Basics
Description
Clinical syndrome of severe respiratory failure and hypoxia in a neonate characterized by high systemic pulmonary arterial pressures, tricuspid regurgitation, and intracardiac shunting from right to left when pulmonary vascular resistance fails to decrease after birth
Epidemiology
- Incidence of ¢ ¼2 " 6 per 1,000 term live newborns, decreasing incidence with the decreased number of deliveries >41 weeks gestation
- Mostly occurs in full-term newborns, owing to the presence of the muscular layer of arterioles, the risk of uteroplacental insufficiency, and the potential for the passage of meconium in utero, but it can complicate the course of an older premature baby with chronic lung disease.
- Meconium aspiration is the number one cause of persistent pulmonary hypertension of the newborn (PPHN).
- PPHN complicates the course of about 10% of newborns with respiratory failure.
Risk Factors
Genetics
- Sporadic in occurrence
- Alveolar capillary dysplasia has been documented to be a rare cause of PPHN. The genetic cause is unknown, but it appears to be familial.
- Surfactant B deficiency has also been implicated, but it is a rare, lethal, autosomal recessive disorder.
Pathophysiology
- At a neonate 's first breath after delivery, the pulmonary vascular resistance normally decreases to redirect ¢ ¼50% of the cardiac output to the pulmonary circulation. This phenomenon fails to occur in PPHN, hence the previous name of this condition, "persistent fetal circulation. "
- Increased pulmonary vascular resistance increases right ventricular afterload, causing a backflow of blood to the right heart. This leads to increased right heart pressures (and subsequent tricuspid regurgitation), which can lead to right ventricular failure.
- Increased pulmonary arterial pressures also cause intracardiac shunting across any patent foramen ovale, ductus arteriosus, or atrioseptal or ventriculoseptal defect that may be present. This shunting causes more deoxygenated blood to go to the left heart and to be pumped to the body. The oxygen saturations postductally are lower than preductally.
- Deoxygenated blood in the left heart can lead to ischemic damage to the heart and right or left ventricular failure.
- If there is no shunting of blood, or the blood cannot get from the right to left heart because of a lack of persistent fetal pathways, a neonate may develop poor systemic perfusion, severe acidosis, shock, right ventricular failure, and even death.
- Any hypoxia, acidosis, or stress that occurs after birth further increases pulmonary vascular resistance.
Etiology
- Abnormal persistence of pulmonary vasculature constriction after birth secondary to underlying disease: infection, pneumonia, or meconium aspiration
- Secondary to an anatomic abnormality that has caused hypoplastic vasculature: congenital diaphragmatic hernia, oligohydramnios and pulmonary hypoplasia, or alveolar capillary dysplasia
- Idiopathic: The pulmonary vasculature is remodeled due to chronic in utero stress or hypoxia or the maternal use of nonsteroidal anti-inflammatory drugs (NSAIDs) near term. Data is unclear on maternal use of selective serotonin reuptake inhibitors (SSRIs) in the 2nd trimester and PPHN.
Commonly Associated Conditions
Related to the underlying disease or as a complication of treatment
- Pneumothorax or air leak syndrome
- Chronic lung damage
- Long-term developmental delays
- Cerebral palsy
- Sensorineural hearing loss
Diagnosis
History
- Pregnancy history
- Congenital diaphragmatic hernia, congenital pulmonary airway malformation, and congenital heart disease can all be diagnosed with a prenatal ultrasound.
- History of oligohydramnios, which may be associated with pulmonary hypoplasia in the neonate
- Problems during labor and delivery
- Events that can cause fetal distress and/or hypoxia: maternal chorioamnionitis, group B streptococcal infection, difficult delivery, or meconium aspiration
- Initial clinical course
- Infants with PPHN usually present with mild respiratory distress that worsens in the 1st minutes to hours of life, progressing to respiratory failure, labile oxygenation with pre- and postductal saturation differences >5%, hypoxia, and poor perfusion.
- Infants with cardiac disease, congenital pulmonary airway malformation, or congenital diaphragmatic hernia are usually cyanotic and in significant distress from birth.
Physical Exam
- The following physical exam findings suggest a diagnosis of PPHN:
- Significant respiratory distress with tachypnea, nasal flaring, grunting, and retractions and cyanosis
- Lung sounds may be clear or coarse.
- Pale, gray color with poor perfusion
- Tricuspid regurgitation murmur heard at the left lower sternal border or prominent S2
- The following physical exam findings suggest diagnoses other than idiopathic PPHN:
- Barrel chest shape suggests a pneumothorax or meconium aspiration.
- Scaphoid abdomen suggests congenital diaphragmatic hernia.
Diagnostic Tests & Interpretation
Lab
- CBC with differential: leukocytosis, leukopenia, bandemia, or neutropenia suggests bacterial infection
- Blood culture: should be performed in all cases of PPHN to rule out infection
- Frequent arterial blood gases
- Help to determine degree of hypoxia, hypercapnia, acidosis, and illness
- Help manage ventilator support
- Determine need for extracorporeal membrane oxygenation (ECMO) by calculating the oxygenation index (OI)
- OI
- OI = (mean airway pressure FiO2/PaO2) 100
- Used to express severity of respiratory distress and to determine if neonate is a candidate for ECMO
- Should be calculated with every blood gas: 3 OIs >40 suggest the need for ECMO.
- Hyperoxia test: While exposed to FiO2 of 100% oxygen, a PaO2 >250 mm Hg almost completely rules out cyanotic heart disease.
Imaging
- Chest radiograph
- In idiopathic disease, usually shows clear lungs
- Will help diagnose pneumothorax, hyperinflation, meconium aspiration, and atelectasis
- Assessing cardiac silhouette and pulmonary vascular markings may help rule out some congenital heart disease.
- Echocardiogram (very important)
- To exclude congenital heart disease
- To diagnose PPHN with right to left blood flow in the patent ductus arteriosus (PDA) and can estimate pulmonary artery pressure by septal positioning and tricuspid regurgitation
- To follow cardiac output and function
Differential Diagnosis
- Congenital
- Cyanotic congenital heart disease
- Total anomalous pulmonary venous return
- Congenital diaphragmatic hernia
- Congenital pulmonary airway malformation
- Alveolar capillary dysplasia
- Infectious
- Pulmonary
- Meconium aspiration syndrome
- Blood or amniotic fluid aspiration
- Pneumothorax or air leak syndrome
- Surfactant deficiency (respiratory distress syndrome [RDS])
- Pulmonary hypoplasia
- Idiopathic pulmonary hypertension
Treatment
General Measures
- All infants should be transferred to a level III neonatal intensive care unit where high-frequency ventilation (HFV) and inhaled nitric oxide (iNO) are available. If the neonate meets or nearly meets criteria for starting ECMO (OI >40 on 3 different blood gases), then ECMO should be available at the receiving institution.
- Support respiratory status
- Conventional ventilation or HFV to improve oxygenation and ventilation while minimizing lung damage
- No set guidelines for ventilator management
- Most institutions feel that HFV minimizes lung damage when high mean airway pressures (>15 cm H2O) are needed.
- Frequent monitoring to keep PaO2 between 60 and 90 mm Hg, PCO2 >35 " 45 mm Hg, and OI below ECMO criteria (OI >40 times 3)
- Avoid hyperventilation, which has been associated with poor neurodevelopmental outcome.
- Lower the pulmonary vascular resistance and thus promote pulmonary blood flow:
- Give 100% oxygen.
- Keep blood gas pH normal (7.3 " 7.4) while keeping PaCO2 >35 " 45 mm Hg by ventilator manipulation.
- Keep systemic BP high (mean BP >45 " 50 mm Hg) with volume, transfusions, or medications.
- Treat acidosis with fluid, blood, or bicarbonate infusion.
- Improve O2 saturation and O2 tissue delivery:
- Initially, 100% O2 should be used to keep the PaO2 >60 " 90 mm Hg and the O2 saturation around >97%. The O2 can be weaned very slowly (2% per hour).
- iNO, a pulmonary vasodilator, should be used if the infant is on 100% (FiO2) O2 and the OI is >20 on two blood gases.
- Has been shown to decrease the need for ECMO in term neonates with hypoxic respiratory failure secondary to PPHN, except for those babies with congenital diaphragmatic hernia
- Wean slowly: If oxygen and iNO are weaned too quickly, the infant can become critically ill because PPHN is a very labile condition.
- 30% of infants with PPHN do not respond to iNO and will need ECMO.
- Reduce oxygen demand:
- Sedatives and paralytics may be given to prevent fluctuations in oxygenation during care. Minimize the use of paralytics because they have been shown to increase mortality.
- Minimize stimulation
- Treat any underlying lung disease with the following, if applicable:
- Antibiotics
- Surfactant (especially in meconium aspiration)
Alert
- Can be difficult to differentiate cyanotic congenital heart disease from PPHN. Infants who fail to improve should be reevaluated for an underlying disease process.
- PPHN is a very labile condition. Neonates can change from being stable to being very sick and emergently needing ECMO.
- ECMO, although lifesaving and with a good survival rate, is not without problems. Side effects include the following:
- Repeated exposure to blood products
- Risk of bleeding
- Potential for long-term neurologic sequelae
- Long-term risk of having only one patent carotid artery
Ongoing Care
Prognosis
- PPHN usually resolves either spontaneously or as the underlying parenchymal lung disease improves.
- Survival rate is good even for neonates who receive ECMO. Survival rate and incidence of long-term sequelae depend on underlying disease and severity of illness.
- Survival rate for all causes of PPHN in patients not requiring ECMO is >90%. ¢ ¼10 " 20% has sensorineural hearing loss or an abnormal neurologic exam at follow-up.
- For those requiring ECMO, survival rate is 80% for idiopathic disease, 90% for meconium aspiration syndrome, 80% for disease secondary to sepsis, and 50 " 60% for patients with congenital diaphragmatic hernia. Roughly 20% of these survivors have sensorineural hearing loss or abnormal neurologic examinations at follow-up.
Complications
- Myocardial dysfunction
- Congestive heart failure (CHF)
- Hypoxic ischemic insult
Additional Reading
- Iacovidou N, Syggelou A, Fanos V, et al. The use of sildenafil in the treatment of persistent pulmonary hypertension of the newborn: a review of the literature. Curr Pharm Des. 2012;18(21):3034 " 3045. [View Abstract]
- Konduri GG, Kim UO. Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatr Clin North Am. 2009;56(3):579 " 600. [View Abstract]
- Lipkin PH, Davidson D, Spivak L, et al. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. J Pediatr. 2002;140(3):306 " 310. [View Abstract]
- Sadiq HF, Mantych G, Benawra RS, et al. Inhaled nitric oxide in the treatment of moderate persistent pulmonary hypertension of the newborn: a randomized controlled, multicenter trial. J Perinatol. 2003;23(2):98 " 103. [View Abstract]
Codes
ICD09
- 747.83 Persistent fetal circulation
ICD10
- P29.3 Persistent fetal circulation
SNOMED
- 233815004 persistent pulmonary hypertension of the newborn (disorder)
FAQ
- Q: Does iNO improve outcome in newborns with severe PPHN?
- A: Yes. iNO has been shown to decrease the need for ECMO by 40%. Recommended starting dose is 20 ppm. Follow-up studies have shown no difference in long-term disabilities between those babies treated and not treated with iNO. Long-term outcome is mainly determined by the underlying disease and the severity of illness.
- Q: Are there any other potential therapies for treating PPHN?
- A: Yes. Inhaled tolazoline, other smooth muscle relaxants (dipyridamole, zaprinast, and E4021), iloprost, and bosentan have been studied and have been shown to be effective in enhancing the vasodilatory effects of iNO. Sildenafil has been shown to be beneficial but is being used in select cases under special guidance due to concerns for increased mortality in children with pulmonary artery hypertension.