Bronchopulmonary dysplasia (BPD), a pulmonary disease associated with preterm birth, is the most frequent adverse outcome of prematurity and the most common chronic lung disease in infancy.1 Infants affected may be challenged by both long-term pulmonary morbidity as well as neurodevelopmental delays. At greatest risk of developing BPD are vulnerable infants who, because of preterm birth and lung immaturity, require mechanical ventilation and/or supplemental oxygen therapy. However, a growing body of literature has identified that premature birth alone impacts postnatal lung development and long-term respiratory health.2
The past 2 decades have seen significant advances in the pulmonary management of premature infants, most notably increased use of antenatal steroids and surfactant with less aggressive use of invasive ventilation. These trends have resulted in both clinical and pathologic changes in the appearance of BPD. Whereas BPD as originally described by Northway et al.3 was characterized by significant lung fibrosis and high risk of mortality, the “new BPD” demonstrates arrested alveolarization, altered development of the pulmonary vasculature, and a less severe clinical course.4 Paralleling the change in appearance of BPD have been modifications to the definition of the disease itself, complicating the tracking of BPD prevalence. Several large data sets have trended outcomes and suggested relatively stable incidence of approximately 40% in surviving infants ≤28 weeks gestation.5 In contrast, the incidence of other morbidities associated with prematurity have decreased with advances in care.6 Improved survival of extremely premature infants, therefore, results in a larger population of infants surviving with BPD, placing greater demands on medical systems and providers. These patients require longer lengths of stay in the neonatal intensive care unit (NICU) and often need advanced medical care after discharge. They are at higher risk for hospital readmission, use greater amounts of medical resources, and necessitate close surveillance for both pulmonary setbacks and developmental delays. This growing burden highlights the critical need for improved strategies for prevention and treatment as well as multidisciplinary approaches to optimize outcomes for infants surviving with BPD.
BPD is recognized to be multifactorial in origin and the outcome of a range of insults on the immature lung. Most notably, inflammation, infection, ventilator, and oxygen-induced injury all contribute to compromised development of the premature lung. Additional risk factors include in-utero growth failure or exposure to environmental toxins including tobacco and nicotine. Postnatal growth failure further contributes to disease and, despite significant progress in optimizing enteral and parenteral nutritional strategies, inadequate weight gain remains common in premature infants. Fluid overload and a patent ductus arteriosus have been implicated in some studies although their contribution to neonatal lung injury remains controversial. Beyond these pre- and postnatal factors, genetic predisposition influences outcomes as supported by several twin- and genome-wide association studies.7
The combined effect of these intrauterine and postnatal insults is most notable with extreme prematurity. Barotrauma induced by ventilators and oxidative stress associated with oxygen therapy or inflammation can all impact lung cell function and viability. Altered growth factor signaling further contributes to compromised lung growth with excess extracellular matrix production, lung fibrosis, and both alveolar and vascular remodeling. The cumulative phenotype observed with “new BPD” includes enlarged alveolar structures and a dysplastic pulmonary vascular tree8 (Figure 1).
Stages of lung development, potentially damaging factors, and types of lung Injury. In premature newborns, the lungs are often exposed to several sources of injury, both before and after birth. Such exposures, as well as genetic susceptibility to problematic lung development, may cause direct airway and parenchymal damage and induce a deviation from the normal developmental path. Depending on the timing and extent of the exposures, lung injury may range from early developmental arrest (new bronchopulmonary dysplasia) to structural damage of a relatively immature lung (old bronchopulmonary dysplasia). Premature infants born at a gestational age of 23 to 30 weeks (region shaded light red) during the canalicular and saccular stages of lung development are at the greatest risk for bronchopulmonary dysplasia. Reprinted from Baraldi and Filippone36 with permission from the Massachusetts Medical Society. © 2007 Massachusetts Medical Society.
Definition and Prevalence
As noted, tracking trends in the prevalence of disease remain a challenge as criteria to define BPD have historically lacked uniformity. Whereas the earliest definitions were limited to oxygen requirement at 28 days with radiologic changes, followed by oxygen requirement at 36 weeks, a consensus definition published by the National Institute of Child Health and Human Development Neonatal Research Network in the year 2000 outlined BPD classifications by severity.9 For infants born at ≤32 weeks gestation, mild BPD was defined as a need for supplemental oxygen for at least 28 days of life but not at 36 weeks postmenstrual age (PMA or discharge, whichever comes first), moderate BPD as oxygen supplementation at 28 days of life as well as an oxygen requirement of <30% at 36 weeks PMA (or discharge), and severe BPD as requiring oxygen therapy for 28 days plus an oxygen requirement at least 30% and/or positive pressure at 36 weeks PMA (or discharge). Highly variable practices with respect to use of oxygen have led to proposals to include physiologic definitions, most notably tolerance of a trial of oxygen therapy.10 Although these modifications greatly assist in defining severity of disease, numerous limitations remain. Notably, future risks of pulmonary disease and the presence of associated morbidities including airway pathology (ie, tracheo- or bronchomalacia) or pulmonary vascular disease are not addressed. Further, contemporary management strategies (including use of high-flow nasal cannula) are not considered,5 potentially leading to misclassification.
Acknowledging the limitations of current definitions, recent prevalence data suggest rates of approximately 40% in infants <28 weeks gestation, suggesting approximately 10,000 to 15,000 new cases annually in the United States.11
Prevention of BPD
As the pathogenesis of disease is multifactorial, diverse preventive approaches exist including both ventilation and medical strategies. Interestingly, both antenatal steroids and surfactant therapy have been shown to reduce rates of respiratory distress syndrome and mortality; however, neither intervention protects against the development of BPD.5,6
Ventilation strategies focus on limiting exposure to barotrauma and supraphysiologic oxygen concentrations, as both can result in inflammation and oxidative stress with injury to the vulnerable developing lung. Reduction of barotrauma can be achieved through multiple approaches, including avoidance of intubation with preferential utilization of noninvasive ventilation, continuous positive airway pressure or high flow nasal cannula for respiratory support. Although studies evaluating outcomes with these modes of support are mixed, several studies suggest reduced rates of BPD with avoidance of intubation in the delivery room.5 Further, when invasive ventilation is needed, early extubation has been shown to reduce risks of prolonged pulmonary disease or BPD.12
Reduction of barotrauma can be further achieved through strategies supporting “gentle ventilation.” These include use of volume targeted ventilation and tolerance of higher carbon dioxide (CO2) levels with permissive hypercapnia. Volume ventilation allows pressures to be continuously adjusted with changes in compliance, avoiding unnecessary barotrauma. A meta-analysis including nine trials identified decreased days of mechanical ventilation as well as the combined outcome of BPD or death with volume targeting.13 Tolerance of higher CO2 levels similarly avoids more aggressive ventilation. However, the evidence to support this strategy has been inconsistent and long-term neurodevelopmental outcomes remain unknown.5 Nonetheless, many NICUs have adopted this practice, recognizing data supporting significant reduction in the need for mechanical ventilation with minimal liberalization of CO2 targets (>52 versus <48 mm Hg).14
Finally, judicious use of oxygen with optimization of saturation targets may protect against oxidative lung injury resulting from supraphysiologic oxygen exposure. The immature lung is uniquely susceptible to oxidative stress as it exhibits both reduced antioxidant capacities and exaggerated reactive oxygen species production with oxygen exposure.15 However, a meta-analysis of five large studies evaluating optimal target saturations in premature infants failed to identify a significant difference in rates of BPD.16 Nonetheless, avoidance of high saturations remains a standard practice in neonatal care.
Despite notable efforts to identify therapies, treatment options to protect the immature lung remain limited. Corticosteroids have long been recognized to induce lung maturation and assist in weaning from mechanical ventilation; however, systemic administration has been associated with adverse outcomes, including poor growth, gastrointestinal perforation, cerebral palsy, and hypertension.17 Many providers have moved away from use of systemic steroids, especially early in an infant's clinical course with concerns for neurodevelopmental risks. However, questions remain whether a subpopulation of infants at high risk might ultimately benefit from this intervention. Some providers have opted for use of inhaled corticosteroids; however, systematic reviews suggest there is inadequate data to support these practices.18 More recently, Yeh et al.19 reported reduced incidence of the combined outcome of BPD or death in infants who received endotracheal budesonide coadministered with early surfactant doses. At present, this approach remains under clinical investigation.
Additional medications that may offer benefit include caffeine and vitamin A. In the recent randomized, multicenter Caffeine for Apnea of Prematurity trial, early initiation of caffeine was found to result in lower incidence of BPD in infants with birth weights <1,250 g, in part due to a shorter course of respiratory support as compared to controls.20 As a result, many providers have opted for early initiation of caffeine for infants at risk.
Vitamin A deficiency may predispose to chronic lung disease as it plays a critical role in maintaining the integrity of respiratory tract epithelium and is a key regulator of normal lung growth.5 Although a recent meta-analysis suggests supplementation of preterm infants with vitamin A results in a reduction in the combined outcome of death or BPD, clinical use of this therapy is highly variable as benefits were only observed in infants weighing <1,000 grams and the results were marginal.21
There is growing recognition for the critical contribution of nutrition to pulmonary outcomes of prematurity. As postnatal growth failure increases risks of BPD, aggressive nutritional support of those at greatest risk for disease is key. Provision of 3.5 to 4 g/kg per day of protein and 120 kcal/kg per day for extremely premature infants is currently recommended to prevent postnatal growth failure.22 Intravenous amino acid solution by way of parenteral nutrition should be provided soon after birth with transition to enteral feedings when possible. Careful attention to protein and calorie intake in enteral feedings can be achieved through the use of higher calorie and high-protein formulas as well as human milk fortifiers.
Treatment of BPD
Parallel to pharmacologic options for prevention of disease, options for treatment of BPD are limited. Wide variation in the use of therapies including diuretics, inhaled corticosteroids, and inhaled beta agonists has been documented, with notable controversy regarding their use.23
Diuretics are commonly used to treat pulmonary edema or fluid retention that may be associated with BPD. However, they have not been shown to decrease duration of respiratory support or length of hospital stay in infants with BPD.24 Use of diuretics creates risk of electrolyte abnormalities as well as problems with calcium and phosphorus metabolism. As a result, infants may require nutritional supplementation to prevent osteopenia. Despite common use of these medications in patients with BPD, standardized approaches to use, monitoring and weaning off the medications fail to exist.
Use of inhalation therapies including bronchodilators and corticosteroids is also common despite a lack of evidence to support improved outcomes. However, a recent meta-analysis suggested heterogeneity in response to these therapies and highlighted the need for identification of infants who might benefit from these interventions.18
Compromised Respiratory Health
Challenges in defining the outcomes of BPD exist as current adult populations represent survivors of outdated care. Nonetheless, numerous concerns for prolonged pulmonary morbidity have been documented in pediatric and adult patients after diagnosis of BPD.5
Compromised pulmonary function has been documented in teenage and young adult survivors of BPD as evidenced by lower forced expiratory volume in 1 second, as well as decreased forced vital capacity (FVC) and forced expiratory flow rate at 50% of FVC as compared to controls.25 In addition, high-resolution computed tomography imaging has confirmed architectural distortion of lung parenchyma in BPD survivors, which correlated with compromised pulmonary function.26 Beyond compromised pulmonary function, studies have documented increased susceptibility to pulmonary infection in BPD survivors.27 Compromised pulmonary defenses may be the result of altered inflammatory responses or disrupted immunoregulatory pathways.28
Hyper-reactive airway disease or asthma-like symptoms have also been shown to be more common in pediatric survivors of BPD. However, these children have been noted to be less responsive to bronchodilator therapies as they likely suffer fixed airway narrowing from compromised lung development associated with BPD.29 Similarly, increased risks of hypoxia-induced bronchoconstriction and exercise intolerance have been noted in this population.30
Finally, dysmorphic pulmonary vasculature and compromised angiogenesis with BPD results in increased risks of BPD-associated pulmonary hypertension (PH). The presence of PH greatly impacts pulmonary morbidity with high risk of early mortality. However, the threshold for intervention and optimal treatment of BPD-associated PH remains elusive with limited evidence to guide medical care.31
Beyond concerns for the impact on respiratory health, the diagnosis of BPD has been shown to correlate with poor neurodevelopment outcomes in survivors. Survivors of BPD have been shown to be at increased risk for cerebral palsy, delays in speech and language development, behavioral problems, attention disorders, and cognitive delays with learning disabilities.32 These deficits may in part be attributable to medical comorbidities such as intraventricular hemorrhage, compromised nutrition, or history of recurrent hypoxemia associated with lung disease. With increased concerns for developmental delay, utilization of early intervention programs and close developmental follow-up is indicated for all infants with a diagnosis of BPD.
Hospital Discharge and Transition of Care
Special consideration should be taken for the transition of infants with BPD to the outpatient setting. As noted, close monitoring of growth, respiratory health, and neurodevelopment status is indicated for all infants with BPD. A multidisciplinary outpatient care plan needs to optimize use of nutritional support and pulmonary therapies, include developmental screening (and intervention as indicated), and address infection prevention.
Infants with BPD have increased caloric requirements and are at higher risk for poor growth after discharge from the NICU.22 Higher calorie postdischarge formulas or breast-milk fortification is recommended for children age 6 to 12 months after discharge.33
These infants also may have feeding difficulties associated with prematurity related to gastroesophageal reflux disease, poor oromotor coordination, or oral aversion. Swallow evaluations or feeding therapy may be required to improve oral intake and some infants may require nutritional support via gastrostomy tube. Close monitoring of weight, length, and head circumference is necessary to ensure optimal growth for all infants with BPD.
Infants with BPD may be discharged home on diuretics, inhalational medications, and in some cases supplemental oxygen. Home-oxygen therapy can reduce postdischarge growth failure and prevent the development of cor pulmonale.33 The management of outpatient pulmonary therapies should involve a pediatric pulmonologist; however, there is no standardized approach to weaning off these interventions. Infants that are not able to wean off oxygen support should be evaluated by cardiology for evidence of cor pulmonale.
Infants with BPD are more likely to be hospitalized for RSV than infants born at term and are more likely to require both longer length of stay and NICU admission.34 Therefore, RSV prophylaxis is indicated for all infants born before 29 weeks gestational age and all infants with evidence of chronic lung disease of prematurity. Prophylaxis is only indicated during the second year of life for patients that continue to require home-oxygen therapy or chronic pulmonary medications.
The pathophysiology, definition, and management of BPD have evolved significantly since the disease was first described more than 50 years ago.5 Advances in neonatal care have resulted in improved survival of extremely premature infants leading to a growing population of long-term survivors of BPD. Multidisciplinary care to address the complex pulmonary, nutritional, and developmental needs of these patients is critical to optimizing outcomes.35 At present, highly variable management practices argue the need for improved understanding of long-term morbidities as well as guidelines and standardized approaches to care.
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