Rudolph's Pediatrics, 22nd Ed.

CHAPTER 59. Bronchopulmonary Dysplasia

Alan H. Jobe

Bronchopulmonary dysplasia (BPD) was described by Northway and colleagues1 in 1967 as a syndrome of severe lung injury in preterm infants who had received mechanical ventilation and high levels of supplemental oxygen. This initial description of BPD occurred in the era when mechanical ventilation was just beginning to be used for preterm infants and the mean birth weight of the infants who survived mechanical ventilation to develop BPD was 2.3 kg. The pathology was characterized by prominent airway injury, epithelial metaplasia, smooth muscle hypertrophy, and parenchymal fibrosis alternating with emphysema. The experimental work during that era demonstrated that the causes of BPD were primarily mechanical ventilation of and oxygen exposure to the developing lung.2

Neonatal care practices have changed over the last 30 years. Many extremely low-birth-weight infants (< 1 kg) with gestational ages under 28 weeks now survive, and these more immature infants are at higher risk for BPD.3 The epidemiology of BPD has changed because factors other than mechanical ventilation and oxygen exposure contribute to the occurrence of BPD in extremely low-birth-weight infants. Major associations are postnatal sepsis, patent ductus arteriosus, and antenatal chorioamnionitis.4 Some extremely low-birth-weight infants now develop BPD without initially having severe respiratory distress syndrome or initially requiring much supplemental oxygen or mechanical ventilation.5

DIAGNOSIS OF BPD

The diagnosis of BPD is confounded by a series of definitions that have changed over the years as the patients at risk have become increasingly premature.6 Many recent reports define BPD as the need for supplemental oxygen at 36 weeks postconceptional age. However, because clinicians use supplemental oxygen inconsistently, oxygen use and target saturations vary widely in clinical practice. A National Institutes of Health workshop in 2000 recommended a graded diagnosis for BPD to better describe the clinical status of infants with BPD6 (see eTable 59.1 ). More recently, Walsh and colleagues7 developed an oxygen-need test to make the diagnosis of BPD more uniform. Neonates on positive pressure support or receiving >30% supplemental oxygen with saturations between 90% and 96% were diagnosed with BPD and not tested further. Those receiving <30% oxygen or effective oxygen >30% with saturations >96% underwent a room-air challenge with continuous observation and oxygen-saturation monitoring. Those that could not maintain saturations >90% during weaning and in room air for 30 minutes were also diagnosed with BPD. With the use of the oxygen-need test, the diagnosis of BPD decreased from 35% to 25% of the infants with birth weights below 1250 grams. The diagnostic definition of BPD as oxygen need at 36 weeks does not require antecedent exposures (eg, respiratory distress syndrome, mechanical ventilation), abnormalities on a chest radiograph, or any laboratory test. This is not a precise diagnosis relative to most diagnoses in medicine, which generally include specific clinical associations and laboratory findings. While the diagnosis of BPD is made at 36 weeks, efforts to prevent BPD need to begin with antenatal exposures and to focus on the known associations with BPD in the minutes to weeks after preterm birth.

PATHOPHYSIOLOGY

The human lung has completed about 16 generations of dichotomous airway branching, termed primary septation, by about 18 weeks’ gestation8 (Fig. 59-1). Secondary septation is the process of alveolarization of distal lung saccules. Alveolarization is the anatomic description of the protrusion of elastin fibers and mesenchyme containing a double capillary network into a saccular or alveolar lumen with subdivision of that lumen.9 In humans, alveolarization normally begins at 32 to 36 weeks’ gestation and continues for several years. However, BPD occurs most frequently following preterm birth between 23 weeks and 28 weeks of gestation. This gestational interval begins about a month after airway branching has finished and as much as 3 months before alveolarization begins. Between about 22 weeks and about 32 to 36 weeks, saccular septations form respiratory bronchioles and alveolar ducts. This complex period of lung development between airway branching and alveolarization is the anatomic substrate on which BPD is initiated and progresses. Concurrently with the development of the epithelial surface areas of the fetal lung, there is a large expansion of the pulmonary microvasculature.

FIGURE 59-1. Developmental context for BPD. Fetal lung development is divided into stages based on morphology. Airway branching for about 18 generations occurs during the canalicular stage. Subsequent division of the distal saccules into bronchioles and alveolar ducts and vascularization occur during the saccular stage between about 23 and 37 weeks’ gestation. Alveolar septation with microvascular development begins after 32 weeks and is most active from 36 weeks to the end of the first year or two of life. Preterm delivery from the limit of viability at about 23 weeks to about 28 weeks is associated with bronchopulmonary dysplasia, with less risk as delivery occurs at later gestational ages. The diagnosis of established bronchopulmonary dysplasia is made by the need for supplemental oxygen at 36 weeks, which is early in the period of alveolarization.

The lungs of infants who have died from BPD demonstrate multiple changes that are consistent with an arrest of lung development. The lungs have increased alveolar (saccular) diameters and fewer alveoli (saccules).10 The collagen network around the saccules is disrupted, and elastin is not localized to fibers at sites for future alveolar septations.11 The saccules are lined with dysplastic type II cells, and the pulmonary microvasculature is decreased.12Acute severe inflammation is not apparent unless there has been a secondary infection. The most striking abnormality in the lungs of infants with BPD is the arrest of alveolarization resulting in the appearance of emphysema. There is very little anatomic information available for the great majority of infants who survive BPD. Although not well documented, some alveolarization and lung growth must occur during the resolution phase of BPD, or the infants would not survive.

RISK FACTORS

BPD in very low-birth-weight infants is thought to result primarily from the interference with lung development by lung injury and repair pathways (eFig. 59.1 ). The risk factors are a series of events or hits that can injure and interfere with the immature lung beginning in fetal life and continuing postnatally after preterm birth. A large body of experimental evidence from transgenic mice demonstrates that expression of proinflammatory mediators such as interleukins 1, 6, 8, and 13 during late fetal or early postnatal life cause decreased alveolar septation and a BPD-like lung.13 The common thread is the presence of inflammation. Chorioamnionitis and colonization of the fetal lung with Ureaplasma also cause lung inflammation and are associated with BPD in infants.14 Chorioamnionitis induced with Escherichia coli lipopolysaccharide arrests septation and microvascular development in fetal sheep.15Similarly, high supplemental oxygen exposure causes inflammation and an arrest in septation in multiple animal models. Mechanical ventilation causes lung stretch, which can transduce an inflammatory response.16 However, mechanical ventilation of the saccular lung also will interfere with septation even if inflammation is not evident.17 Routine clinical maneuvers such as ventilatory assistance accompanying the resuscitation of the preterm at birth can induce inflammation in the lungs.18 Postnatal sepsis with its associated inflammation also contributes to the risk of BPD. The common theme is that clinical interventions and fetal or neonatal exposures that are proinflammatory have the potential to interfere with lung development and contribute to progression toward BPD. Other factors also contribute to the risk of BPD.19 A patent ductus arteriosus may increase risk because of the need for more supplemental oxygen or ventilation, but increased pulmonary blood flow also may alter lung development. In animal models, calorie deprivation causes emphysema, suggesting that nutrition is important for normal lung growth and development. Inhibition of inflammation also may contribute to BPD. Corticosteroids are given routinely to women at risk of preterm delivery because they decrease the infant’s risk of respiratory distress syndrome, intraventricular hemorrhage, and death.20 However, corticosteroids also cause decreased septation in multiple animal models.21 Postnatal corticosteroids given in high dose and for long periods probably interfere with lung development. The important concept is that multiple risk factors contribute to the development of BPD in very low-birth-weight infants.

PREVENTION

PREMATURITY

There is no single intervention to prevent BPD because of the multifactorial nature of the pathophysiology. Although the incidence of BPD in extremely low-birth-weight infants has changed little over many years, the survival of these infants has increased and the severity of the BPD has decreased.22 Given that the severely immature lung is the substrate on which BPD develops, the most effective strategy for the prevention of BPD would be to decrease the births of very-low-birth-weight infants with gestations between 23 and 28 weeks. In fact, prematurity rates in the United States are increasing rather than decreasing.23 Respiratory distress syndrome and the requirement for mechanical ventilation are 2 major predictors of BPD. The 2 major advances in neonatal care have been the prenatal use of corticosteroids in women at risk of preterm delivery and postdelivery surfactant treatment to decrease the incidence and severity of respiratory distress syndrome. Both therapies decrease mortality but do not consistently decrease BPD, presumably because the decreased mortality results in the survival of more marginal infants at high risk of developing BPD.

MECHANICAL VENTILATION

Mechanical ventilation is a major cause of the lung injury that progresses to BPD. Many very preterm infants are intubated in the delivery room to assist with ventilation and to transition the infant to air breathing. The mechanical ventilation delivered in the delivery room is poorly controlled, without regulation of positive end-expiratory pressure, tidal volumes, or pressures, and many infants arrive in the special care units hyperoxic and hypocarbic as a result of overventilation.24 This ventilation of the fluid-filled lung is very likely to result in an initial lung injury, which can progress with subsequent mechanical ventilation.18There have been significant advances in infant ventilators and monitoring and changes in ventilation goals in the neonatal community. Strategies to decrease ventilator-mediated injury include the use of infant-triggered ventilation, low tidal volume targets of 4 to 6 ml/kg, pressure or volume assists with spontaneous breaths, and setting PCO2 and pH targets to permit mild hypercarbia using conventional ventilators. High-frequency oscillatory or jet ventilators also can gently ventilate infants, but their superiority to conventional ventilation is not compelling.25 Neonatologists are trying to ventilate infants as gently as possible and to extubate infants as soon as tolerated to avoid prolonged mechanical ventilation.

An old strategy for managing infants with respiratory distress syndrome was the use of continuous positive airway pressure (CPAP), first described by Gregory and colleagues in 1971.26 In recent years, CPAP is being applied in the delivery room and continued for subsequent ventilatory assistance, even for extremely low-birth-weight infants. The majority of infants greater than 28 weeks’ gestation can be managed with CPAP only and will not require surfactant treatments.27 More immature infants can be initially adapted to air breathing and then can receive surfactant electively if they have significant respiratory distress. The use of CPAP soon after birth will decrease mechanical ventilation and may decrease the incidence and severity of BPD, although this outcome has not been demonstrated in randomized trials to date.28 Hybrid approaches are also being developed to avoid mechanical ventilation by triggering ventilatory breaths while an infant is on nasal CPAP. The use of CPAP for preterm baboons preserved lung septation relative to conventional mechanical ventilation.29 The careful monitoring of how mechanical ventilation is used, the clinical targets (ie, PCO2, tidal volumes), and the use of options that avoid mechanical ventilation are ways to avoid causing BPD or promoting its progression. However, some infants with minimal respiratory distress syndrome and who do not receive mechanical ventilation will progress to BPD.5 Some of these infants may have been exposed to chorioamnionitis, but spontaneous ventilation with CPAP and room air or low amounts of supplemental oxygen may be sufficient to disrupt normal lung development in some extremely low-birth-weight infants.

SUPPLEMENTAL OXYGEN

Supplemental oxygen also can initiate or promote progression of BPD. In animal models, oxygen exposure of the saccular immature lung initiates inflammation and disrupts alveolar septation and microvascular development, resulting in an anatomy similar to that of infants who have died of BPD.30 The preterm lung has deficiencies of antioxidants and the enzymes that detoxify oxidants. However, treatment of infants with antioxidants has not decreased the incidence of BPD in several clinical trials. Attempts to keep the oxygen saturation below about 95% in infants with BPD have resulted in more rapid resolution.31 Trials are now in progress to try to establish an oxygen saturation target range that will minimize the risks of oxidant exposure while not compromising growth and neurodevelopment of the infant. In the meantime, accepted practice is to keep oxygen saturations in the range of 85% to 95% for infants on supplemental oxygen. The major focus should be on using upper saturation limit alarms on pulse oximeters to limit oxygen exposure.32

INFECTION

BPD is increased by chorioamnionitis and postnatal sepsis, both inflammatory syndromes. Chorioamnionitis causes fetal lung inflammation, and organisms such as Ureaplasma can colonize the fetal lung and persist in the lungs of the preterm infant with an associated increased risk of BPD.14 However, these associations can be complex. For example, Ureaplasma in the preterm lungs may not increase the risks of BPD unless the organisms persist over weeks. Similarly, chorioamnionitis may decrease the risks of respiratory distress syndrome and BPD unless the infant is mechanically ventilated or becomes septic, which then increase the risk of BPD.33 Postnatal nosocomial sepsis is very frequent in very low-birth-weight infants and increases the BPD risk. These relationships suggest that infection/inflammation is a potent promoter of BPD, especially if other contributors to BPD are present. The prevention strategy is to minimize the risk of infection with avoidance of catheters when possible and to pay careful attention to minimizing infectious risk to the infant.

PATENT DUCTUS ARTERIOSUS

A patent ductus arteriosus (PDA) is a strong risk factor for BPD. Many clinicians treat very low-birth-weight infants with the prostaglandin synthetase inhibitors indomethacin or ibuprofen to close the PDA. The goals are to simplify management and to decrease the BPD risk. The mechanisms by which a PDA increases risk of BPD are probably multiple. Very low-birth-weight infants with a PDA tend to be exposed to more supplemental oxygen and to be ventilated for more prolonged periods. Their nutritional state also may suffer. However, increased blood flow through the preterm lungs may also interfere with normal development.

NUTRITION

Infants at risk of BPD are very immature, and adequate nutritional support is difficult. In developing an adult animal models, calorie deprivation can interfere with alveolar septation and increase the toxicity of oxygen.34 While there is no information about calorie limitations and lung development in preterm infants, the infants with BPD tend to be the most difficult to adequately feed. Vitamin A is the one nutritional component that was demonstrated in a large randomized multicenter trial to decrease the risk of BPD, although the effects were modest.35 Nutrition may be more important than generally appreciated in the pathogenesis of BPD.

TREATMENT AND MANAGEMENT

Treatments for BPD are divided into 2 broad categories: treatments in the first months of life to decrease the severity of BPD as it is developing and treatments for the chronic and resolution phases of BPD, which may take years. Treatments for the late phases of BPD and outcomes are presented in Chapter 513. While multiple drugs are frequently used to treat the early progression to BPD, trial data to support their use are lacking. Part of the problem is selection of patients because the diagnosis of BPD is made only at 36 weeks. Furthermore, the infant on low supplemental oxygen at 36 weeks who is discharged on no medications or oxygen at term is not of much concern beyond the normal risks of prematurity.36 Drug therapies initiated in the first days or weeks of life are designed to mitigate lung problems that may progress to BPD. Diuretics, such as furosemide, can acutely improve lung function in infants progressing toward BPD. However, chronic diuretic use may not be helpful and will interfere with bone mineralization. Surfactant treatment can effectively treat respiratory distress syndrome and limit the oxygen and mechanical ventilation required in the first days of life. However, surfactant function also may be abnormal during the early weeks of life because of abnormal metabolism and inactivation from inflammatory and edema components in the airspaces.37 Surfactant treatments after the resolution of acute respiratory distress syndrome need to be formally studied. Similarly, inhaled nitric oxide seems to be an anti-inflammatory and pulmonary vasodilator that can decrease the severity of lung disease in infants progressing toward BPD.38 Caffeine treatments are routine for infants with apnea of prematurity, and a recent large trial demonstrated that infants randomized to caffeine had less BPD than did control infants.39 An explanation for less BPD is that the caffeine-treated infant had less supplemental oxygen exposure and mechanical ventilation, and fewer infants had a patent ductus arteriosus. The caffeine decreased the exposures associated with BPD.

The most intensively studied drug class to prevent or treat BPD is corticosteroids. The use of corticosteroids to decrease inflammation soon after birth or at later ages became very popular, but there were minimal benefits on survival and concerns about neurodevelopmental outcomes.40 In 2002, the American Academy of Pediatrics and the Canadian Pediatrics Association strongly recommended that corticosteroids not be used to treat infants at risk of BPD, primarily because of risks of adverse neurodevelopmental outcomes. Highdose, long-course corticosteroid treatments were associated with the neuroinjury. However, corticosteroids do facilitate extubation of infants who are ventilator dependent and may decrease mortality when used selectively for the highest risk ventilated infants.41 Short treatment courses with lower doses may benefit the lungs of the highest risk infants and not interfere with neurodevelopment. The safest corticosteroid and dosing schedule remain to be determined.

There is no consensus as to the management of infants at risk for BPD, and practice changes such as the timing of surfactant treatment or the early use of CPAP may not decrease the incidence of the disease.28,42 These experiences reinforce the concepts that BPD is a multifactorial disease that primarily results from interferences with the normal development of the lung. The best that can be done is to optimize delivery (antenatal steroids), facilitate a gentle transition to air breathing, give surfactant for respiratory distress syndrome, minimize mechanical ventilation and supplemental oxygen, support nutrition, and hope the infant will not progress to BPD. Although not part of the diagnosis, infants with severe lung injury from prolonged mechanical ventilation have findings on chest films of cystic emphysema, fibrosis, and hyperinflation. More frequently in the current era, the findings on chest film are some hyperinflation with diffusely hazy lungs but without cystic changes or fibrosis. Progression of BPD is characterized by an increasing need for supplemental oxygen and by chronically increased PCO2 values. The infants are tachypneic with an increased work of breathing. This increased metabolic demand for breathing may require extra calories to support growth. A major complication of severe BPD is the development of pulmonary hypertension because of loss of the cross-sectional area of the pulmonary vasculature.43 Unfortunately, the clinical team cannot predict with any accuracy who will get BPD and how severe that BPD will be.