Bronchopulmonary Dysplasia

After completing this article, readers should be able to: Despite clinical advances in antepartum, intrapartum, and neonatal care, bronchopulmonary dysplasia (BPD) continues to challenge infants who have been in neonatal intensive care units and their caretakers. BPD is the most common cause of chronic respiratory disease during infancy and remains a major cause of long-term medical, pulmonary, and neurodevelopmental morbidity, increasing the cost of health care and the utilization of medical and educational resources throughout childhood.BPD is a clinical diagnosis, defined by oxygen dependence for a specific period of time after birth and accompanied by characteristic radiographic findings that correspond to anatomic abnormalities. Thus far, a precise physiologic definition of BPD is lacking. As the clinical presentation has evolved over the past 30 years, so has the definition. As originally described by Northway in the 1960s, the diagnosis of classic BPD was based on progressive radiographic changes in preterm infants who were treated for severe respiratory distress syndrome (RDS) immediately after birth and had prolonged ventilator and oxygen dependence. This form of BPD occurred in larger, relatively mature preterm infants, who required treatment with high-pressure mechanical ventilation and high concentrations of oxygen. Although the acute respiratory disease initially improved in these infants, oxygen requirements increased 7 to 10 days after birth and persisted for at least 28 days. The definition of BPD subsequently was modified by Bancalari to include preterm infants who had less severe RDS that initially required short-term mechanical ventilation, but who also developed persistent respiratory symptoms and an oxygen requirement for at least 28 days after birth accompanied by radiographic abnormalities. The presentation of BPD continued to evolve with the advent of antenatal steroids and postnatal surfactant administration, which reduced the incidence and severity of RDS and increased the survival of extremely small, very immature infants (<30 weeks’ gestation or <1,250 g birthweight). These infants had milder chronic pulmonary problems that often resolved by discharge. Shennan noted that the need for supplemental oxygen until at least 36 weeks postconceptual age (PCA) in these infants was much more predictive of later pulmonary morbidity. He, therefore, recommended that oxygen dependence at 36 weeks PCA, instead of 28 days after birth, be used as a more clinically relevant definition of BPD.Some very low-birthweight (VLBW), extremely preterm infants born between 23 and 28 weeks’ gestation and weighing less than 1,250 g develop increasing oxygen requirements 1 to 2 weeks after birth, even without preceding lung disease, mechanical ventilation, or oxygen therapy. This form of atypical BPD is reminiscent of Wilson-Mikity disease that was described contemporaneously with classic BPD. The clinical onset of atypical BPD is characterized by a delayed, gradual increase in oxygen dependence, milder symptoms overall, and more rapid resolution of symptoms and weaning to room air. The term chronic lung disease (CLD) often is used instead of BPD to denote persistent pulmonary insufficiency and oxygen requirement beyond 36 weeks PCA regardless of the cause or need for mechanical ventilation. Defining BPD by the need for supplemental oxygen alone at a specific point in time does not take into account different parameters for oxygen use or adjunctive therapies, such as diuretics, fluid restriction, bronchodilators, or steroids, that affect the need for supplemental oxygen. Consequently, it is difficult to determine accurately the incidence and prevalence of BPD or to compare treatments or outcomes among different neonatal centers.The risk of BPD is multifactorial. It is related directly to the severity of the initial lung disease (most often RDS) and the duration of mechanical ventilation and oxygen administration. BPD is related inversely to birthweight and gestational age, with the smallest, sickest, most immature infants being at highest risk. The increased susceptibility of the very preterm infant may reflect the anatomic, developmental, and reparative immaturity of the neonatal lung at the time of lung injury. The risk of BPD is also increased by a hemodynamically significant patent ductus arteriosus, postnatal sepsis, antenatal maternal infection (eg, chorioamnionitis), and maternal or neonatal colonization with Ureaplasma histolyticum. In the case of maternal infection, it is postulated that circulating maternal cytokines gain access to the fetal circulation and injure fetal tissues, including lung and brain, thereby increasing the risk of BPD as well as brain injury. Although some studies report an association between a family history of atopy or asthma and BPD, others have failed to confirm this relationship.Term and near-term infants also are at risk for BPD following severe respiratory failure treated with very high oxygen concentrations, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO). BPD occurs in up to 27% of term or near-term infants who have very severe primary respiratory disease (ie, RDS, meconium aspiration, pneumonia, sepsis) and in up to 50% of those who have underlying pulmonary hypoplasia (eg, congenital diaphragmatic hernia) and are treated with or are eligible for ECMO.Advances in neonatal care have decreased the incidence of BPD only in larger, more mature preterm infants. The risk of BPD in VLBW infants is not reduced by antenatal steroids, surfactant administration, or any specific type of respiratory support (eg, conventional ventilation or high-frequency ventilation), although the disease is less severe than in the past. However, there are substantial differences in the incidence of BPD between individual neonatal units, suggesting that the overall approach to respiratory support is important. Centers that emphasize “gentle” ventilation that minimizes lung injury (eg, permissive hypercapnea, lower airway pressures, avoidance of intubation or early extubation) have substantially lower rates of BPD. Vitamin A, known to protect epithelial integrity and promote normal cell differentiation and growth, is associated with a small, but significant decrease in the risk of BPD when administered parenterally immediately after birth. Postnatal dexamethasone has been reported by some to decrease oxygen dependence at 36 weeks after birth, but serious short- and long-term complications preclude routine use. Prevention of BPD remains elusive, ultimately depending on avoiding or delaying premature delivery whenever possible, reducing antenatal and postnatal infections, and minimizing postnatal exposure to noxious agents, such as intubation, oxygen, and ventilation. It is possible that for the most immature infants, even exposure to room air is injurious.As noted previously, the incidence of BPD depends on the definition used. Fewer than 50% of extremely preterm infants who require supplemental oxygen at 28 days after birth remain oxygen-dependent at 36 weeks PCA, and fewer still remain oxygen-dependent at 42 weeks PCA. For all VLBW neonates (<1,500 g at birth), the incidence of oxygen dependence at 28 days is about 30% to 50%; at 36 weeks PCA, the incidence of oxygen dependence in these same infants falls to 4% to 30%. For VLBW infants who require mechanical ventilation and surfactant, approximately 60% are oxygen-dependent at 28 days, and 30% remain oxygen-dependent at 36 weeks PCA. In some series, up to one third of VLBW infants have the milder form of atypical BPD. Because the incidence of BPD is highest in the most premature and lowest birthweight infants and because more of these very immature neonates now survive, the total number of children living with BPD is increasing, albeit in a clinically less severe form than seen previously.BPD appears to be the final common path of lung injury. Initially it was believed to be the consequence of direct trauma from mechanical ventilation and oxygen toxicity. As the clinical presentation of BPD has changed and oxygen dependence has developed in the absence of RDS or initial oxygen exposure, inflammation has emerged as the central disease process. Anatomic and developmental immaturity modify the lung’s response to trauma and inflammation. Evidence of an inflammatory response that accompanies RDS, including activated inflammatory cells, inflammatory mediators, and cytokines, persists in infants who develop BPD.Barotrauma and volutrauma from mechanical ventilation may injury airways and lung parenchyma directly and indirectly. Intubation traumatizes local tissue surfaces, destroys normal ciliary action, and introduces pathogens and exogenous gases directly into the airway. Air leaks (eg, pulmonary interstitial emphysema) further disrupt lung tissue. Oxygen exposure generates toxic free radicals that cause acute tissue injury, incite inflammation, and inhibit normal repair and development.Developmentally immature lung tissue may be both more susceptible to injury and less effective at tissue repair. At autopsy, infants dying of BPD have evidence of abnormal lung morphology and development, with decreased alveolarization and septation. Ultimately, BPD must be “outgrown.” As airways become larger, alveolarization proceeds, and the previously injured lung represents a smaller proportion of total lung volume. Fortunately, alveolar growth continues up to 5 years of age, allowing most infants who have BPD to recover clinically even though pathologic and radiologic abnormalities often persist into adulthood.BPD results in chronic respiratory insufficiency and prolonged oxygen dependence for many weeks or months. Clinical manifestations include tachypnea, retractions, wheezing, and rales. Ventilation/perfusion mismatch and increased physiologic dead space result in hypercapnia and hypoxemia. The risk of superimposed infection is increased. For all forms of BPD and CLD, oxygen requirements begin to increase at the end of the first week after birth, reaching a stable plateau by the beginning of the third week. Clinical exacerbations occur in association with pulmonary edema, superimposed infection, or right heart failure.Northway described four distinct radiographic stages of BPD: I-RDS, II-diffusely hazy, III-diffusely bubbly, interstitial pattern, and IV-hyperaeration, focal hyperlucency, alternating strands of opacification. These stages correspond to a pathologic progression from acute RDS to interstitial and airway edema, inflammation, and squamous metaplasia and finally to areas of emphysema, fibrosis, and atelectasis and increased peribronchiolar and perivascular smooth muscle. Milder or atypical BPD is radiographically less severe, with diffuse haziness or interstitial prominence, often with normal inflation, and less severe anatomic abnormalities.Bronchospasm, episodes of cyanosis, and chronic hypoxemia often accompany BPD. Early pulmonary function abnormalities in infants who have BPD include decreased lung compliance, ventilation perfusion mismatch, and increased lung volume, airway resistance, and air trapping.Clinical improvement in BPD usually is heralded by improvement in somatic growth. Infants who develop BPD are at increased risk of patent ductus arteriosus, sepsis, intraventricular hemorrhage (IVH), retinopathy of prematurity, and death.The treatment goals of BPD focus on relieving respiratory symptoms, improving lung function, minimizing ongoing lung injury, reducing inflammation, maintaining adequate oxygenation, and facilitating lung growth. BPD itself, as well as the treatment regimens used to improve respiratory function, results in an assortment of associated problems (Table 1). Although diuretics can reduce pulmonary edema and oxygen requirements, they also cause electrolyte depletion, bone loss, and nephrocalcinosis. High-dose systemic corticosteroids facilitate extubation and decrease neonatal respiratory support and oxygen exposure. However, these short-term benefits are achieved at the expense of serious neonatal complications (eg, hyperglycemia, hypertension, intestinal perforation, infection), poor brain and somatic growth, and substantially worse neuromotor and developmental outcomes, including cerebral palsy (CP), in early childhood. Postnatal corticosteroids have not been shown to convey any long-term respiratory benefit. It is not known whether the deleterious effects of systemic steroids are related to the specific type of steroid administered, the pharmacologic doses used, or the duration of treatment. Although aerosolized steroids are associated with fewer complications, they are also less effective therapeutically. Randomized, controlled trials are needed to define the role, if any, of postnatal steroids or other anti-inflammatory agents. Because of concerns about short- and long-term adverse effects, it is recommended that postnatal steroids be used only in exceptional clinical circumstances (eg, severe respiratory failure with maximal ventilatory and oxygen support). It is possible that the treatments used to reduce oxygen dependence may be more detrimental to the infant than oxygen itself and that the efforts to reduce oxygen dependence are misguided.A nurturing home environment improves physical growth and psychosocial development. Infants who have BPD should be discharged from the hospital to consistent caretakers as soon as feasible. This often necessitates continuing complex treatments at home, including oxygen, hypercaloric feedings, fluid restriction, diuretics, bronchodilators, and cardiorespiratory monitors. Medical treatment and home oxygen therapy may be needed for many months or even years. The abrupt transition from intensive care to the home is difficult for families and requires comprehensive parent education before discharge and ongoing psychosocial and medical support. A specific plan must be in place at discharge, including how the parent will monitor the infant’s respiratory status, when to provide extra oxygen, which physician to call when respiratory problems arise, and when to call for emergency transport. Acute respiratory exacerbations are likely and can be life-threatening. Valuable time will be lost unless the parent knows when and who to call for help.Parents need to be aware of the high risk of superimposed respiratory infection and rehospitalization despite optimal care and appropriate precautions. the for their infant’s treatment (eg, hypercaloric feedings, fluid restriction, oxygen, respiratory the time of and the need for medical and the with the and that accompany improving cardiorespiratory are recommended for children oxygen at Oxygen should be to of during both and until supplemental oxygen, fluid restriction, or are needed to adequate is for children who have severe disease and require changes in oxygen delivery throughout the to adequate oxygen and fluid should be one at to be that changes in treatment are well who have BPD and are discharged from the hospital on oxygen or should be by pulmonary in to their primary until the disease has resolved including and is for lung growth and repair. has deleterious effects on both lung function and who have BPD often to increased rates of increased and requirements, and fluid and restriction, infection, and rehospitalization all difficult and to growth gain may be a of at when oxygen falls during must focus on an and extra and for tissue repair and growth. After discharge, children who have BPD to need extra and to and to normal growth. support may be required for at least 1 to be in the or treatment of BPD include and A, and Thus far, only A, administered after birth, has been shown to have a small, specific in reducing the risk of BPD. and as soon as possible is with and to after birth loss, minimizes and and Early and of with less fluid of improves utilization of and specific to the infant who has BPD. However, of is required to provide adequate and to all infants are less than is an if is for VLBW infants. and preterm provide that can be increased up to 30 when are to reduce lung and pulmonary may be needed for many months. in VLBW infants who not have chronic disease, the use of preterm until to months PCA appears to improve long-term growth. of growth including and as well as is to that requirements for growth are being complications related to BPD are shown in pulmonary initially was described for infants who had classic BPD, continued to have respiratory symptoms as and Although less severe BPD is associated with a long-term children who have BPD still have the risk of or asthma or lower respiratory infections, and of being to respiratory during infancy and early with gestational preterm infants who not have BPD. In 50% of all VLBW children who had a history of BPD had been in the first to months after birth, and 50% had a history of or asthma at during infancy has been shown to the risk of for and to reduce both the of and the duration of oxygen therapy if the infant is which is common in preterm infants, to acute and chronic airway inflammation, edema, pneumonia, and of infants who have BPD have a or of following initial This risk appears to decrease with The risk of an acute or of infant is in VLBW infants who have BPD. Fortunately, the number of children who require to airway or the need for prolonged ventilation is However, airway by and has been by in 27% of infants who have BPD and is associated with a duration of intubation, increased of initial airway clinically severe BPD, and lower gestational of these infants had respiratory symptoms during abnormal (eg, or and after discharge home is less common than previously, but it occurs in up to of infants who have BPD, usually to function abnormalities are in children who have a history of BPD. These abnormalities include decreased volume, and and increased volume. evidence of and persist throughout even among clinically The severity and of the abnormalities and with the duration of mechanical ventilation, oxygen and treatment. for increased airway resistance, abnormalities usually improve by 7 to years of age and by early At least 50% of children who have a history of BPD have evidence of even without a clinical history of or airway abnormalities (eg, hyperlucency, and also persist throughout childhood. Despite the abnormal results of and most children have normal by childhood. The long-term of BPD on pulmonary response to respiratory pulmonary function, and respiratory disease in later is with to the risk of chronic pulmonary and children should be to and other respiratory growth is in infants who have BPD. somatic growth may reflect to or or chronic oxygen during Although and who have a history of classic BPD were smaller than in one their growth still was the normal studies of children who have milder BPD not significant differences in and at age with preterm who not have BPD, although children who had BPD to have lower and lower bone episodes of hypoxemia and may to pulmonary hypertension, and heart occurs in to of infants, often is not until after discharge, and may to heart failure if and Although usually after diuretics are it may persist and can be associated with abnormalities of should be by until who have BPD also are at increased risk for loss, and are as common among VLBW preterm infants who have BPD and the often to may be associated with and and should be as soon as before discharge to is being most by neonatal brain injury (eg, gestational age or status, and In neonatal (eg, severity of neonatal disease, or gestational are of short-term at fewer than months PCA, and long-term is by such as and The to neurodevelopmental accurately changes over time as improve and the developmental The of in children who have BPD is by the of BPD, the clinical presentation of BPD and neonatal care over and at age, children who have severe any postnatal age far, neurodevelopmental is by BPD. is controlled for other such as gestational age, brain injury and status, and BPD for adverse in areas of as with medical and pulmonary is by the need for supplemental oxygen at 36 weeks PCA than at 28 days after birth. studies of more less preterm infants born in the after the routine use of antenatal steroids and surfactant, are beginning to Although antenatal steroids have been associated with a decreased risk of severe and during this postnatal steroids, used have been associated with an increased risk of neuromotor including It therefore, possible that neurodevelopmental for these children may be worse than previously is associated with an increased risk of neuromotor abnormalities. of children born in the reported that those who had BPD had a incidence of to and a risk of overall with preterm and cerebral as well as an associated with and have been described during infancy in children who had very severe BPD. These infants had prolonged and persistent episodes of respiratory or heart In infants who have less severe BPD, is during The with improvement in respiratory symptoms, and somatic growth. In these developmental usually is in those areas of less on such as and studies of and in have children who have a history of milder BPD born in the with preterm who had a history of BPD were more likely to require resources or to have and to have and also had more adverse and educational outcomes, including lower and increased and worse function, and At to 10 years of age, of the children who required oxygen at home for more than 1 after discharge from the neonatal intensive care have been reported to have or abnormal findings on neuromotor including poor poor or The severity of BPD (ie, duration of and oxygen severity of and lower were the only of these abnormalities. neuromotor and abnormalities be to have adverse effects on outcomes of children who have had the more less severe forms of BPD are A in VLBW children who antenatal steroids and surfactant noted that those who had a history of BPD were more likely than preterm to have or at years the risk only BPD and the risk the severity of neonatal brain injury, decreased on the of In function was by and but not by BPD. In this same after for BPD and was associated with both and The physiologic for the adverse of BPD on neurodevelopmental is but prolonged and of specific toxic of therapies, and of appropriate all may a in brain growth, development, and is an for high developmental, and risk throughout that children who require neurodevelopmental Although most neurodevelopmental and are on infants and the most developmental effects of BPD or in during the years. Because many of the neurodevelopmental abnormalities associated with BPD are and not children who have a history of BPD are by comprehensive and by who have BPD need a consistent primary care to medical and developmental care from neonatal intensive care discharge to (Table goals include optimal growth, adequate oxygenation, infection by and appropriate developmental and and the family with the physical and of for a The primary care who is of and educational will be a that appropriate psychosocial and educational are and that appropriate and resources are throughout childhood. Despite their early physical and increased neurodevelopmental most children who have BPD have an of who are with their of and are able to to their families and