as nitric oxide and prostaglandins are low.[9] Pulmonary reactivity to vasodilators increases with increasing gestational age.
During normal transition after birth, several events occur simultaneously, which results in a smooth transition to extrauterine life. A drastic fall in pulmonary arterial pressure following the first breath accompanies increased pulmonary blood flow when the umbilical cord is clamped. The increased partial pressure of oxygen and the initiation of ventilation also stimulate the production of vasodilators such as nitric oxide and prostacyclins; cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) mediate pulmonary vasodilation through endothelial nitric oxide.[10]
Cyclooxygenase enzyme mediates the conversion of arachidonic acid to prostacyclin and is a rate-limiting enzyme. COX-1 is found in the lung and is upregulated when the fetus reaches term gestation. Prostacyclins increase cAMP levels which in turn cause vasorelaxation by decreasing intracellular calcium concentration. Nitric oxide - cyclic guanosine monophosphate (NO- cGMP) and nitric oxide- cyclic adenosine monophosphate (NO-cAMP) pathways are extensively studied in the pathophysiology of persistent fetal circulation.[11][12] Subsequent clinical studies supported the widely accepted inhaled nitric oxide therapy in persistent pulmonary hypertension in newborns.
Persistent pulmonary hypertension in the newborn is categorized into three types:
- Maladaptation: abnormal pulmonary vascular response in lung parenchymal disorders such as meconium aspiration syndrome
- Underdeveloped vasculature: decreased pulmonary vasculature as seen in small for gestational age or oligohydramnios
- Idiopathic persistent pulmonary hypertension in the newborn, likely due to excessive pulmonary vascular smooth muscle thickness
These categories can overlap in any given condition.[1] [Level 4]
High PVR decreases pulmonary blood flow. This causes ventilation-perfusion mismatch and right to left shunting of blood across the foramen ovale and ductus arteriosus resulting in refractory hypoxemia. Extra-cardiac shunting across patent ductus arteriosus (PDA) results in more than a 10% differential between pre and post-ductal saturations.[13]
Infants with persistent pulmonary hypertension are vulnerable to wide swings in oxygen saturation and increased left to right shunting with minimal stimulation and agitation.
History and Physical
Infants usually present within a few days after birth. Prenatal history should be obtained at the time of NICU admission and should include maternal medical conditions as well as drug exposure. Providers should obtain prenatal and perinatal factors such as chorioamnionitis, meconium-stained amniotic fluid, and perinatal asphyxia, as these contribute to persistent pulmonary hypertension.[14]Level 4]
Newborn assessment usually occurs simultaneously with resuscitation in conditions such as meconium aspiration. On exam, an infant with persistent fetal circulation appears cyanotic. Respiratory distress can manifest as labored breathing with subcostal, suprasternal and intercostal retractions due to lung parenchymal disease. Infants with congenital diaphragmatic hernia have a scaphoid abdomen on the exam. Septic infants can present with refractory hypotension, multiorgan failure, and easy bleeding due to disseminated intravascular coagulopathy (DIC).[15] [Level 4]
Evaluation
Evaluation of an infant with suspected PPHN includes obtaining blood gas, chest X-ray, and echocardiogram. Sepsis should be ruled out with complete blood count with differential (CBC with diff), C- reactive protein (CRP), and blood culture. If ECMO support is anticipated, coagulation studies and a head ultrasound should be done before cannulation.
Arterial blood gas demonstrates low partial pressure of arterial oxygen (paO2). In sepsis, leucocytosis or leucopenia may be seen. CRP may be high in sepsis. Chest radiographs may show signs of underlying lung parenchymal disease.
Oxygenation Index (OI) = Mean airway pressure * FiO2*100/PaO2. OI >15, along with pre-post ductal saturation difference of >10%, are suggestive of high pulmonary vascular resistance.[15](level 4)
Echocardiography is the gold standard for confirming the diagnosis. It is also used to follow therapeutic efficacy. The direction of flow across PDA and PFO, interventricular septal deviation or flattening, and regurgitation across the tricuspid valve (TR jet) are used to estimate right ventricular and/or pulmonary vascular pressure.
TR jet may not be accurate in 30% of cases due to poor right ventricular dysfunction. Echocardiography also provides information about right and left ventricular function, which is vital in treating persistent pulmonary hypertension.[16][13] [Level 4] Poor right ventricular function coupled with low right and left ventricular output is predictive of poor outcomes.[17] [Level 3]
Brain natriuretic peptide (BNP) is a hormone produced by stressed right ventricles. BNP levels are elevated in babies with PPHN. BNP level of more than 550pg/ml is predictive of persistent pulmonary hypertension.[18]
Treatment / Management
Management of persistent pulmonary hypertension includes maintaining temperature, glucose, cardiovascular support, and intravascular volume.[1] Treatment includes lung recruitment and vasopressor support along with pulmonary vasodilator therapy. Inhaled nitric oxide (iNO) is the most studied agent in large randomized clinical trials. It is the only United States FDA-approved vasodilator agent for persistent pulmonary hypertension.
Past therapeutic interventions included hyperventilation, alkali infusion, sedation, paralysis, inotropes, and tolazoline, but most of these strategies are outdated and not being used anymore. The response to alkalosis induced by hyperventilation and alkali infusion is short-lived and prolonged alkalosis can cause reactive hyperreactivity, worsening persistent pulmonary hypertension.[19] Alkalosis also causes cerebral vasoconstriction and may be associated with worse neurologic outcomes.(B3)
Inotropes: Ionotropic agents are often used in persistent pulmonary hypertension. Dopamine and milrinone are commonly used medications. Dopamine is a non-selective vasoconstrictor and should be used with caution in higher doses.[20] [Level 4] Increasing systemic blood pressure helps reduce the extra-cardiac shunting across the PDA, although the ideal blood pressure values are not known yet.
Oxygen therapy and mechanical ventilation: The mainstay of treatment is improving oxygenation by optimizing mechanical ventilatory support. Gentle ventilation and maintaining adequate lung volume is an essential management strategy in persistent pulmonary hypertension. Though oxygen is a potent vasodilator, fractional inspired oxygen concentration (fiO2) over 50% is rarely beneficial.[21] (B3)
Achieving adequate lung volume improves oxygenation and pulmonary vascular resistance in newborns with parenchymal lung disease. A conventional or high-frequency ventilator can be used to correct any ventilation-perfusion mismatch.[22](A1)
Surfactant therapy: Studies show conflicting results with surfactant use in PPHN. In infants with parenchymal lung disease, surfactant use is associated with improved oxygenation in mild disease (OI 15-25).[23](A1)
The oxygenation index (OI) is used to assess the severity of the disease. Persistent OI > 40 is often used to indicate the severity and the need for extracorporeal membrane oxygenation (ECMO). ECMO is life-saving but is invasive, labor intensive, and associated with severe complications such as intracranial hemorrhage.[24] [Level 2](A1)
Pulmonary Vasodilators
Inhaled nitric oxide (iNO): iNO is the only FDA-approved pulmonary vasodilator therapy in neonates with persistent pulmonary hypertension. iNO causes selective pulmonary vasodilation. It is a rapid and potent vasodilator used in inhaled form. iNO treatment should always start at 20ppm to evaluate for a response. Large trials showed the efficacy of iNO in decreasing the need for ECMO.[25][26] (A1)
While iNO is the mainstay of treatment for persistent fetal circulation, it did not decrease mortality, hospital stay, or risk of neurologic impairment. Early initiation of iNO did not affect the need for ECMO or the risk of death or neurodevelopmental outcomes.[27] iNO may not work in the presence of severe left ventricular dysfunction or sub-optimal management of severe parenchymal disease. iNO improves clinical outcomes when OI is between 15 and 40. It is rarely helppul in OI>40, and aggressive measures such as ECMO are important to prevent death.[14](A1)
Milrinone: It is an inotropic vasodilator that inhibits phosphodiesterase III. It improves right and left ventricular function and can improve oxygenation in infants with severe pulmonary hypertension.[15] Milrinone reduces systemic vascular and pulmonary venous pressure, thereby improving left ventricular performance. It is used as adjunctive therapy to iNO.[28] Milrinone is non-selective and can cause systemic hypotension, which may negatively affect myocardial perfusion and cardiac function.[29](B2)
Sildenafil: Sildenafil is a phosphodiesterase V inhibitor. Though not yet approved by the FDA for the treatment of persistent fetal circulation, clinical data suggest beneficial effects of sildenafil in infants who did not respond to iNO. It is usually administered orally since the intravenous form is rarely available. Studies showed improvement in oxygenation with oral and intravenous forms of sildenafil.[30][31] [Level 2](B3)
Sedation: Agitation can increase pulmonary vascular resistance and further worsen persistent pulmonary hypertension. Sedatives and anti-anxiolytic are used in infants with PPHN as adjunctive therapy to reduce wide swings in saturations.[32] These medications can be given as continuous infusions or on an as-needed basis.
ECMO: ECMO bypasses the heart and lungs, providing the necessary time for resolving lung pathology. In severe respiratory failure, ECMO use was associated with improved survival.[33] [Level 2] The results of ECMO use in persistent pulmonary hypertension depend on the underlying etiology.(A1)
The best outcomes in survival are seen in infants with meconium aspiration syndrome (MAS). ECMO use in other conditions such as trisomy 21 or CDH had post-ECMO morbidity or a low survival rate of one year. Very few infants survived with no long-term sequelae (12%).[34] (B2)
Though its use in persistent fetal circulation drastically decreased since improved ventilation strategies and the introduction of iNO, it is still an effective rescue therapy. ECMO use remains controversial in babies with CDH.
Differential Diagnosis
Differential diagnosis includes cyanotic congenital heart disease, which presents with cyanosis. iNO treatment worsens the clinical condition in total anomalous pulmonary venous return and should be avoided. Infants with PDA, transposition of great vessels, and coarctation of the aorta can present with differential cyanosis.[16]
Prognosis
Outcomes of persistent pulmonary hypertension of the newborn are dependent on the underlying etiology. Surviving infants with persistent pulmonary hypertension have long-term neurodevelopmental, cognitive, and hearing problems.[35][36][37]
Approximately one in four infants with persistent pulmonary hypertension have neurodevelopmental delays and hearing impairment. The risk is higher in infants with underlying conditions such as CDH or genetic disorders. In addition to the severity and etiology of persistent pulmonary hypertension in newborns, small for gestational age and Hispanic ethnicity are independent risk factors for higher mortality and morbidity in the first year after discharge.[8]
Infants with mild disease are at higher risk for hospital readmission than term infants with no persistent pulmonary hypertension of the newborn.
Complications
Complications of persistent pulmonary hypertension of newborns are related to the underlying cause. In MAS, air leaks such as pneumothorax and pneumomediastinum occur very frequently due to the ball-valve phenomenon or the need for high ventilator settings.[38]
In infants with profound hypoxemia, multiorgan dysfunction can manifest as oliguria and bleeding diathesis due to DIC.
Deterrence and Patient Education
Parents should be educated about the long-term effects of hypoxic injury on the neonatal brain. Follow-up therapies play a crucial role in improving outcomes in these infants. These infants have a higher risk of readmission and increased mortality and morbidity in the first year of life.[8]
Enhancing Healthcare Team Outcomes
Persistent pulmonary hypertension of the newborn is a life-threatening condition in the immediate neonatal period. It may be due to lung parenchymal disease such as respiratory distress syndrome or due to underdeveloped lung vasculature in conditions such as congenital diaphragmatic hernia and small for gestational age infants. Quick diagnosis and appropriate management are extremely important in the management of these infants. While the neonatologist plays an important role in the management of Persistent pulmonary hypertension of the newborn, an interdisciplinary team approach is vital to early identification and providing timely treatment.
The nurses in the delivery room and newborn services are crucial in identifying newborns with cyanosis. Respiratory therapists provide valuable input regarding the ventilatory support required by the infant. Respiratory therapists also initiate iNO and thus monitor for response with iNO. NICU nurses monitor the infant's vitals and assist with parent education. Pharmacists provide recommendations on medications used for persistent pulmonary hypertension of the newborn. Cardiologists and echocardiogram technicians play a vital role in diagnosing and recommending appropriate therapy for persistent pulmonary hypertension of the newborn.[39]
The surgeons, along with the ECMO team, play a major role in initiating ECMO. Radiologists also play a vital role in identifying the underlying causes of persistent pulmonary hypertension of newborn.
The interprofessional healthcare team, including nurses and respiratory therapists in the newborn nursery, should receive education to identify the signs and symptoms of persistent pulmonary hypertension of the newborn. Pharmacists will play a role when medication is part of the management plan, including medication reconciliation, verifying doses, and coordinating their activities with the ordering clinician. Speech, occupational and physical therapists are very important in improving neurologic outcomes of babies with persistent pulmonary hypertension, especially after ECMO.[35]
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