Persistent Pulmonary Hypertension

Introduction

Definition: Persistent pulmonary hypertension (PPHN) is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia due to abnormal shunting of blood (right to left shunt) from increased pulmonary vascular resistance (PVR) after birth

Epidemiology:

  • 1.9/1000 live births.
  • Primarily in term or late preterm infants ≥ 34 weeks.
  • Often associated with
    • Meconium aspiration syndrome (41%)
    • Pneumonia (14%)
    • Respiratory Distress Syndrome (13%)
    • Congenital diaphragmatic hernia (10%)
    • Pulmonary hypoplasia (4%)

Pathophysiology

In utero PVR is higher than systemic vascular resistance (SVR), thus blood shunts towards systemic circulation and away from the undeveloped, fluid filled lungs. After birth there is an immediate rise in SVR and decline in the PVR (decreased PVR/SVR ratio). Increases in SVR are attributed to catecholamine surge associated with birth and removal of the placenta, whereas decreases in PVR are attributed to expansion of the lung tissue with adequate ventilation and clearance of lung fluid.

Etiologies that interfere with the PVR/SVR ratio decline can result in persistent pulmonary hypertension, and these can be broken into three major categories:

  1. Underdevelopment: pulmonary hypoplasia leads to reduced cross sectional area of the pulmonary vasculature and elevation of PVR. Common causes of pulmonary hypoplasia include:
    • Congenital diaphragmatic hernia
    • Cystic adenomatoid malformation of the lung
    • Renal agenesis
    • Oligohydramnios
    • Intrauterine growth restriction
  2. Maldevelopment: A disruption to normally developed pulmonary vasculature. This is characterized by abnormal thickening of the pulmonary arteriole muscular layer and muscularization of smaller vessels. The mechanism of how this process occurs is unknown, but it has been reported that these patients have increased sensitivity to vasoconstrictors (endothelin-1 (ET-1)) and decreased response to the vasodilator, nitric oxide (NO). Predisposing factors to vascular maldevelopment include:
    • Post-term delivery
    • Meconium staining / meconium aspiration syndrome
    • Disorders producing excessive perfusion of the fetal lung (e.g. premature closure of ductus arteriosus, Total Anomalous Pulmonary Venous Return (TAPVR))
  3. Maladaptation: Pulmonary vasculature is normally developed, then adverse perinatal conditions cause active vasoconstriction interfering with the normal decline in PVR. Some of these conditions include:
    • pulmonary parenchymal disease
    • bacterial infections

Clinical manifestations:

Prenatal:

  • Fetal heart tone abnormalities (bradycardia or tachycardia)
  • Meconium-stained amniotic fluid
  • Prolonged rupture of membranes

Neonatal:

  • Respiratory distress (e.g. tachypnea, subcostal retractions, grunting)
  • Cyanosis
  • >50% with low APGAR scores
  • Nearly 100% receive delivery room interventions
  • Meconium staining of skin and nails
  • Prominent precordial impulse and a narrowly split and accentuated second heart sound
  • +/- harsh systolic murmur at left lower sternal border (LLSB) (if tricuspid regurgitation is present)
     

Workup:

  • Pulse Oximetry: >10% difference between pre and post ductal oxygen saturation (specific, not sensitive)
  • ABG: Partial pressure of arterial oxygen (PaO2) below 100 mmHg in patients receiving 100% fraction of inspired oxygen (FiO2) (differentiate from cyanotic cardiac lesions because PPHTN infants tend to have at least one PaO2 above 100 mmHg early in the course)
  • CXR: Normal or an associated pulmonary condition (e.g. pneumonia)
  • EKG: Normal or right ventricular deviation
  • Echocardiogram: Used for definitive diagnosis. Normal structural cardiac anatomy. Evidence of pulmonary hypertension (i.e. flattened or displaced ventricular septum). Doppler studies show RàL shunting through patent ductus arteriosus (PDA) or foramen ovale (FO).
  • Oxygenation Index (OI): Used to assess the severity of hypoxemia.        OI= (mean airway pressure x FiO2 / PaO2) x 100. A higher OI signifies more severe hypoxemic respiratory failure. Severe PPHTN when OI≥25.

Treatment:

  • General supportive care: supplemental oxygen, mechanical ventilation, fluid therapy, ionotropic agents and correction of respiratory acidosis
  • OI >25 despite high frequency oscillatory ventilation is indication for inhaled nitrous oxide (iNO)
  • OI >40 despite iNO: extracorporeal membrane oxygenation (ECMO) based on criteria (> 60 based on some clinicians’ preferences)
  • Medications: used if iNO and ECMO are not adequate
    • Sildenafil: inhibitor of cGMP phosphodiesterase type-5 in smooth muscle. Results in increased cGMP within vascular smooth muscle cells resulting in relaxation and vasodilation. This leads to vasodilation of the pulmonary vasculature.
    • Bosentan: a dual endothelin receptor antagonist. ET-1 is a neurohormone and potent vasoconstrictor with the ability to promote fibrosis, cell proliferation and tissue remodeling. ET-1 is elevated in plasma and lung tissue of patients with PHTN

*All patient that have iNO or ECMO should have neurodevelopmental follow up*

References:

  1. Curtis J, Kim G, Wehr NB, Levine RL. Group B streptococcal phospholipid causes pulmonary hypertension. Proc Natl Acad Sci U S A 2003; 100:5087.
  2. Dhillon R. The management of neonatal pulmonary hypertension. Arch Dis Child Fetal Neonatal Ed 2012; 97:F223.
  3. Jain, A, McNamara PJ. Persistent pulmonary hypertension of the newborn: Advances in diagnosis and treatment. Seminars in Fetal & Neonatal Medicine 2015; 20:262-271.
  4. Murphy JD, Rabinovitch M, Goldstein JD, Reid LM. The structural basis of persistent pulmonary hypertension of the newborn infant. J Pediatr 1981; 98:962.
  5. Rosenberg AA, Kennaugh JM, Moreland SG, et al. Longitudinal follow-up of a cohort of newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension. J Pediatr 1997; 131:70.
  6. Steinhorn, Robin H. “Neonatal Pulmonary Hypertension.” Pediatric critical care medicine: a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 11.2 Suppl (2010): S79–S84. PMC. Web. 8 Nov. 2015.
  7. Truven Health Analytics Inc. (2015) Micromedex Solutions. Retrieved from micromedexsolutions.com/micromedex2/librarian
  8. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000; 105:14.

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