Definition

1. 
   

   The adult definition of primary pulmonary hypertension (PH) (mean pulmonary arterial pressure greater than 25 mm Hg at rest) is often applied to preterm infants with PH secondary to bronchopulmonary dysplasia (BPD), which may not necessarily be applicable.

   
   
2. 
   

   Clinically, pulmonary pressures in preterm infants are often reported as a percentage of systemic pressure with pulmonary pressures greater than 50% of systemic pressures being diagnostic for PH, and suprasystemic (>100%) pressures being considered a marker for severe disease.

Incidence

1. 
   

   As a result of growing awareness among clinicians, PH is more commonly being diagnosed in preterm infants with BPD.

   
   
2. 
   

   The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry reported that 12% of pediatric PH cases were secondary to chronic respiratory disease in their registry, with BPD being the most common respiratory disease associated with pediatric PH.

   
   
3. 
   

   Retrospective studies demonstrate that 17% to 43% of preterm infants with BPD may have PH. The only prospective study to date documented that 18% of ELBW infants were diagnosed with PH while in the intensive care setting.

Pathophysiology

1. 
   

   The interplay of factors leading to the development of PH in the preterm infant is poorly understood, but the development of PH is likely multifactorial. The underlying deficit may be a poorly developed vascular bed in the preterm lung due to alveolar hypoplasia accompanied by dysynaptic airway growth, resulting in a “fixed” component responsive only to lung growth and development.

   
   
2. 
   

   In vitro work suggests that imbalances in the nitric oxide pathway may also play a role, which may represent a “responsive” component amenable to pulmonary vasodilator therapies.

Risk factors

1. 
   

   Birthweight and BPD severity play a substantial role in the development of PH, but other factors are involved as not every ELBW infant with severe BPD develops PH.

   
   
2. 
   

   Infants born small for gestational age (SGA) also appear to be at higher risk for developing PH, but it is unclear whether this is due to a smaller pulmonary vascular bed or an SGA-associated in utero exposure.

   
   
3. 
   

   Other risk factors identified through retrospective studies include maternal preeclampsia and oligohydramnios. Preeclampsia may act through interference with VEGF pathways.

   
   
4. 
   

   Theoretical risk factors may include persistent ventilation-perfusion mismatch, intermittent hypoxia or hypercarbia, aspiration from dysphagia or gastroesophageal reflux, infections, suboptimal nutrition for lung growth, shunts that increase pulmonary blood flow (eg, intracardiac shunts, PDAs), and/or airway anomalies that impede gas exchange (eg, subglottic stenosis, airway malacia).

Clinical presentation

1. 
   

   Signs and symptoms

   
   
   
   
   1. 
      

      Physical exam findings and basic clinical test results can be subtle or nonspecific for preterm infants with PH.

      
      
   2. 
      

      Physical findings may include tachypnea, respiratory distress, hypoxemia, and signs of right heart overload or failure, such as parasternal lift or the quality of the second heart sound.

      
      
   3. 
      

      Chest radiography may demonstrate cardiomegaly, right atrial/ventricular dilatation, and/or enlarged central arteries.

      
      
   4. 
      

      EKG findings may include right axis deviation or right ventricular hypertrophy.

      
      
   5. 
      

      Premature infants with PH are also subject to pulmonary hypertensive crises, which represent an acute worsening of PH, often associated with the induction of anesthesia or respiratory infections. The exact physiological mechanism of these episodes is unknown, but may relate to a drop in alveolar oxygen tension and hypercarbia. These crises may present with increased respiratory effort or failure, hypoxemia, cardiac insufficiency, or even cardiopulmonary arrest.

   
   
2. 
   

   Condition variability

   
   
   
   
   1. 
      

      The severity of PH in the preterm infant can be highly variable, ranging from being an incidental finding on echocardiography to severe disease requiring continuous infusions of pulmonary vasodilators in an intensive care setting.

      
      
   2. 
      

      Additionally, degree of responsiveness to pulmonary vasodilator therapies may be dependent on the variable contribution of the fixed and responsive components of disease.

Diagnosis

1. 
   

   Cardiac catheterization is the gold standard for diagnosing PH, and risks may be minimized with experienced operators, but it is invasive and requires anesthesia.

   
   
2. 
   

   Due to the potential risks of cardiac cath, echocardiography remains the primary tool for screening for PH and following its clinical course.

   
   
3. 
   

   When it can be ascertained, tricuspid regurgitation jet velocity serves as the primary means of estimating pulmonary vascular pressures.

   
   
4. 
   

   Other quantitative measures include VSD, PDA, or pulmonary regurgitation velocities.

   
   
5. 
   

   Qualitative measures include the systolic interventricular septal position, and/or right ventricular hypertrophy, dilation and/or dysfunction.

   
   
6. 
   

   Echocardiography may also be diagnostic for other cardiac and vascular lesions that could contribute to PH, including left ventricular dysfunction, VSD, ASD, PDA, and pulmonary venous stenosis.

   
   
7. 
   

   Although echocardiography is likely sensitive in detecting the presence or absence of PH, it has limited sensitivity with regards to ascertaining severity in the pediatric population. Cardiac catheterization can provide useful data regarding hemodynamics and response to vasodilator therapies, but has been associated with higher complication rates with both catheterization and anesthesia in a preterm infant with PH.

   
   
8. 
   

   There are no guidelines regarding which infants should be catheterized and optimal timing of catheterization during the disease course. However, cardiac catheterization should be considered in cases where the diagnosis or severity is unclear, where the response to pulmonary vasodilators needs to be assessed, and/or where contributing vascular lesions or intracardiac shunts are amenable to treatment.

Management

1. 
   

   Medical

   
   
   
   
   1. 
      

      There are no clinical guidelines for the management of PH with a lack of evidence to support either aggressive pulmonary management or vasodilator therapy.

      
      
   2. 
      

      Appropriate management of respiratory symptoms in the infant with BPD should be implemented and may include diuretics, inhaled or systemic corticosteroids, chest physiotherapy, bronchodilators, optimal nutrition, gastroesophageal reflux therapies, and immunoprophylaxis.

      
      
   3. 
      

      Ventilatory strategies that minimize ventilation-perfusion mismatch and episodes of hypoxia and hypercarbia should also be used. However, it should be noted that there is no evidence demonstrating that these strategies reduce the incidence or severity of PH.

      
      
   4. 
      

      Likewise, there has been increasing off-label use of pulmonary vasodilators, such as sildenafil, bosentan, and iloprost, with no randomized control trials to support their use. It should be noted that the US Food and Drug Administration (FDA) recommended in 2012 that sildenafil not be prescribed to children. (Readers are advised to consult the FDA Web site for up-to-date drug safety information.) Furthermore, it is suggested that pulmonary vasodilator therapy only be prescribed in consultation with a pediatric cardiologist and informed consent should be considered for the use of sildenafil depending on institutional protocols.

      
      
   5. 
      

      Oxygen is a known pulmonary vasodilator, and it has been suggested that maintaining oxygen saturations ≥95% is beneficial for PH. While judicious use of supplemental oxygen may be beneficial, its use and goal oxygen saturations must be considered in the context of the corrected gestational age of the infant and the risk/severity of retinopathy of prematurity.

   
   
2. 
   

   Surgical

   
   
   
   
   1. 
      

      Possible cardiothoracic procedures may include treating PDAs, vascular narrowings, or intracardiac shunts directly contributing to PH.

      
      
   2. 
      

      Gastric tube placement and/or Nissen fundoplication may help prevent further lung injury caused by dysfunctional swallow and/or aspiration of gastric contents, where medical management has proven ineffective.

      
      
   3. 
      

      Airway surgery for conditions may be necessary where effective gas exchange is significantly hampered or long-term ventilatory therapy is needed.

      
      
   4. 
      

      Owing to the potential for life-threatening pulmonary hypertensive crises with any surgical or anesthetic procedure, consultation with a pediatric cardiac anesthesiologist should be considered prior to general anesthesia in preterm infants with PH. Careful collaborative planning with preoperative sedatives, and ready access to inotropic agents and vasodilators (eg, nitric oxide), may decrease the risk of intra- or postoperative adverse events.

Early developmental/therapeutic interventions

1. 
   

   There are no screening guidelines for PH in the intensive care setting. However, screening echocardiography should be considered in preterm infants with BPD who require any respiratory support after 2 months of age, including supplemental oxygen and/or positive pressure ventilation, preterm infants who were SGA, and preterm infants growing slower than expected.

   
   
2. 
   

   In infants who unexpectedly develop PH, a formal swallow evaluation by a speech therapist skilled in infant feeding should be considered. A videofluoroscopic swallow study may demonstrate aspiration as a possible contributing cause.

   
   
3. 
   

   Infants with unstable PH should be kept in a minimal stimulation environment.

Prognosis

1. 
   

   Early predictors

   
   
   
   
   1. 
      

      There are no identified genetic or epigenetic modifiers known for the prediction of clinical course of PH, limiting the use of genetic testing.

      
      
   2. 
      

      PH that is associated with pulmonary vein stenosis may carry a worse prognosis.

   
   
2. 
   

   Outcomes

   
   
   
   
   1. 
      

      Unfortunately, mortality rates are high among preterm infants with PH.

      
      
   2. 
      

      Several retrospective studies have observed mortality ranging from 14% to 38%, with the only prospective study documenting a mortality rate of 12% (Figure 30-1).

      
      
   3. 
      

      Limited data suggest that preterm infants with PH have longer initial NICU admissions, although it is unknown whether this is directly due to PH or associated comorbidities.

Definition: See above.

Incidence: See above.

Pathophysiology:

1. 
   

   Theoretically, with lung growth, the vascular bed can achieve catch-up growth, thus eliminating the fixed component of PH in preterm children with BPD.

   
   
2. 
   

   As most alveolar growth is completed by 2 years of age, this period of time is essential for ensuring good somatic growth.

Risk factors

1. 
   

   Ongoing aspiration through dysphagia or reflux.

   
   
2. 
   

   Intermittent hypoxia/hypercarbia.

   
   
3. 
   

   Respiratory viral infections are a significant etiology of worsening of PH or pulmonary hypertensive crises in convalescence and outpatient settings.

   
   
   
   
   1. 
      

      Measures to limit exposure to viruses such as avoiding sick nonparental contacts, hand-washing, and infectious prophylaxis (RSV and influenza) when appropriate should be universally employed.

      
      
   2. 
      

      In addition, parents should be aware upon discharge of the increased risks of contracting respiratory viral infections in daycare settings.

Clinical presentation: See above.

Diagnosis: See above.

Management

1. 
   

   Medical

   
   
   
   
   1. 
      

      Feeding: In the transition to oral feeding, the infant must be monitored closely for aspiration. Aspiration through gastroesophageal reflux or dysphagia can lead to further lung injury and may worsen PH.

      
      
   2. 
      

      Eyes: As the risk for the development of retinopathy decreases, oxygen supplementation may be beneficial to maintain oxygen saturations ≥95% in infants with PH.

      
      
   3. 
      

      Pulmonary vasodilators should be titrated in consultation with a pediatric cardiologist with periodic echocardiography.

      
      
   4. 
      

      Ventilation perfusion mismatch should be minimized treating small airway dysfunction as clinically indicated.

   
   
2. 
   

   Surgical: As even ongoing microaspiration may lead to worsening PH, placement of feeding tubes should be considered if PH persists or worsens.

Ongoing developmental/therapeutic interventions: See above.

Prognosis/outcomes

1. 
   

   There are no biomarkers for PH in preterm infants.

   
   
2. 
   

   However, levels of the cardiac hormone brain natriuretic protein (BNP) have been shown to correlate with disease severity and prognosis for pH in adults. Currently, BNP and its prohormone N-terminal pro-BNP (NT-proBNP) are being used in some centers to follow the clinical course of preterm infants with PH. A single level may not be diagnostic, but trends in levels may be helpful in ascertaining clinical improvement as well as assessing for pulmonary hypertensive crises. It should be noted that BNP and NT-proBNP have also been subject to scrutiny owing to nonspecificity, heterogeneity in assay platforms, and developmental changes in these levels over time.

   
   
3. 
   

   The course of PH in the preterm infant is unknown. With appropriate management and time, most cases appear to resolve on echocardiography, but long-term sequelae are also unknown, including risk for chronic lung conditions or recurrence of PH with age (Table 30-1).

   
   
   
   
   1. 
      

      Given the mortality rates associated with PH, including deaths that occur after initial discharge from the inpatient setting, parents and pediatricians alike should be aware of the risks associated with PH.

      
      
   2. 
      

      There should be a low threshold for seeking acute care or subspecialty consultation with any change of cardiorespiratory status postdischarge.

Discharge

1. 
   

   Teaching

   
   
   
   
   1. 
      

      Parents should understand that their infant with PH is very fragile and that a minor illness or change in status (feeding, activity level, work of breathing, etc) should not be overlooked and needs urgent evaluation.

      
      
   2. 
      

      Parents should be taught how to give medications, the purpose of each med, and the importance of not missing doses or running out.

      
      
   3. 
      

      Parents should understand how to evaluate their baby’s cardiorespiratory status and recognize signs of distress.

      
      
   4. 
      

      For infants going home on oxygen therapy or ventilator support, extensive teaching must begin early and parents should demonstrate readiness (see Chapter 7).

   
   
2. 
   

   Monitoring

   
   
   
   
   1. 
      

      Infants with PH going home on supplemental oxygen therapy should be discharged home on a continuous pulse oximeter.

      
      
   2. 
      

      Consider arranging for overnight oximetry 1 to 2 weeks postdischarge in infants with PH who are not being discharged home on oxygen.

      
      
   3. 
      

      Follow-up echocardiogram should be arranged for about 1 month postdischarge in infants with PH at the time of NICU discharge.

   
   
3. 
   

   Safety

   
   
   
   
   1. 
      

      Parents should learn infant CPR prior to discharge.

      
      
   2. 
      

      Parents should understand the importance of minimizing infectious exposures postdischarge. Infants with PH should receive RSV prophylaxis (if in season) and influenza vaccine (if >6 months old) prior to NICU discharge and plans to receive subsequent doses should be arranged.

      
      
   3. 
      

      The discharging provider should contact the child’s primary care provider prior to discharge to give a direct sign-out on the medically fragile infant with PH.

      
      
   4. 
      

      An emergency plan should be discussed with the parents, outlining what to do (increase oxygen, call PCP, call cardiologist, call 911, etc) and where to go (ER, PCP office, etc) in the event of acute or worsening condition.

      
      
   5. 
      

      A car seat safety test of at least 90 minutes, monitoring for cardiorespiratory instability, should be completed prior to discharge.