Bronchopulmonary dysplasia (BPD) is an iatrogenic, chronic lung disorder of infancy that results in persistent respiratory symptoms, medical fragility, and in most cases, the long-term need for supplemental oxygen. With continuing advances in the care of critically ill neonates, the nomenclature of BPD is evolving, as is its incidence and pathogenesis. Today, BPD is often referred to as chronic lung disease of infancy (CLDI).¹ Both BPD and CLDI are chronic pulmonary disorders that result from an acute and often critical respiratory illness in a newborn infant, and there is considerable overlap in their pathogenesis, risk factors, and manifestations. Thus, the two terms are generally considered to be interchangeable.

BPD and CLDI develop in premature infants or critically ill neonates as a consequence of therapeutic maneuvers (oxygen and positive-pressure ventilation) required for survival. The risk of an infant developing BPD is related to gestational age, the severity of the initial illness, the duration and intensity of oxygen and ventilator therapy, and other factors that are less well characterized. These prognostic factors include variables specific to the infant, such as gender, race, genetic predilection, nutritional status, presence of patent ductus arteriosus, and other complications of newborn intensive care as well as maternal variables such as cigarette smoking during pregnancy and the presence of amnionitis.¹ These factors often result in significantly different clinical courses and outcomes in infants despite apparently similar care.

Most children with BPD have multisystem disease rather than isolated pulmonary involvement. The medical fragility associated with BPD and CLDI results in an increased risk of re-hospitalization after discharge from the nursery. The pediatric hospitalist will therefore encounter infants with BPD and CLDI and will be called on to address the problems unique to this complex group of patients. Many infants with BPD or CLDI are readmitted to the hospital within the first 2 years of life, with the highest incidence of re-hospitalization being in those born most prematurely.² Respiratory illness, most notably due to respiratory syncytial virus (RSV) or other viruses, is the most common reason, causing up to two thirds of readmissions, followed by gastroenteritis, feeding difficulties, and seizures.² Further, BPD and CLDI often have systemic manifestations that may complicate the respiratory management of these infants. If the extra-pulmonary manifestations are not recognized and addressed, they can interfere with lung growth and healing, which are necessary for the resolution of BPD and CLDI. Often the goal of therapy is to re-establish the infant’s baseline state or to diagnose and treat a new problem rather than to provide a definitive cure. This requires both skilled medical management and attention to the details of discharge planning.

When originally described by Northway and colleagues,³ BPD occurred primarily in relatively mature infants with an average birth weight of nearly 2 kg and a gestational age of 32 weeks, who developed hyaline membrane disease due to surfactant deficiency, termed neonatal respiratory distress syndrome. These infants received what would now be considered aggressive therapy consisting of high levels of inspired oxygen and ventilator pressures that are toxic to the lung and result in a specific pattern of lung and airway injury (“classic” BPD).³ The adverse effects of oxygen and barotrauma affected primarily the distal airways, resulting in diffuse airway damage and airway obstruction that was either complete (resulting in atelectasis) or partial (resulting in a ball-valve effect and gas trapping).⁴ An intense inflammatory reaction ensued, which could hinder lung healing and promote further lung injury (see Figure 143-1 for pathological features of severe BPD). This nonspecific airway injury also resulted in distinctive and evolving radiographic manifestations (Figure 143-2). With a heterogeneous pattern of focal gas trapping, atelectasis, and interstitial infiltrates followed by fibrosis (Figure 143-3).³

Owing to improvements in neonatal care and medical technology and recognition of the adverse effects of aggressive mechanical ventilation and oxygen therapy, few mature infants with hyaline membrane disease now develop BPD. Concurrently, increasing numbers of infants born at less than 28 weeks gestation are surviving. In these infants, respiratory failure occurs due to lung immaturity as well as surfactant deficiency, because in extremely premature infants, the alveoli and peripheral airways are unformed. Oxygen therapy and mechanical ventilation necessary for survival cause alveolar growth arrest, resulting in pulmonary hypoplasia in addition to an element of peripheral airway damage and chronic inflammation (“new” BPD).⁵ Radiographically, the pattern is more homogeneous.

Evolving medical practice and a better understanding of disease pathogenesis have resulted in altered disease definitions, incidence estimates, and risk factors. Northway originally defined BPD as occurring in any premature infant who still required oxygen past 28 days of age.³ Although various criteria have been proposed, most authorities agree that an infant should also be at least 36 weeks postconception.⁶ As shown in Table 143-1, a consensus conference proposed a severity-based definition of BPD for infants born at less than 32 weeks.⁷ This definition was recently validated to accurately identify infants at risk for adverse pulmonary and neurodevelopmental outcomes.⁸

The absence of a consistent definition or a standardized BPD severity score makes it difficult to compare changes in incidence over time. Nevertheless, there seems to have been a real change in the incidence of BPD and CLDI (Table 143-2). During the 1980s, the decreasing incidence of BPD at any given gestation was offset by an increased survival rate in more premature infants. Further increases in survival rates in the early 1990s, resulted in an overall increase in the occurrence of BPD.^9,10 Subsequently, during the latter half of the 1990s and into the early 2000s, there was a plateau; ongoing improvements in neonatal care did not reduce the incidence of BPD, although there appears to have been a reduction in overall severity.^10,11

BPD and CLDI occur primarily in premature infants. However, any neonate requiring prolonged respiratory support, such as those with sepsis, congenital diaphragmatic hernia, or persistent pulmonary hypertension of the newborn, is at risk for BPD and CLDI. BPD and CLDI are therefore heterogeneous disorders with a wide spectrum of causes, variable patterns, and different degrees of lung damage.^1,4 Most critically ill neonates who survive the newborn period survive their initial illness and are discharged from the nursery, but they may have significant residual lung damage, persistent reduction in pulmonary function, and ongoing disabilities that place them at high risk for repeated hospitalizations in the first 2 years of life, primarily for respiratory illnesses.¹² BPD and CLDI thus constitute a spectrum of disease relating to various underlying diagnoses; affected infants range from those with only minimal hypoxemia to infants who require long-term invasive mechanical ventilation for survival. The most severely affected infants are at the highest risk for re-hospitalization, medical complications (including death), and long-term pulmonary and neurologic sequelae.

Although the degree of hypoxemia is commonly used to assess the severity of BPD as shown in Table 143-1, with an oxygen requirement at 36 weeks postmenstrual age (PMA) suggested as a standard,⁷ other clinical parameters are important as well. Although oxygen saturation is easily measured, it can change significantly from day to day and even from wakefulness to sleep. Therefore a combination of other parameters may be useful to obtain an overall assessment of an infant’s clinical status. These include growth, arterial carbon dioxide levels (pH corrected),¹³ and the actual FiO₂ required to maintain a target oxygen saturation.

“Classic” BPD in the neonatal period is initially an inflammatory disorder of the distal airways.³ Once past 1 month of age, however, although still primarily a disorder of the distal airways, it evolves into a reparative disorder, with ongoing lung growth and healing³ resulting in steady improvement (though not necessarily normalization) of lung function. Consequently, therapies which may be effective during the first few weeks of life, when inflammatory changes predominate, aimed at preventing the evolution of the disease are not necessarily effective later, during the reparative phase of illness.^1,14 Moreover, BPD is a multisystem disorder, involving many other organs and systems. Consequently, during the first 2 years of life infants with BPD/CLDI remain medically fragile, with both a significant increase in healthcare usage and markedly increased risk of readmission (up to 50%, below).¹²

Even at discharge from the neonatal unit, infants with BPD/CLDI are left with significant pulmonary damage. As a consequence, they are more likely to have ongoing respiratory symptoms, need for respiratory therapy, and increased risk of respiratory exacerbations requiring hospitalization.¹⁵ However, with increasing age there is ongoing lung growth and repair, thereby decreasing the risk of hospitalization. In fact, hospitalization is unusual after 2 years of age and rare after 10 years of age. Those with the most severe disease may, however, continue to have significant, though usually mild, abnormalities on pulmonary function, with both fixed and reversible airway obstruction as well as bronchial hyperreactivity persisting into adolescence and even adulthood.^15-17

Once the neonatal period is over, the treatment of BPD and CLDI is primarily supportive, aimed at maximizing lung growth and healing over time while preventing any further pulmonary damage.¹⁸ Owing to the heterogeneity of clinical disease in infants with BPD, there is no standard therapy. Treatment must be individualized, depending on each infant’s pattern and disease severity.

PERSISTENT HYPOXEMIA

As previously stated, BPD is associated with inflammation and lung scarring and peripheral airway damage, resulting in areas of hyperinflation and atelectasis as well as alveolar growth arrest (Figure 143-1). Hypoxemia due to ventilation-perfusion mismatch is a primary feature of BPD and CLDI, making long-term oxygen therapy a mainstay of treatment.¹⁹

Although there are data supporting the effectiveness of long-term oxygen therapy in improving the outcome in infants with BPD and CLDI, the optimal target saturation is still debated. In general, supplemental oxygen is considered for infants who cannot maintain oxygen saturations greater than 93% during sleep or quiet wakefulness.²⁰ Infants provided with sufficient supplemental oxygen to maintain arterial saturations around 92% to 94% have better growth and neurologic outcomes and less risk of pulmonary hypertension than do those in whom the saturation goal is less than 90%.¹ Further, sudden death²⁰ and hypoxic bronchoconstriction²¹ may be reduced. Two large studies suggest that maintaining oxygen saturations above 95% may not confer any additional advantage over oxygen saturations greater than 89% to 94%^18,22 or 91% to 94%;²³ rather, this may simply prolong the duration of oxygen therapy.^22,23 A subsequent study showed that targeting saturations below 90% resulted in a reduced rate of retinopathy of prematurity and BPD/CLDI,²⁴ but an increased rate of death.²⁵ There, consequently, remains some debate about optimal saturation targets in young infants.²⁶ It should be noted, however, that these studies were performed on infants still in the newborn intensive care unit, so it is uncertain whether the findings apply to older infants with established BPD.

Notwithstanding these limitations and the lack of complete data, most authorities use target saturations between 92% and 95%, with no more than 5% of time spent at less than 90% saturation.²⁷ In the vast majority of infants, this is achievable with oxygen provided in the home, as discussed later.

HYPERCAPNIA

Infants with BPD may have hypercapnia in addition to chronic hypoxemia, reflecting the severity of chronic lung disease and an inability to maintain sufficient alveolar ventilation for normal carbon dioxide levels.²⁸ With lung growth and repair, carbon dioxide levels return to normal, but until that occurs, any additional stress or insult can result in overt respiratory failure. In the most severely affected infants, long-term invasive mechanical ventilation (via tracheostomy) may be required to achieve adequate growth.^29,30 The decision to initiate long-term invasive ventilation is individualized, based on the infant’s clinical status; it is most often considered in those with refractory respiratory failure, failure to thrive, or extreme cardiorespiratory instability.

AIRWAY HYPERREACTIVITY

Infants with BPD and CLDI often have increased nonspecific airway hyperreactivity,³¹ the precise mechanism of which is unclear. This results in episodic bronchospasm due to a variety of irritants, with viral respiratory infection being the most common. Contributing to airway hyperreactivity is the residual inflammation associated with BPD and CLDI. Persistent wheezing in infants with BPD and CLDI must be evaluated thoroughly because it may reflect a comorbid condition. Airway hyperreactivity may persist into late childhood.³²

Many infants with BPD demonstrate a significant bronchodilator response to inhaled β₂-agonist agents.³³ A therapeutic trial of bronchodilators is indicated if there is evidence of persistent or acute bronchospasm and gas trapping. Bronchodilators should not be used routinely in the absence of a therapeutic response.³³

Airway inflammation is a primary factor in the pathogenesis and persistence of BPD and CLDI. Systemic corticosteroid therapy has been used to prevent the onset of BPD—either before delivery, to stimulate lung maturation, or early after delivery, to minimize subsequent pulmonary inflammation.³⁴ Reports of worse neurologic outcomes in neonates receiving systemic corticosteroids in the first week of life have raised concerns about their use.³⁵ Although inhaled corticosteroids are frequently used in infants with BPD and CLDI, there is debate both about their efficacy as well as their potential toxicity. Infants with overt airway hyperreactivity may benefit from long-term inhaled corticosteroids, but their precise role remains unproven.³⁶ The potential risk of adrenal suppression, hyperglycemia, inhibition of somatic growth, and neurologic insult should limit their use to infants in whom there is a clear therapeutic response.³⁷

The differential diagnosis of wheezing in an infant with BPD or CLDI is similar to that of any infant with chronic wheezing. Specific problems that may occur more frequently in this group, however, include tracheobronchomalacia, dysphagia, and gastroesophageal reflux (GER). As with all children, the avoidance of exposure to tobacco smoke is critical.

RESPIRATORY VIRUSES

Depending on the severity of residual lung disease, infants with BPD may have up to a 50% chance of requiring readmission to the hospital, usually within the first 2 years of life, and usually owing to viral respiratory tract infection.^38,39 Infants with BPD are particularly at risk from RSV.³⁸ Therapy, using monoclonal antibodies has been developed that provide partial passive immunity. Although not completely effective at preventing RSV infection, they do reduce both the incidence and the severity of RSV infection.^40,41 Further discussion of bronchiolitis, its management, and the role of monoclonal antibody therapy is provided in Chapter 66. Parents of infants with BPD are advised to obtain all routine pediatric vaccinations on schedule, to minimize the infant’s exposure to respiratory viruses; this includes rigorous hand washing, obtaining influenza vaccinations for themselves, and to avoid anyone who is potentially infectious. These precautions must be followed during hospitalization as well, owing to the risk of nosocomial infections.