Bronchopulmonary Dysplasia

Abstract

The 2010 NICHD Neonatal Research Network report used new severity-based and physiologic definitions of bronchopulmonary dysplasia (BPD) to estimate that as many as 68% of very-low-birthweight infants can be diagnosed with BPD. As the definition of the condition changes, recommendations for management continue to evolve.After reading this article, readers should be able to:Many advances in neonatology in the last several decades have allowed for the resuscitation, support, and survival of more preterm infants. The mortality associated with respiratory disease in this population of micropremies has been altered significantly by the use of antenatal corticosteroids, postnatal surfactant, improved respiratory support technology, and enhanced nutritional strategies, but the risk of developing long-term respiratory morbidity remains very high. Although the clinical presentation now differs from its original description, BPD continues to be one of the most common complications of premature infants. This disease presents several challenges to clinicians, and its effects can be seen not only in the lungs of these infants but also in many other organ systems.Before the 1960s and the advent of mechanical ventilation, premature infants who developed respiratory distress syndrome (RDS) either died in the first week after birth or survived without respiratory morbidity. The introduction of mechanical ventilation to neonatal intensive care improved survival of infants who otherwise would have died from RDS but also resulted in a new form of lung injury.In 1967, Northway et al (1) described the development of a new chronic lung disease in a group of premature infants who had RDS and had received prolonged ventilation with high concentrations of oxygen and high peak inspiratory pressures. The mean age of these infants was 34 weeks’ gestation with a mean weight of 2.4 kg. These infants all required oxygen at 28 days after birth and had progressive changes on chest radiograph that were graded in severity.Pathologic examination of lung tissue in these infants revealed necrotizing bronchiolitis, vascular changes consistent with pulmonary hypertension, infiltration with inflammatory cells, and alternating areas of alveolar overinflation and atelectasis with pulmonary fibrosis (Fig 1). This disease was termed BPD to emphasize that both the airway and parenchyma of the lung tissues were affected. These abnormalities were attributed to ventilator-induced injury as well as to oxygen therapy.Since that time, there have been several advances in the care of preterm infants. These advances (prenatal corticosteroids, surfactant therapy, gentle ventilation techniques, postnatal corticosteroids, and improved nutritional support, etc) have altered the course of lung disease in this population. As a result, our understanding and definition of BPD also have changed over time. In 1979, Bancalari and colleague (2) offered the first alteration to Northway’s original definition: supplemental oxygen requirement at 28 days, chronic changes on chest radiograph, and tachypnea with crackles or retractions. A grading system was omitted.With advances in medical care, more preterm infants needing oxygen at 28 days did not require its use in later weeks and before discharge. For that reason, the definition was altered again in 1988: a criterion for BPD was then defined as oxygen supplementation at 36 weeks’ postmenstrual age (PMA). (2) This definition proved more useful than one in which the infant had an oxygen need at 28 days after birth; several studies revealed that requiring supplemental oxygen at 36 weeks’ PMA more accurately predicted abnormal pulmonary outcome at 2 years of age.In one study, the need for supplemental oxygen at 36 weeks’ PMA in very low birthweight (VLBW) infants (birthweight <1,500 g) had a better positive predictive value than the 28 postnatal day definition for abnormal outcome (63% vs 38%). Outcome was normal in 90% of infants who did not require oxygen at 36 weeks’ PMA. (3)Over time, this definition (oxygen requirement at 36 weeks’ PMA) has become less useful and predictive because of increased survival of extremely low birthweight (ELBW) infants (birthweight <1,000 g or gestational age <30 weeks) and the widening spectrum of disease severity with improved treatment of RDS. The failure to include gestational age at birth or disease severity has led to concerns that this definition is inadequate, especially when comparing the efficacy of different therapeutic interventions or long-term outcome of ELBW infants who develop BPD.The definition of BPD/chronic lung disease of infancy in preterm infants was reviewed at a June 2000 National Institute of Child Health and Human Development (NICHD)/National Heart, Lung, and Blood Institute workshop. As a result of this meeting, a consensus, severity-based definition of BPD was proposed. (2) The consensus addressed two groups of infants born at <32 weeks’ estimated gestational age. For infants requiring supplemental oxygen at 28 days, there was an assessment done at 36 weeks’ PMA. Those infants breathing room air at 36 weeks’ PMA were defined as having mild BPD. Those infants needing <30% fraction of inspired oxygen concentration (Fio2) supplementation were defined as having moderate BPD. Those infants requiring >30% Fio2 or positive pressure ventilation were defined as having severe BPD.Although not specified in the consensus BPD definition, it was recommended that a physiologic test confirming the need for supplemental oxygen be performed. The primary objective of this project was to determine the predictive validity of the proposed severity-based diagnostic criteria for BPD on pulmonary, neurodevelopmental, and growth outcomes at 18 to 22 months corrected age.Preterm delivery affects 12.5% of pregnancies in the United States, and preterm infants are at high risk for long-term medical impairments, including BPD and chronic lung disease of infancy. (4) Risk of BPD is inversely related to both birthweight and gestational age at birth. The incidence of BPD has not changed substantially since Northway first described it in 1967, but the characteristics of the infants who have BPD have changed dramatically.Classically, BPD occurred in preterm infants who had been treated with high ventilation pressures and oxygen concentrations for severe RDS. The mean birthweight of these infants was ∼1,900 g, and the mean gestational age was 32 weeks. (5) With the advent of antenatal corticosteroids, continuous positive airway pressure (CPAP), surfactant, and improvements in ventilation techniques, the epidemiology of BPD has changed. BPD is now infrequent among infants weighing >1,200 g or born at >30 weeks’ gestation. (2)With advances in neonatal care, more and more infants whose birthweights are <1 kg and who are born at <28 weeks’ gestation are surviving and being diagnosed with BPD. These infants frequently have been treated with antenatal corticosteroids and postnatal surfactant and often have mild RDS and require much less respiratory support after birth than patients who have classic BPD. These new infants have not been exposed to the aggressive ventilation pressures and high oxygen concentrations as were the infants who have classic BPD; thus, other factors must be contributing to lung disease also.The evolving definition of BPD confounds the literature that identifies BPD as an outcome measure. The NICHD Neonatal Research Network released a report in 2010 combining data from infants from the Neonatal Research Network VLBW registry with birthweights of 401 to 1,500 g and gestational ages of 22-0/7 to 28-6/7 weeks born at 20 centers in the United States from 2003 to 2007. Using the new severity-based definition, 68% of these infants were diagnosed with BPD: 27% mild, 23% moderate, and 18% severe. Using the traditional (supplemental oxygen at >36 weeks’ PMA) definition, 42% of these infants were diagnosed with BPD; and using the physiologic definition, 40% of these infants were diagnosed with BPD. (6) These percentages are similar to those reported by Ehrenkranz et al (5) in 2005 in a study designed to validate the NICHD definition of BPD. The authors of this study looked at infants from 14 centers who were delivered before 32 weeks’ gestation. With the traditional (oxygen requirement at 36 weeks) definition, 44% were diagnosed with BPD. Employing the severity-based definition, 76% had BPD: 30% mild, 30% moderate, and 16% severe. Standardization of this definition becomes critical as we research prevention and intervention.As discussed, the old BPD was a condition diagnosed in preterm infants who had hyaline membrane disease treated with high ventilator pressures and high oxygen concentrations before the introduction of antenatal corticosteroid and postnatal surfactant therapy. This disease was hallmarked by airway inflammation, fibrosis, and smooth muscle hypertrophy. The new BPD is a form of chronic lung disease that occurs despite the better neonatal care: CPAP, improved ventilators, antenatal corticosteroids, and surfactant.In normal human lung development, alveolarization begins at ∼36 weeks’ gestation. In the new BPD, lung development arrests before alveolarization, and the lungs have larger but much fewer alveoli than normal lungs (Fig 2). (7) The pulmonary microvasculature is likely to be dysmorphic in the new BPD, but there is controversy over whether it is increased or decreased. (8) Lung biopsy typically is not performed in patients who have BPD, so the histopathologic information available is from infants who have died and is therefore biased toward severe changes and may not be completely representative of the lung anatomy of those living with less severe BPD.Infants born prematurely have underdeveloped lungs and also have faced stressors that contributed to their prematurity. Many of these same insults may play a role in the development of BPD by directly halting lung development or by triggering an inflammatory response.Chorioamnionitis, which is inflammation of the fetal membranes, usually caused by an ascending infection, has long been investigated as a possible cause of BPD. Multiple studies have revealed an increased risk of BPD in the presence of maternal chorioamnionitis, whereas others have revealed no difference or decreased risk. In 2009, in a large 13-year hospital cohort study aimed at studying the relationship between BPD and chorioamnionitis, umbilical vasculitis, and neonatal sepsis, Lahra et al (9) found histologic chorioamnionitis to be protective against BPD. In this same study, umbilical vasculitis conferred more protection against BPD than chorioamnionitis alone, leading Wright and Kirplani (4) to postulate whether the fetal response to chorioamnionitis may play a role in BPD development in a recent review article. This article provides an overview of the potential role of transcription factor nuclear factor kB and inflammation in the pathogenesis of BPD.A potential role of Ureaplasma colonization in the infant lung in the pathogenesis of BPD has been considered for several years. U urealyticum and U parvum are isolated commonly from the chorioamnion in histologic chorioamnionitis and can colonize the skin, eyes, mucous membranes, and respiratory tract of infants. Schelonka et al (10) published a meta-analysis of 23 studies in 2005, which revealed a significant association between Ureaplasma spp colonization and BPD at 36 weeks’ corrected gestational age (P < .001); however, the largest reported effect was seen in the smallest studies, and the authors cautioned that this finding may be due to reporting bias.Bacterial sepsis has been shown consistently to be associated with higher rates of BPD. In one cohort study, BPD rates went from 35% to 62% after early onset sepsis, a result that was validated subsequently in a population study. (4) Neonatal sepsis is a strong indicator of chronic lung disease, and, notably, coagulase-negative staphylococcal infection has been shown to be as strongly associated with BPD as infection with other gram-positive and gram-negative pathogens. (9)In addition to infection, the presence of a hemodynamically significant patent ductus arteriosus (PDA) has been shown to be associated with increased risk of BPD. Lung endothelial damage from left-to-right shunting through a PDA as well as an increased need for mechanical ventilation due to pulmonary edema and lung dysfunction may play a role in increasing BPD risk. However, indomethacin prophylaxis does not decrease rates of BPD despite decreasing the incidence of PDA, and PDA ligation increases BPD risk rather than decreasing it, so the relationship between PDA and BPD does not appear to be a direct cause-and-effect one. (11) High volumes of fluid intake in the first few days after birth may predispose to both conditions, leading to an apparent association. Lower serum cortisol levels in VLBW infants correlate with both PDA and BPD risk, indicating that early adrenal insufficiency may explain the association between PDA and BPD. (12)Mechanical ventilation places an infant at risk for barotrauma and volutrauma if the body is ventilated at high tidal volumes. This association was seen with the old BPD, but it may still play a role in the new BPD as well. Although airway overdistension is seen most often in infants requiring prolonged mechanical ventilation, even a small number of large volume breaths can create injury, especially in surfactant-deficient lungs that do not inflate uniformly. Injury is most likely to happen during initial resuscitation efforts, due to the fine balance of establishing functional residual capacity while attempting to use ventilatory volumes below the total lung capacity.Oxygen toxicity also can put infants at risk for developing BPD. Hyperoxia can arrest lung development, create reactive oxygen species, and trigger the inflammatory cascade. (7)(13) In a recent clinical study, preterm infants born at 24 to 28 weeks’ gestation were randomly assigned to initial neonatal resuscitation with 30% or 90% oxygen, and the incidence of BPD was reduced in half in the 30% oxygen group, 15.4% vs 31.7%. Additionally, this study revealed that biomarkers of oxidative stress were increased in the 90% oxygen group and correlated with later development of BPD. (13)BPD is a chronic illness that persists after hospital discharge, and infants afflicted with BPD have up to 50% higher rates of rehospitalization in the first year after birth. (8) Lung disease can persist into adulthood, including such pathology as airway obstruction, reactive airways, and emphysema. (8) Aside from chronic lung disease, BPD has other sequelae that affect growth, cardiovascular health, and neurodevelopment.Increased respiratory effort in infants who have BPD increases their metabolic demands and, therefore, increases the number of calories needed per day. Adequate nutrition is important in these infants also to help improve their overall health, to help repair any damaged lung tissue, and to decrease the risk of respiratory tract who have chronic lung disease also may need and only A has shown when as a to these infants. to nutrition and growth of these patients during as well as in is important to who have BPD are at high risk for cardiovascular including pulmonary and that to of patients who have BPD develop as a and in to of those who develop the condition is The is to the of consensus for when and to infants who have BPD for is to that small for gestational age infants who have BPD are at an increased risk for of also with severity of BPD. infants have an increased risk of outcomes when with and BPD is an risk who have birthweights <1,500 g who have BPD have as well as increased fine and (8) A study a cohort of who have BPD revealed that the of seen in patients who have BPD with the severity of their lung disease, and that the is still at and years of age. potential for BPD begins while the infant is still in and prevention at that as well. BPD is a disease of the premature so decreasing the number of infants born prematurely would result in fewer patients who develop BPD. corticosteroids is now the of care for at 24 to 34 weeks’ gestation with preterm to with fetal lung but their effect on the incidence of BPD is studies whereas others no (8) is also from studies that corticosteroids may to the arrest of alveolarization and the pathogenesis of BPD, a of and ventilatory play a role in BPD prevention as corticosteroid to help BPD is an of in This was the of care for these with that early corticosteroid the first 2 weeks after to ventilated preterm infants decreased the risk of BPD and decreased to weeks after corticosteroid did not decrease BPD risk but did the effects of with corticosteroid use in preterm infants were the same as those for and hypertension, and studies have now revealed a between postnatal corticosteroid and including the use of postnatal corticosteroids in patients who have BPD or at risk for BPD is on a and not recommended and other have as well as effects and are against Ureaplasma so these have been as potential for BPD prevention in preterm infants. In a no was found VLBW infants a course of with the of infants who were found to be with however, did decrease the incidence of BPD. A is in the of lung development and injury and low A levels in preterm infants have been associated with increased risk for developing BPD. A has been shown to decrease significantly the risk of BPD development in ELBW no difference in at to has been seen between ELBW infants A and has been investigated as a possible for BPD, but study have been have to infants who have from those without it when the role of supplementation in BPD. with to and supplementation of preterm infants who have has not been shown to risk of BPD the for of that to the first days after a significant in BPD at 36 weeks’ PMA was seen in the group vs The by which the risk of BPD is is a that has been shown to decrease pulmonary In one study comparing the of to or decreased the risk of BPD by 27% (P was no significant difference between the group treated with and the group treated with is a frequently used to have to any protective effects of against BPD. have shown from on oxidative stress and lung however, studies in have had (11) The National of Health does not support the use of in the care of preterm but does that research and studies have important information the of on lung development and in infants at high risk for BPD, despite the that clinical have been only able to this The National of Health on to research in this is a that has been investigated for its potential role in BPD development when to ventilated is no that the the risk of BPD has the care of preterm infants who have respiratory but this has not led to a decrease in the incidence of BPD at 36 weeks. As surfactant has contributed to the from the old BPD to the new BPD by respiratory care in ELBW infants. surfactant treatment as of the surfactant in which infants are for a after birth for surfactant by to respiratory support, is associated with a risk of BPD than later surfactant for BPD have and gentle is a for ventilated preterm infants that for of to and in to high tidal volumes and pulmonary (11) have not revealed a significant difference in BPD rates when is but the studies have revealed toward BPD without ventilation to the smallest of respiratory support to and ventilation while significant barotrauma and is a because the for preterm infants are and not well of studies have different ventilation in an to determine the respiratory care for BPD. High ventilation and ventilation have been shown to have rates of associated BPD. (11) A 2010 review revealed rates of or BPD among infants ventilated by using ventilation than those ventilated by using has been a recent in neonatology to from of ELBW infants to has been used in the primary treatment of RDS to as of the and as a after initial ventilation the infant is able to of in preterm infants by for respiratory support has been gestational age with studies that of ELBW infants on be ventilated (11) The as is associated with rates of BPD than initial by surfactant mechanical ventilation, and from respiratory ventilation have been as with the ventilation and positive pressure ventilation often used (11) ventilation has been shown to decrease the of BPD when with for treatment of the authors that the number of infants who have birthweights <1,500 g in the study was and the need to be validated in a study in the VLBW and ELBW infants at risk for BPD often are that fluid intake in the first days after birth has been associated with an increased risk of developing BPD. of often is to up for the calories otherwise by fluid developing BPD may need up to to 40% more than their who have BPD, continue to have increased their and 30% to of these infants growth failure after initial hospital discharge. corticosteroids have long been used as a for patients who have developing or BPD, but the their use is A review of revealed that there is no that corticosteroid weeks after to ventilated preterm infants the incidence of BPD. the same risk of long-term outcomes for patients corticosteroids for BPD with those corticosteroids remains often are used in patients who have BPD in an to decrease pulmonary alveolar and edema and to improve lung A review of clinical the use of or in infants who have evolving or BPD revealed no effect or effects in infants weeks of age and only in lung with a of in infants weeks of age. use of is not recommended in infants who have of studies have reviewed the use of in infants who have moderate BPD, and a of the available literature revealed that chronic of to infants weeks of age pulmonary for weeks improved lung and decreased the incidence of but there is no to that this the long-term outcome in preterm infants who have BPD. also have been investigated but have not long-term and are not recommended have revealed that most commonly can with in lung and may be to infants who have BPD during the role of in the prevention of BPD revealed no difference in of BPD, of ventilation support, and of oxygen among ventilated preterm infants 28 days of or the of efficacy is due in to much is to the remains but for the therapeutic role of in patients who have BPD is for and not chronic research for this article and the first were contributed by of of