The introduction of mechanical ventilation for the management of premature infants with severe respiratory distress syndrome (RDS) in the 1960s changed the natural course of the disease, resulting in increased survival of smaller and sicker infants, many of whom had severe chronic lung damage. Northway and associates were the first to describe this condition in 1967 and introduced the term bronchopulmonary dysplasia (BPD).49 Currently, this severe form of chronic lung disease (CLD) is less common and has been replaced by a milder form of chronic lung damage that occurs in many very small preterm infants who, with increasing frequency, are surviving after prolonged periods of respiratory support. This milder form of lung damage often occurs in infants who initially have mild pulmonary disease and do not require high airway pressures or Fio2.38,55 The terms BPD and CLD have been used interchangeably, but because BPD is more specific to the neonatal lung disease, this term is preferred here. The incidence of BPD varies widely among different centers.4 This is not only because of differences in patient susceptibility and in management, but also to discrepancies in the way BPD is defined.9 In 2001, a workshop conducted by the National Institutes of Health (NIH) proposed a definition that divides BPD into three categories based on the duration and level of oxygen therapy required (Table 77-1). Ehrenkranz and colleagues explored the validity of the NIH consensus definition in the large NICHD Neonatal Research Network database.28 Use of the consensus definition increases the number of infants diagnosed with BPD by including the group who was on oxygen at 28 days of age, but in room air at 36 weeks, to those defined as having BPD. The overall rate of BPD was increased from 46% to 77%. The assessment of severity of BPD adds richness to the outcome measure and identifies a spectrum of adverse pulmonary and neurodevelopmental outcomes. As the severity of BPD increases, the incidence of adverse events also increases. Also, the clinical criteria for administering supplemental oxygen can greatly affect the reported incidence of BPD. A physiologic test to standardize the need for supplemental oxygen has been proposed as a way of reducing the variability in diagnostic criteria.72 TABLE 77-1 Definition of Bronchopulmonary Dysplasia: Diagnostic Criteria Adapted from Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723. With increasing survival of very small premature infants, the number of patients at risk of developing BPD increases. Available data suggest that surfactant therapy for RDS decreases mortality without independently affecting the incidence of BPD, but when both end points are combined, the number of survivors without BPD is increased.58 The incidence of BPD in infants with RDS who receive intermittent positive-pressure ventilation (IPPV) is inversely related to gestational age and birth weight, and although it can occur in full-term infants, it is uncommon in infants born after 32 weeks of gestation. Figure 77-1 shows the incidence of BPD in infants between 22 and 28 weeks’ gestation born in the United States between 2003 and 2007.61 The radiographic features of the more severe forms of BPD include hyperinflation and nonhomogeneity of pulmonary fields, with multiple fine or coarser densities extending to the periphery (Figure 77-2). Only a radiographic picture showing chronic pulmonary involvement, plus a clinical course that is compatible with BPD justifies this diagnosis with some degree of consistency. Once lung damage has occurred, these infants frequently require respiratory support and supplemental oxygen for weeks or months. Presently, most of these small infants have mild respiratory disease, initially requiring continuous positive airway pressure or ventilation with low pressures and oxygen concentration, but after a few days or weeks they show progressive deterioration in their lung function and BPD develops. This deterioration may be triggered by pulmonary or systemic infections or increased pulmonary blood flow secondary to a large patent ductus arteriosus (PDA).30 In these cases, the functional and radiographic changes are usually milder, revealing more diffuse haziness without the marked changes observed in the severe forms of BPD (Figure 77-3). This entity has been termed new BPD.17,38 Infants with more severe lung damage may die of progressive respiratory failure, cor pulmonale, or acute complications, especially intercurrent infections. In these infants, severe airway damage with bronchomalacia can lead to severe airway obstruction, especially during episodes of agitation and increased intrathoracic pressure.44 Furthermore, anastomoses between the systemic and pulmonary circulations can aggravate their pulmonary hypertension. Macroscopically, the lungs of infants with severe BPD have a grossly abnormal appearance. They are firm and heavy and have a darker color than normal. The surface is irregular, often showing emphysematous areas alternating with areas of collapse (Figure 77-4). On histologic examination, the lungs are characterized by areas of emphysema, sometimes coalescing into larger cystic areas, surrounded by areas of atelectasis (Figure 77-5). Widespread bronchial and bronchiolar mucosal hyperplasia and metaplasia reduce the lumina in many of the small airways and can interfere with mucus transport (Figure 77-6). In addition, there is interstitial edema and an increase in fibrous tissue with focal thickening of the basal membrane separating capillaries from alveolar spaces. Lymphatics are usually dilated and tortuous. Often, there are vascular changes of pulmonary hypertension such as medial muscle hypertrophy and elastic degeneration. There also may be evidence of right ventricular hypertrophy and, in some cases, left ventricular hypertrophy as well. Infants who receive antenatal steroids and surfactant and have milder forms of BPD have a more diffuse injury with less emphysema and little or no fibrosis. A characteristic morphologic change in lungs with BPD is a marked reduction in the number of alveoli and capillaries and a reduction in the gas exchange surface area.18,36,38 It is not known to what extent this alteration is reversible with increasing age. Although some forms of chronic lung damage have been described in infants who were not ventilated, most premature infants with BPD have received mechanical ventilation, although this may not be prolonged. This, plus the frequent association between pulmonary interstitial emphysema (PIE) and BPD, has led to the conclusion that lung overdistention secondary to positive-pressure ventilation plays an important role in the pathogenesis of BPD. In fact, the lower incidence of BPD at some centers could be largely attributable to avoidance of mechanical ventilation in extremely premature infants.66 The role of the endotracheal tube itself is difficult to separate from that of mechanical ventilation, but the tube hinders the drainage of bronchial secretions and increases the risk of pulmonary infections. Although high peak inspiratory pressure is a major factor implicated as a cause of BPD, it is difficult to determine whether the high pressures have a causal effect on the chronic lung damage or whether these high settings are required after lung damage is already established. The damaging effect of high airway pressure and tidal volume on the surfactant-deficient lung has been demonstrated in preterm lambs. Lung compliance was decreased after only a few breaths with excessive tidal volumes given before surfactant replacement.13 Experimental evidence strongly suggests that excessive tidal volumes can damage the lung, initiate an inflammatory cascade, and interfere with normal lung development. Increasing evidence supports the role of antenatal and postnatal infections in the development of BPD. The role of infection appears to be especially important in very small infants in whom the occurrence of nosocomial infections is associated with a marked increase in the risk for development of BPD.55 This is even more striking when the infection occurs in an infant with a PDA.30 Evidence suggests that perinatal adenovirus and cytomegalovirus infection might also increase the risk for BPD. Several studies have suggested an association between Ureaplasma urealyticum tracheal colonization and the development of severe respiratory failure and BPD in infants with very low birth weight, but results have not been consistent.19,34,50,73 There is also increasing evidence that maternal infections, and specifically chorioamnionitis, are associated with an increased risk of BPD in the infant.74,81 The role of inflammatory reaction in the development of BPD is receiving more attention. Inflammation could be triggered by factors such as oxygen, positive-pressure ventilation, PDA, and prenatal or postnatal infections. Increased concentration of inflammatory mediators could contribute to the bronchoconstriction and vasoconstriction and the increased vascular permeability characteristic of these infants.31 The inflammatory reaction might also be responsible for the decreased alveolarization characteristic of infants with BPD.15,38,78 Bronchoalveolar fluid examinations in infants with BPD reveal elevated neutrophil counts and increased elastase.76 Increased desmosine excretion in the urine during the first week of life has been described in infants who subsequently develop BPD, indicating increased elastin degradation resulting from lung inflammation and injury. On the other hand, higher concentrations of fibronectin have been measured in tracheal lavage fluid from infants with BPD, which could foster the development of interstitial fibrosis in these patients. Inflammatory mediators such as chemokines, interleukin, leukotrienes, and platelet-activating factor also are found in high concentrations in lung lavage fluid of infants with BPD.5,11,31 The potential role of inflammation is supported by the reported beneficial effects of steroids in infants with BPD.23 See Chapter 83. There is an association between the presence of a PDA and an increased risk for BPD (Figure 77-7).30,55 Clinical evidence suggests that infants with RDS who receive greater fluid intake or do not show a diuretic phase during the first days of life have a higher incidence of BPD.65 This may be because high fluid intake increases the incidence of a PDA and the resultant increased pulmonary blood flow produces an increase in interstitial fluid and a decrease in pulmonary compliance.29 Combined with increased airway resistance, this can prolong the need for mechanical ventilation with higher ventilatory pressures and oxygen concentrations, increasing the risk for BPD. Moreover, the increased pulmonary blood flow can damage the pulmonary capillary endothelium and induce neutrophil margination and activation in the lung, contributing to the progression of the inflammatory cascade.69 Data from studies in preterm baboons also showed decreased alveolarization in animals that remained for a longer time with an open ductus arteriosus, supporting the role of a persistent ductus arteriosus in the pathogenesis of BPD.45 Presently, there is no agreement among clinicians regarding the role of different PDA management strategies in the development of BPD. Although most of the epidemiologic data suggest that a long persistence of a PDA is associated with an increased incidence of BPD, the results of two prospective clinical trials to evaluate whether early closure of the PDA would improve pulmonary outcome have not confirmed this hypothesis.60,68 Infants with BPD also have increased plasma levels of vasopressin and reduced urine output and free water clearance.41 This additional alteration can contribute to increased lung water in these patients. The abnormal accumulation of lung fluid in infants with BPD further compromises lung function, perpetuating a cycle in which more aggressive respiratory assistance is required, which produces further lung damage.
Bronchopulmonary Dysplasia in the Neonate
Gestational Age
<32 Weeks
≥32 Weeks
Time point of assessment
36 weeks’ PMA or discharge to home, whichever comes first
>28 days but <56 days’ postnatal age or discharge to home, whichever comes first
Treatment with >21% Oxygen for at Least 28 Days PLUS
Mild BPD
Breathing room air 36 weeks’ PMA or discharge, whichever comes first
Breathing room air by 56 days’ postnatal age or discharge, whichever comes first
Moderate BPD
Need for <30% oxygen at 36 weeks’ PMA or discharge, whichever comes first
Need for <30% oxygen at 56 days’ postnatal age or discharge, whichever comes first
Severe BPD
Need for ≥30% oxygen and/or positive pressure (PPV or NCPAP) at 36 weeks’ PMA or discharge, whichever comes first
Need for ≥30% oxygen and/or positive pressure (PPV or NCPAP) at 56 days’ postnatal age or discharge, whichever comes first
Clinical Presentation
Pathology
Pathogenesis
Mechanical Trauma
Infection and Inflammation
Pulmonary Edema and Patent Ductus Arteriosus
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