PERSISTENT PULMONARY HYPERTENSION IN NEWBORN (PPHN)
Dr. G. P. Parale*, Dr. S. S. Pawar**
Department of Pediatrics*, Department of Pediatrics**
Introduction
During intrauterine life, less than 10% of combined cardiac output is directed to the lungs which is due to high pulmonary vascular resistance (PVR). Numerous factors, including hypoxia contribute for PVR during fetal life. Following birth, PVR decreases and pulmonary blood flow increases dramatically as lungs assume the function of gas exchange. The combination of increased alveolar oxygen tension and rhythmic ventilation are responsible for these changes. Each of these pulmonary hypertension in newborn (PPHN) is a syndrome, resulting due to failure of normal circulatory transition that occurs after birth and characterized by inadequate pulmonary perfusion resulting into refractory hypoxemia, respiratory distress and acidosis. Since, etiological factors contributing to PPHN are numerous and the mortality rate due to PPHN is nearly 40%, neonate with PPHN should be assessed and treated vigorously, so as to prevent consequent neurologic disability.
Frequency
Recent data suggests that PPHN syndrome occurs as often as 2-6 cases per 1000 live births. The mortality rate reached 40%, while the prevalence of major neurologic disability was 15-60%. With advent of newer modalities of treatment, the mortality rate associated with PPHN has been reduced to < 10% but prevalence of major neurologic disabilities among surviving newborn remains approximately 15-20%
Causes
PPHN is most commonly associated with 1 of 3 underlying etiologies:
  1. Most commonly encountered scenario is Acute Pulmonary Vasoconstriction due to acute perinatal events, such as -Alveolar hypoxia secondary to parenchymal lung disease Respiratory Distress Syndrome (RDS) or Pneumonia.
    • Hypoventilation due to asphyxia
    • Hypothermia
    • Hypoglycemia
  2. Idiopathic PPHN/Black-lung PPHN/Clear-lung PPHN
    • Most common cause in newborns born at term, near-term (> 34 weeks gestation)
    • It is associated with normal chest radiograph and no parenchymal lung disease
    • Newborns with idiopathic PPHN presents with pure vascular disease
    Etiological factors for this variety are:
    • Abnormally remodeled pulmonary arterial bed, with vascular wall thickness and smooth muscle hyperplasia, probably secondary to chronic stress in utero.
    • Other potential associations include, maternal use of NSAIDS (non-steroidal anti-inflammatory drugs) like ibuprofen or naproxen especially during 3rd trimester, which causes constriction of fetal ductus arteriosus in utero and consumption of SSRI (Selective serotonin reuptake inhibiter) e.g., fluoxetine, during 2nd trimester. So, careful history of maternal drug exposure should be sought.
  3. Hypoplasia of Pulmonary vascular bedis another cause. Contributing events to this are -
    • Congenital diaphragmatic hernia
    • Patient may have an oligohydramnios sequence Rare association with congenital cystic adenomatoid malformation
Evaluation
I) History:
Newborns with PPHN typically present with cyanosis and tachypnea. Marked liability in oxygenation is frequently part of their history. Two another important points that should be looked for in history are:
  • Perinatal distress or meconium staining of amniotic fluid which usually occurs in 13% of all live births.
  • Maternal History of drug consumption, especially of NSAIDs and SSRIs.

II) Physical examination:
Typically infants with PPHN are phenotypically normal, however syndrome may occur most frequently in newborns with Down's syndrome. On initial examination, the primary finding is cyanosis, associated with tachypnea and respiratory distress - cardiac examination reveals loud, single S₂ or harsh systolic murmur due to tricuspid regurgitation.

III) Lab studies:
  • Arterial Blood Gas Analysis (ABGA) -Usually demonstrates decrease in PaO2; increase in PaO₂ & decrease in blood pH suggesting respiratory and metabolic acidosis.
  • Oxygenation is often assessed by using Oxygenation Index (OI).

OI = (mean airway pressure x fraction of Inspired O₂ (FiO₂)/ Postductal PaO₂) X 100. OI of 40 typically warrants invasive management.
  • Complete blood count -
    Evaluate the CBC for high Hematocrit level, because Polycythemia and hyperviscosity syndrome aggravate PPHN.
    Total and differential WBC counts help to determine underlying sepsis syndrome or pneumonia.
    Platelet count is frequently depressed in patients with asphyxia or meconium aspiration syndrome (MAS).
  • Serum electrolytes -
    Monitor serum electrolyte and glucose levels at frequent intervals. In particular, maintaining glucose and ionized calcium levels within reference ranges is important because hypoglycemia and hypocalcemia tend to worsen PPHN.

IV) Imaging studies:
  • Chest radiography -
    It is useful in determining presence of underlying parenchymal lung diseases e.g., meconium aspiration syndrome; pneumonia; hyaline membrane disease.
    It also assists to rule out presence of other underlying disorders like congenital diaphragmatic hernia and congenital cystic adenomatoid malformation.
    In newborns with Idiopathic PPHN, the lung fields appear clear with decreased vascular marking. Heart size is typically normal or slightly enlarged.
  • Echocardiography -
    It is necessary to exclude congenital cyanotic heart disease. However, defining anatomy of the pulmonary veins is extremely difficult in the setting of right to left extrapulmonary shunting.
    Echocardiography is must prior to beginning of treatment with iNO. Presence of left sided obstructive lesions like aortic Stenosis; hypoplastic left ventricle and interrupted aortic arch are contraindications to iNO treatment.
    Cardiac catheterization is rarely required.
Treatment
  • Continuous monitoring of oxygenation, blood pressure and perfusion is critical.
  • Maintenance of fluid and electrolyte balance is important. An adequate circulating blood volume is necessary to maintain right ventricular filling and thus cardiac output. However, repeated bolus administration of crystalloid and colloid solutions does not provide additional benefit.
  • Ionotropic support with dopamine; dobutamine and/or milrinone alone or in combination, is frequently helpful in maintaining adequate cardiac output and systemic blood pressure while avoiding excessive volume administration.
Mechanical Ventilation
  • Mechanical ventilation is usually needed to maintain adequate oxygenation. Determine the exact strategy on the basis of the underlying lung disease. For instance, newborns with clinically significant airspace disease due to pneumonia or RDS likely require airway pressure higher than those needed for patients with idiopathic black-lung PPHN. Likewise, newborns with clinically significant airspace disease are most likely to respond to other lung recruitment strategies, such as surfactant administration and/or high-frequency oscillatory ventilation.
  • A frequent concern is determining the target arterial PaO2 level. Levels of = 50 mm Hg typically provide for adequate oxygen delivery. Aiming for high PaO₂ concentrations may lead to increased ventilator support and barotraumas. Because of their lability and ability to fight the ventilator, newborns with PPHN nearly always require sedation, Fentanyl is usually preferred (often in combination with a benzodiazepine) because it tends to decrease the sympathetic response to pain and noxious stimuli.
Acidosis and Alkalosis
  • Metabolic acidosis and respiratory acidosis require correction. Sodium bicarbonate is typically used to correct metabolic acidosis. However, if carbon dioxide clearance is a problem, administering bicarbonate may produce a respiratory acidosis. In these situations, tromethamine (THAM) 1-2 mmol/kg to patients with anuria or uremia.
  • Forced alkalosis by using sodium bicarbonate and hyperventilation were popular therapies in the past because of their ability to produce acute pulmonary vasodilation and increase PaO2. However, hypocarbia is associated with construction of the cerebral hypotension. Extreme alkalosis and hypocarbia are strongly associated with late neurodevelopmental deficits, including a high rate of sensorineural hearing loss.
  • An alternate approach is maintaining an alkaline pH level of 7.45-7.5 by using sodium bicarbonate infusion. Serum sodium concentration should carefully be monitored if bicarbonate infusions are used and ventilation must be adequate to allow for carbon dioxide clearance.
  • In 2000, Walsh - Sukys and colleagues reported that the use of alkaline infusions is associated with increased use of ECMO and oxygen when the newborn is aged 28 days. Therefore, use this approach with caution.
  • Many clinicians have good success without using alkalinization. In a series of 15 patients, Wung et al (1985) applied a strategy designed to maintain PaO2 at 50-70 mm Hg and PaCO2 < 60 mm Hg (ie gentle ventilation). This approach resulted in excellent outcomes and a low incidence of chronic lung disease.
Induced paralysis
  • The use of paralytic agents is highly controversial and typically reserved for newborns who cannot be treated with sedatives alone. Be aware that paralysis, in particular with pancuronium, may promote Atelectasis of dependent lung regions and promote ventilation-perfusion mismatch.
  • In their review of 385 newborns with PPHN by Walsh-Sukys and colleagues (2000) suggests that paralysis may be associated with an increased risk of death.
  • Another report indicates that prolonged administration of pancuronium during the neonatal period is associated with sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia.
Treatment with iNO
  • Treatment with iNO is indicated for newborns with an OI > 25. Nitric oxide (NO) is an endothelial-derived gas signaling molecule that relaxes vascular smooth muscle and that can be delivered to the lung by means of an inhalation device (INOVent; Datex - Ohmeda Inc, Madison, WI).
  • In 2 large randomized trials, NO reduced the need for ECMO support by approximately 40%.
  • Contraindications to iNO include congenital heart disease characterized by left ventricular outflow tract obstruction (e.g., interrupted aortic arch, critical aortic Stenosis, hypoplastic left heart syndrome) and severe left ventricular dysfunction.
  • The appropriate starting dose is 20 ppm. Doses higher than this have not been shown to be more effective and have been associated with adverse effects, including methemoglobinemia and increased levels of nitrogen dioxide (NO₂).
  • Appropriate lung recruitment and expansion are essential to achieve the best response. If a newborn has severe parenchymal lung disease and PPHN, strategies such as HFV may be required.
  • Most newborns require iNO for < 5 days. In general, the dose can be weaned slowly and discontinued when the FiO₂ is < 0.6 and the iNO dose is 1 ppm. Abrupt discontinuation should be avoided become it.
High-frequency ventilation (HFV)
  • HFV is another important modality if a newborn has underlying parenchymal lung disease with low lung volumes. This modality is best used in a center with physicians experienced in achieving and maintaining optimal lung distension.
  • The response to HFV can be rapid, and care must be taken to prevent hypocarbia and lung over distension.
Extracorporeal membrane oxygenation
  • ECMO is used when optimal support fails to maintain acceptable oxygenation and perfusion. This therapy, which is an adaptation of cardiopulmonary bypass.
    Recent developments allow ECMO support to be provided by using a double - lumen catheter in the internal jugular vein; thus, ligation of the right common carotid artery can be avoided.

Medications:

Drug

Pediatric dose

Remarks

1) Tolazoline
Slow iv bolus
0.5-1 mg/kg
  • Acts as alpha blocker, causes pulmonary vasodilation.
  • Useful for emergency where setup for iNO is not available.
2) iNO
Inhalation 5-20 ppm
Taper dose before
discontinuing
  • Increases levels of intracellular cGMP
? Vasodilation
  • Monitor for excess PaO 2 methemoglobin;
       NO 2
  • Caution in thrombocytopenia anemia,
    leukopenia or bleeding disorder.
3) Sildenafil
1-2 mg/kg iv
  • Selective pulmonary vasodilator; decreases PAP without change in wedge pressure and increases cardiac output.
  • No adverse effect on systemic hemodynamics or oxygenation.
4) Sodium
Bicarbonate
Slow. Bolus
infusion: 2-3 mcg/kg iv
  • Corrects metabolic acidosis
    - Administer only when ventilation is adequate
  • 1" correct alkalosis, hypernatremia
    hypocalcemia.
  • Contraindicated in severe pulmonary edema
5) Beractant
Intratracheal:
100 mg/kg in 4 doses
at least 6 hr apart
  • It is surfactant; decreases surface tension & stabilizes alveoli. Thus increases compliance &
    decreases work of breathing.
  • Administer only after warming at room temperature & under supervision due to risk of acute airway obstruction.
6) Dopamine
Continuous infusion
2-20 mcg/kg/min iv
  • Increases cardiac output without affecting pulmonary vascular resistance.
  • Incompatible if iv mixed with indomethacin, alpha
    & beta blockers, phenytoin & sod. Bicarbonate
  • Contraindicated in outflow tract obstruction
  • Best administered by central access
7) Dobutamine
Continuous infusion
2-20 mcg/kg/min iv
  • Contraindicated in outflow tract obstruction
  • Correct hypovolemic state before use
8) Fentanyl
Intermittent 1.5 mcg/kg
slow iv bolus
Continuous 1.2
mcg/kg/initially,
followed by
0.5-1 mcg/kg
  • Produces deep sedation & analgesia
  • Enables adequate mechanical ventilation
  • Decreases sympathetic tone
  • Causes little cardiovascular compromise
  • Contraindicated in compromised airways
  • Withdrawal symptoms after infusion for > 5d
9) Pancuronium
0.05-0.15 ng/kg/dose
iv bolus 1-2 hourly
  • For induction of paralysis.
  • Infants often require expansion of intravascular blood volume to maintain blood pressure
  • Consider airway protection

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