PPHN (Persistent pulmonary hypertension of the Newborn, Ventilation &
Nitrogen Oxide therapy, Methemoglobinemia)
 

PPHN

• a diagnosis of exclusion
• increased pulmonary vascular resistance and altered vasoreactivity result in marked pulmonary hypertension
• consequently, R to L extrapulmonary shunting occurs across the foramen ovale and PDA.
• Causes: a wide array of cardiopulmonary disorders, or if unknown, "idiopathic PPHN" or "persistent fetal circulation". However, the root is not usually a single physiologic or structural entity, there is often more than one underlying pathophysiology
• The following conditions may be associated w/ PPHN:
  • Thrombocytopenia is seen in 60%. Specificity of this finding is unknown.
  • Lung disease: Meconium Aspiration, RDS, PNA, Pulmonary hypoplasia, cystic lung dz (i.e. CCAM and congenital lobar emphysema), diaphragmatic hernia, congenital alveolar capillary dysplasia
  • Systemic disorders: polycythemia, hypoglycemia, hypoxia, acidosis, hypocalcemia, hypothermia, sepsis
  • congenital heart disease, esp TAPVR , HLHS, transient tricuspid insufficiency (transient MI), coarct, critical aortic stenosis, ECD, Ebstein's Anomaly, Transposition of the Great Arteries, endocardial fibroelastosis, cerebral venous malformations
  • Perinatal factors: asphyxia, perinatal hypoxia, maternal ingestion of aspirin or indomethacin
  • Misc: CNS d/o, neuromuscular dz, upper airway obstruction

Physiology

• PVR is normally high in fetus, w/ only 5-10% of cardiac output going into lungs
• after birth, lungs expand and PVR drops and blood flow increases tenfold (factors responsible are incompletely understood)
• vasocontrictive: leukotrienes and thromboxanes
• vasodilatory: adenosine, prostaglandin I2, endothelium derived relaxing factors i.e. nitric oxide
• endothelins also regulate pulmonary vascular tone

Pathophysiology

1. underdevelopment of lung and vascular bed e.g. congenital diaphragmatic hernia  and hypoplastic lungs
2. maldevelopment of pulmonary vascular bed
3. pulmonary vascular bed has trouble adapting in the transition phase due to perinatal factors i.e. perinatal stress, hemorrhage, aspiration, hypoxia, hypoglycemia

Clinical features

• tachypnea, respiratory distress with cyanosis and hypoxemia
• onset may be at birth or within 4-8 hrs
• labile oxygenation, i.e. significant desat with movement, noise or minor nursing procedures
• onset at birth or within 8 hours
• look for cardiac signs: prominent R ventricular impulse, single second heart sound, tricuspid insufficiency

Diagnosis

• Measure preductal and postductal sats; a sat difference of >5% or a PaO2 difference of 10-15 mmHg is significant for a R-L ductal shunt. There will be no difference in an atrial shunt
  • preductal sat, right arm; preductal PaO2 right radial artery
  • postductal sat, left arm or feet; postductal PaO2 left radial, umbilical or tibial arteries
  • Normally, L->R shunting occurs through a PDA, so that the aorta contributes to pulmonary flow, and aortic pre-and-post ductal sats are both norml. If R->L shunting occurs through the PDA, the pulmonary flow contributes to blood flowing distal to the PDA; this blood will be relatively desaturated.
• Hyperventilation test
  • hyperventilate for 10 min
  • when a critical ph value is reached (usually 7.55), PVR decreases, less L-R shunting, and PaO2 increases
  • there will be no response in congenital cyanotic heart disease
• CXR: clear lungs or mild dz in setting of severe hypoxemia suggests PPHN. CXR mainly rules out other ddx
• Echo: cyanotic congenital heart disease vs PPHN

Management

• adequate newborn resuscitation and support
• fluid management, to prevent hypovolemia which worsens R-L shunt
• hypoglycemia, acidosis and hypocalcemia will aggravate PPHN
• maintain temperature control
• minimal handling (labile O2), ie, temp ETT suctioning PRN, not routinely
• pre and post ductal pulse ox
• mechanical ventilation, with sedation
  • lowest PEEP possible
  • avoid hyperventilation
  • PCO2 > 30, and even 40-50, if oxygenating well
  • 100% FI02, then wean
  • Consider hi-freq oscillation; High-frequency oscillation (HFO) is a mode of ventilation designed to minimize the lung injury that can accompany broad fluctuations in pressures associated with conventional ventilation. HFO is indicated if conventional ventilation fails to promote adequate gas exchange. The infant described in the vignette has blood gas evidence of  adequate ventilation, as indicated by the normal Pco2. HFO may be useful if the peak inspiratory pressure needed to ventilate the infant is excessive, and it may be beneficial for the infant in the vignette if the requirement for high peak inspiratory pressure persists. HFO is used in conjunction with inhaled NO therapy in some centers. This approach, however, remains investigational.
• The most appropriate next step after Echocardiogram in the management of this infant is to initiate inhaled nitric oxide (NO) administration. NO is a selective pulmonary vasodilator that improves oxygenation by enhancing blood flow through the pulmonary vascular bed.
  • Current evidence supports the use of doses beginning at 20 ppm in term newborns who have PPHN and reducing the dose gradually according to the infant's response.
  • Potential adverse effects of inhaled NO include Methemoglobinemia, nitrogen dioxide exposure, and platelet dysfunction. It is important to monitor carefully for these effects throughout the course of therapy.
  • half-life is measured in seconds. rapid inactivation.
    • combines w/ hemoglobin (to make methemoglobin) then to nitrates/nitrites
    • also produces nitrogen dioxide NO2 (removed from circuit w/ adsorbent)
• Surfactant to reduce PVR in infants w/ RDS
• maintain nl BP, MAP 40, Vasopressor therapy is an important adjunct, but not a replacement, for inhaled NO therapy. Inotropic agents, such as dopamine and dobutamine, are indicated in appropriate doses to support cardiac function, blood pressure, and tissue perfusion. (dopamine better; dobutamine may improve CO, but has less pressor activity).
• alkalinization: Bicarbonate administration to induce metabolic alkalosis has been used both in the treatment of PPHN before the advent of inhaled NO therapy and as an adjunct to NO administration. Alkalosis, whether metabolic or respiratory, attenuates hypoxic pulmonary vasoconstriction and improves oxygenation by enhancing blood flow through the pulmonary vascular bed. This effect is largely mediated by the increased pH, independent of the Pco2. The optimal pH required for reversing hypoxic pulmonary vasoconstriction is not known. The drawbacks to this therapeutic approach are systemic hypotension, decreased cerebral blood flow, reduced cardiac output, and lung injury.
• Extracorporeal membrane oxygenation (ECMO) is warranted if the infant fails to respond to maximal ventilatory support, inhaled NO therapy, and other supportive measures. ECMO is invasive, expensive, and can cause a host of potential complications. Appropriate and earlier use of inhaled NO should result in fewer infants requiring ECMO.
• Muscle paralysis: controversial.Consider in patients fighting the vent
• IV pulmonary vasodilators: Tolazoline (most common), PGE1, prostacyclin, nitroglycerin, nitroprusside.
  • beware of systemic hypotension, give w/ volume support and pressor drugs close at hand, or started prophylactically.
  • mag sulfate and adenosine (being studied, 1999)

Prognosis

• overall survival 70-75%, dependent on etiology

References:

Most of info copied from Gomella. Neonatology, 4th edition.
Finer NN, Barrington KJ. Nitric oxide in respiratory failure in the
newborn infant. Semin Perinatol. 1997;21:426-440
Fox WW, Duara S. Persistent pulmonary hypertension in the neonate:
diagnosis and management. J Pediatr. 1983;103:505-514
Kinsella JP, Abman SH. Controversies in the use of inhaled nitric
oxide therapy in the newborn. Clin Perinatol. 1998;25:203-217