Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in preterm neonates treated with oxygen and positive-pressure ventilation (PPV).

Bronchopulmonary dysplasia (BPD).

Chest radiograph of infant with bronchopulmonary dysplasia.

Northway et al reported clinical, radiographic, and histologic changes in the lungs of preterm infants who had respiratory distress syndrome (RDS) and were treated with oxygen and mechanical ventilation.[3]

Northway et al's original definition has been extensively modified over the last 4 decades. Bancalari et al’s definition involves ventilation criteria, an oxygen requirement at 28 days to maintain arterial oxygen tensions of more than 50 mm Hg, and abnormal findings on chest radiography.[4] Shennan et al proposed that an additional need for supplemental oxygenation at 36 weeks' postmenstrual age may be the most accurate indicator of pulmonary outcome;[5] this criterion decreased the large number of relatively healthy preterm infants Bancalari and others included in their definitions.

Jobe and Bancalari summarized proceedings of a National Institute of Health consensus conference on bronchopulmonary dysplasia.[6] Investigators from the National Institute of Child Health and Human Development (NICHD) have validated their recommendations. This group improved the definition of bronchopulmonary dysplasia and attempted to assign a severity score based on oxygen requirements and the need for respiratory support. However, physicians and institutions may set different standards for oxygen requirements and for target ranges for oxygen saturation. This variation in practice may notably influence the incidence and severity of bronchopulmonary dysplasia in a particular neonatal ICU (NICU).

To overcome this limitation due to subjectivity in "need for oxygen," Walsh et al recently developed a physiologic definition of bronchopulmonary dysplasia.[7] According to this definition, at 35-37 weeks' postmenstrual age, infants treated with mechanical ventilation, continuous positive airway pressure (CPAP), or supplemental oxygen concentration of 30% and oxygen saturations of 90-96% were diagnosed with bronchopulmonary dysplasia without additional testing. Infants with supplemental oxygen concentrations of 30% at rest with oxygen saturations of 90-96% or supplemental oxygen concentrations of 30% with oxygen saturations of more than 96% underwent a timed stepwise reduction to room air.

For infants receiving oxygen by hood, oxygen was weaned in 2% increments. For infants receiving oxygen by nasal cannulae, flow was initially weaned in increments (for flow of 1–2, step down 0.5 liters per minute [lpm]; for flow 0.1-0.99 lpm, step down 0.1 lpm), and then the oxygen concentration was reduced in increments of 20% to room air. Cannulae were removed from the nares for the remainder of the challenge. Oxygen that was given only during feedings was not included for the purposes of eligibility. Those who failed the reduction were diagnosed with bronchopulmonary dysplasia.

No bronchopulmonary dysplasia was defined by requiring treatment with room air with oxygen saturation of more than 90% or passing a timed, continuously monitored oxygen-reduction test.[7] The physiologic definition of bronchopulmonary dysplasia reduced the overall rate of bronchopulmonary dysplasia and reduced the variation among centers. The physiologic definition may facilitate the measurement of bronchopulmonary dysplasia as an outcome in clinical trials and the comparison between and within centers over time.

Recently, models have been developed for predicting the probability of BPD at specific postnatal time points using readily available clinical data.[8] Prediction improved with advancing postnatal age, increasing from a C statistic (area under the curve) of 0.79 on day 1 to a maximum of 0.85 on day 28. On postnatal days 1 and 3, gestational age best improved outcome prediction, while type of respiratory support was most important on postnatal days 7, 14, 21, and 28.[8]

The pathogenesis of bronchopulmonary dysplasia remains complex and poorly understood. Bronchopulmonary dysplasia results from various factors that can injure small airways and that can interfere with alveolarization (alveolar septation), leading to alveolar simplification with a reduction in the overall surface area for gas exchange. The developing pulmonary microvasculature can also be injured. Alveolar and lung vascular development are intimately related, and injury to one may impair development of the other. Damage to the lung during a critical stage of lung growth can result in clinically significant pulmonary dysfunction.

Premature birth and subsequent events (eg, exposure to oxygen, mechanical ventilation, inflammatory agents, infection) likely shifts the balance from lung development consisting of lung alveolar and vascular growth to one of premature maturation, which is associated with an arrest in development and a loss of future gas exchange area; however, alveolar maturation might facilitate gas exchange in the short-term.[9]

While inflammation is associated with development of BPD, the role of chorioamnionitis in development of BPD after adjustment for prematurity is uncertain. Recent large studies indicate that chorioamnionitis is not associated with BPD.[10, 11] However, alterations in the airway microbiome at birth have been noted in infants exposed to chorioamnionitis, and these alterations have been found to be associated with BPD.[12]

United States data

Infants with severe bronchopulmonary dysplasia are often extremely immature and have very low birth weight, although term infants with severe respiratory failure are also at increased risk. Bronchopulmonary dysplasia is uncommon in infants with a birth weight of more than 1250 g and in infants who were born at more than 30 weeks' gestation. Overall, about one fourth of infants who weigh less than 1500 g are diagnosed with bronchopulmonary dysplasia.

Antenatal glucocorticosteroids, early surfactant therapy, and gentle modalities of ventilation have minimized the severity of lung injury, particularly in relatively mature infants. However, improved survival has increased the prevalence of bronchopulmonary dysplasia, especially in small infants who may have been exposed to in utero infection (eg, chorioamnionitis).

Several trials of surfactants revealed that incidences of bronchopulmonary dysplasia widely vary, from 17-57%. No substantial difference between placebo-treated and surfactant-treated survivors has been reported. Kresch and Clive performed a meta-analysis of surfactant-replacement therapy for infants weighing less than 2 kg.[13] Infants receiving modified natural surfactant had improved survival without bronchopulmonary dysplasia. Van Marter and associates described the wide variation in the prevalence of bronchopulmonary dysplasia in different NICUs using various ventilatory strategies.[14] This variation has also been noted among sites in the Vermont Oxford Network (VON) and in the NICHD research network, suggesting that differences in patient populations and clinical practices may directly affect outcomes.

International data

Studies similar to those in the United States have been conducted to compare rates of bronchopulmonary dysplasia in different NICUs in Europe. Results have been similar despite the relatively homogeneous population.

Race-, sex-, and age-related demographics

Compared with white infants, African American infants generally have a lower incidence of severe bronchopulmonary dysplasia, although the combined rate of bronchopulmonary dysplasia and death is often similar in persons of different races.[8]

Male infants with bronchopulmonary dysplasia tend to have more severe disease and worse neurodevelopmental outcome.

Bronchopulmonary dysplasia is most common in the most immature neonates born at 22-30 weeks' gestational age. These patients frequently weigh less than 1000 g at birth.

Prognosis

Most neonates with bronchopulmonary dysplasia ultimately survive. Note the following:

• As infants, patients are at increased risk for repeated and serious pulmonary infections (eg, respiratory syncytial virus [RSV]), asthma, cardiac dysfunction, and neurologic impairments.

• Infants with severe bronchopulmonary dysplasia remain at high risk for pulmonary morbidity and mortality during the first 2 years of life.

• Rehospitalization for impaired pulmonary function is most common during the first 2 years of life.

• Hakulinen and associates found a gradual decrease in symptom frequency among children aged 6-9 years compared with infants aged 0-2 years.[15]

• In children and adults with a history of bronchopulmonary dysplasia, high-resolution chest CT reveals lung abnormalities that are directly correlated with the degree of pulmonary dysfunction.

• The infant with severe bronchopulmonary dysplasia is at high risk for long-term pulmonary and neurologic sequelae.

• Persistent right ventricular hypertrophy or fixed pulmonary hypertension unresponsive to oxygen supplementation is associated with a poor prognosis.

• Northway followed up pediatric patients with bronchopulmonary dysplasia to adulthood and reported that patients had airway hyperreactivity, abnormal pulmonary function, and hyperinflation, as noted on chest radiography.[16]

• Bader et al and Blayney et al found persistence of respiratory symptoms and abnormal pulmonary function in children aged 7 and 10 years.[17, 18]

Morbidity/mortality

Postnatal infection and/or sepsis, periventricular leukomalacia (PVL), severe intraventricular hemorrhage, ventriculomegaly, hearing impairment, and severe retinopathy of prematurity (ROP) are all important confounding variables that can greatly affect an infant's outcome.

Since the introduction of surfactant replacement, survival of the most immature infants has improved. However, the stable 25-50% survival rates in preterm infants at 23-24 weeks' gestation likely reflect the lack of alveolarization and vascular development. Survival and morbidity improved in infants older than 24 weeks' gestation after the widespread administration of antenatal corticosteroids was introduced in 1994.

Along with other advances in technology and an improved understanding of neonatal physiology, infants with bronchopulmonary dysplasia appear to have milder disease today than in years past.

Infants with severe bronchopulmonary dysplasia remain at high risk for pulmonary morbidity and mortality during the first 2 years of life. Infants with bronchopulmonary dysplasia are at risk for repeated pulmonary infections and asthma requiring repeated hospital admissions and office visits.

Abnormal long-term neurodevelopmental outcome, muscular development, slow growth, and chronic pulmonary morbidity are common in infants with bronchopulmonary dysplasia. Whether abnormal neurodevelopmental outcomes are directly related to bronchopulmonary dysplasia or to the patients' marked immaturity and disease severity is hard to determine.

History

There is usually a history of very preterm birth, frequently associated with chorioamnionitis, preterm labor, preterm rupture of membranes, or a need for iatrogenic delivery (due to maternal preeclampsia or other complications). Infants who develop bronchopulmonary dysplasia (BPD) often have a history of persistent need for a high level of respiratory support from birth, often with need for mechanical ventilation or CPAP from soon after birth.

Physical examination

Infants with BPD have abnormal findings on physical examination, chest radiography, pulmonary function testing, and histopathologic examination. Initial findings observed shortly after birth are consistent with respiratory distress syndrome (RDS). Persistence of these abnormalities can be associated with an increased risk of bronchopulmonary dysplasia.

Physical examination may reveal tachypnea, tachycardia, increased work of breathing (with retractions, nasal flaring, and grunting), frequent desaturations, and significant weight loss during the first 10 days of life.

Infants with severe bronchopulmonary dysplasia are often extremely immature and had a very low birth weight. Their requirements for oxygen and ventilatory support often increase in the first 2 weeks of life. At weeks 2-4, oxygen supplementation, ventilator support, or both are often increased to maintain adequate ventilation and oxygenation.

Arterial blood gas (ABG) assessment in patients with bronchopulmonary dysplasia (BPD) may reveal acidosis, hypercarbia, and hypoxia (with increased oxygen requirements).

Continuously monitor oxygenation by using pulse oximeter because of frequent desaturations.

Transcutaneous or end-tidal carbon dioxide monitoring may be helpful in evaluating trends, especially if the results are correlated with ABG levels. A transcutaneous monitor may injure the fragile skin of the very preterm infant. Endotracheal carbon dioxide monitors may increase dead space or become blocked with secretions.

Changes in pulmonary mechanics include increased airway resistance, decreased lung compliance, increased airway reactivity, and increased airway obstruction. Increased resistance and airway hyperactivity may be evident in the early stages of bronchopulmonary dysplasia. With worsening severity, airway obstruction can become clinically significant, with expiratory flow limitation.

In the early and mild stages of bronchopulmonary dysplasia, functional residual capacity can be increased. However, increases in functional residual capacity are noted in severe bronchopulmonary dysplasia secondary to air trapping and hyperinflation. Airway hyperresponsiveness is also increased (with an increased incidence of respiratory syncytial virus [RSV] infections and asthma) in infants in both presurfactant and postsurfactant eras. Lung compliance is reduced in infants with bronchopulmonary dysplasia.

Changes on pulmonary function tests appear to be correlated with radiographic findings. Serial pulmonary function testing may help in assessing therapeutic modalities used to treat bronchopulmonary dysplasia. However, variability related to excessive chest-wall distortion and the location where measurements are made can be problematic. Pulmonary function can slowly improve over time, but abnormalities can persist into late childhood and adolescence.

Structural changes in the lung vasculature contribute to high pulmonary vascular resistance due to narrowing of the vessel diameter and decreased angiogenesis. In addition to these structural changes, the pulmonary circulation is characterized by abnormal vasoreactivity, which also increases pulmonary vascular resistance.

Overall, injury to the pulmonary circulation can lead to pulmonary hypertension and cor pulmonale, which substantially contribute to the morbidity and mortality associated with severe bronchopulmonary dysplasia. Persistent right ventricular hypertrophy or fixed pulmonary hypertension unresponsive to oxygen supplementation on cardiac catheterization portends a poor prognosis.

Infants with bronchopulmonary dysplasia can also develop systemic hypertension; therefore, their blood pressures should be routinely monitored.

Echocardiography

Echocardiographic assessment is an extremely valuable tool in confirming these diagnoses. Prospective studies based on echocardiography findings indicated that pulmonary hypertension is relatively common, affecting at least 1 in 6 extremely low birth weight infants, and persists to discharge in most survivors.[19] However, qualitative variables of pulmonary hypertension are not consistently provided in echo reports, even though the inter-rater reliability of cardiologists is high, especially at 36 weeks postmenstrual age.[20] Recent recommendations for the evaluation and management of pulmonary hypertension in children with BPD have been published.[21] In current practice, the role of brain natriuretic peptide in monitoring pulmonary hypertension and response to therapy in these infants has not been adequately described.

Chest radiography

Chest radiography is helpful in determining the severity of bronchopulmonary dysplasia and in differentiating bronchopulmonary dysplasia from atelectasis, pneumonia, and air leak syndrome. Chest radiographs may demonstrate decreased lung volumes, areas of atelectasis and hyperinflation, pulmonary edema (PE), and pulmonary interstitial emphysema (PIE). Hyperinflation or interstitial abnormalities on chest radiograph appears to be correlated with the development of airway obstruction later in life.

More recently, CT and MRI studies of infants with bronchopulmonary dysplasia have provided detailed images of the lung. High-resolution CT may detect radiographic abnormalities not readily identified with routine chest radiography.

Members of families with a strong history of atopy and asthma may be at increased risk for bronchopulmonary dysplasia and severe bronchopulmonary dysplasia. A review of monozygotic preterm twins revealed concordance of bronchopulmonary dysplasia compared with dizygotic twins.

Polymorphisms in surfactant protein B are associated with bronchopulmonary dysplasia.

Variations in proinflammatory mediators, such as tumor necrosis factor-alpha, are associated with a heightened risk of bronchopulmonary dysplasia.

Future DNA array studies of patients in large multicenter trials may reveal genetic loci specific for abnormal alveolar, pulmonary vascular, and elastin development. Animal studies of the overexpression or underexpression of these genotypes could further elucidate the complex process of pulmonary development.

Four distinct pathologic stages of bronchopulmonary dysplasia are generally described: acute lung injury, exudative bronchiolitis, proliferative bronchiolitis, and obliterative fibroproliferative bronchiolitis.

At present, pathologic examination of extremely low birth weight infants with bronchopulmonary dysplasia reveal greatly reduced total numbers of alveoli and septa. This condition is commonly referred to as the "new" bronchopulmonary dysplasia.[22, 23, 24] A striking arrest in pulmonary alveolar and vascular development is noted, in association with abnormalities in vascular endothelial growth factor and other signaling molecules important for the migration and development of endothelial cells.

Mechanical ventilation

In most cases of bronchopulmonary dysplasia (BPD), respiratory distress syndrome is diagnosed and treated. The mainstay for treating RDS has been surfactant replacement with oxygen supplementation, continuous positive airway pressure (CPAP), and mechanical ventilation. The treatment necessary to recruit alveoli and prevent atelectasis in the immature lung may cause lung injury and activate the inflammatory cascade.

Trauma secondary to positive pressure ventilation (PPV) is generally referred to as barotrauma. With the recent focus on a ventilation strategy involving low versus high tidal volume, some investigators have adopted the term volutrauma. Volutrauma suggests the occurrence of lung injury secondary to excessive tidal volume from PPV.

The severity of lung immaturity, the fetal milieu, and the effects of surfactant deficiency determine the need for PPV, surfactant supplementation, and resultant barotrauma or volutrauma. With severe lung immaturity, the total number of alveoli is reduced, increasing the positive pressure transmitted to distal terminal bronchioles. In the presence of surfactant deficiency, surface tension forces are increased. Some compliant alveoli may become hyperinflated, whereas other saccules with increased surface tension remain collapsed. With increasing PPV to recruit alveoli and improve gas exchange, the compliant terminal bronchiole and alveolar ducts may rupture, leaking air into the interstitium, with resultant pulmonary interstitial emphysema (PIE). The occurrence of PIE greatly increases the risk of bronchopulmonary dysplasia.

Many modes of ventilation and many ventilator strategies have been studied to potentially reduce lung injury, such as synchronized intermittent mechanical ventilation (SIMV), high-frequency jet ventilation (HFJV), and high-frequency oscillatory ventilation (HFOV). Results have been mixed, although some theoretical benefits are associated with these alternative modes of ventilation. Although shorter duration of mechanical ventilation has been demonstrated in some trials of SIMV, most trials have not had a large enough sample size to demonstrate a reduction in bronchopulmonary dysplasia. Systematic reviews suggest that optimal use of conventional ventilation may be as effective as HFOV in improving pulmonary outcomes. Regardless of the high-frequency strategy used, avoidance of hypocarbia and optimization of alveolar recruitment may decrease the risk of bronchopulmonary dysplasia and associated of neurodevelopmental abnormalities.

PPV with various forms of nasal CPAP has been reported to decrease injury to the developing lung and may reduce the development of bronchopulmonary dysplasia. In general, centers that use "gentler ventilation" with more CPAP and less intubation, surfactant, and indomethacin had the lowest rates of bronchopulmonary dysplasia.

Oxygen and PPV frequently are life-saving in extremely preterm infants. However, early and aggressive CPAP may eliminate the need for PPV and exogenous surfactant or facilitate weaning from PPV. Some recommend brief periods of intubation primarily for the administration of exogenous surfactant quickly followed by extubation and nasal CPAP to minimize the need for prolonged PPV. This strategy may be most effective in infants without severe RDS, such as many infants with birth weights of 1000-1500 g. In infants who require oxygen and PPV, careful and meticulous treatment can minimize oxygen toxicity and lung injury. Optimal levels include a pH level of 7.2-7.3, a partial pressure of carbon dioxide (pCO2) of 45-55 mm Hg, and a partial pressure of oxygen (pO2) level of 50-70 mm Hg (with oxygen saturation at 87-92%).

Assessment of blood gases requires arterial, venous, or capillary blood samples. As a result, indwelling arterial lines are often inserted early in the acute management of RDS. Samples obtained from these lines provide the most accurate information about pulmonary function. Arterial puncture may not provide completely accurate samples because of patient agitation and discomfort. Capillary blood gas results, if samples are properly obtained, may be correlated with arterial values; however, capillary samples may widely vary, and results for carbon dioxide are poorly correlated. Following trends in transcutaneous PO2 and pCO2 may reduce the need for frequent blood gas measurements.

Weaning from mechanical ventilation and oxygen is often difficult in infants with moderate-to-severe bronchopulmonary dysplasia, and few criteria are defined to enhance the success of extubation. When tidal volumes are adequate and respiratory rates are low, a trial of extubation and nasal CPAP may be indicated. Atrophy and fatigue of the respiratory muscles may lead to atelectasis and extubation failure. A trial of endotracheal CPAP before extubation is controversial because of the increased work of breathing and airway resistance.

Optimization of methylxanthines and diuretics and adequate nutrition may facilitate weaning the infant from mechanical ventilation. Meticulous primary nursing care is essential to ensure airway patency and facilitate extubation. Prolonged and repeated intubations, as well as mechanical ventilation, may be associated with severe upper airway abnormalities, such as vocal cord paralysis, subglottic stenosis, and laryngotracheomalacia. Bronchoscopic evaluation should be considered in infants with bronchopulmonary dysplasia in whom extubation is repeatedly unsuccessful. Surgical interventions (cricoid splitting, tracheostomy) to address severe structural abnormalities are used less frequently today than in the past.

Oxygen therapy

Oxygen can accept electrons in its outer ring to form free radicals. Oxygen free radicals can cause cell-membrane destruction, protein modification, and DNA abnormalities. Compared with fetuses, neonates live in a relatively oxygen-rich environment. Oxygen is ubiquitous and necessary for extrauterine survival. All mammals have antioxidant defenses to mitigate injury due to oxygen free radicals. However, neonates have a relative deficiency in antioxidant enzymes.

The major antioxidant enzymes in humans are superoxide dismutase, glutathione peroxidase, and catalase. Activity of antioxidant enzymes tend to increase during the last trimester of pregnancy, similar to surfactant production, alveolarization, and development of the pulmonary vasculature. Increases in alveolar size and number, surfactant production, and antioxidant enzymes prepare the fetus for transition from a relatively hypoxic intrauterine environment to a relatively hyperoxic extrauterine environment. Preterm birth exposes the neonate to high oxygen concentrations, increasing the risk of injury due to oxygen free radical.

Animal and human studies of supplemental superoxide dismutase and catalase supplementation have shown reduced cell damage, increased survival, and possible prevention of lung injury. Evidence of oxidation of lipids and proteins has been found in neonates who develop bronchopulmonary dysplasia. Supplementation with superoxide dismutase in ventilated preterm infants with RDS substantially reduced in readmissions compared with placebo-treated control subjects. Further trials are currently under way to examine the effects of supplementation with superoxide dismutase in preterm infants at high risk for bronchopulmonary dysplasia.

Ideal oxygen saturation for term or preterm neonates of various gestational and postnatal ages has not been definitively determined. Many clinicians have adopted oxygen saturation target ranges of 90-95% following results of the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) trial[25] and more recent similar trials, which indicate an increased risk of mortality in infants with target oxygen saturation of 85-89% compared with 91-95%.

In SUPPORT, the rate of oxygen use at 36 weeks was reduced in the lower-oxygen-saturation group compared with the higher-oxygen-saturation group (P = 0.002), but the rates of bronchopulmonary dysplasia among survivors, as determined by the physiological test of oxygen saturation at 36 weeks, and the composite outcome of bronchopulmonary dysplasia or death by 36 weeks did not differ significantly between the treatment groups. A delicate balance to optimally promote neonatal pulmonary (alveolar and vascular) and retinal vascular homeostasis is noted.

In the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial to reduce severe retinopathy of prematurity (ROP), oxygen saturations of more than 95% minimally affected retinopathy but increased the risk for pneumonia or bronchopulmonary dysplasia.

The normal oxygen requirement of a preterm infant is unknown. Pulmonary hypertension and cor pulmonale may result from chronic hypoxia and lead to airway remodeling in infants with severe bronchopulmonary dysplasia. Oxygen is a potent pulmonary vasodilator that stimulates the production of nitric oxide (NO). NO causes smooth muscle cells to relax by activating cyclic guanosine monophosphate. Currently, pulse oximetry is the mainstay of noninvasive monitoring of oxygenation.

Repeated episodes of desaturation and hypoxia may occur in infants with bronchopulmonary dysplasia receiving mechanical ventilation as a result of decreased respiratory drive, altered pulmonary mechanics, excessive stimulation, bronchospasm, and forced exhalation efforts. Forced exhalation efforts due to infant agitation may cause atelectasis and recurrent hypoxic episodes. Hyperoxia may overwhelm the neonate's relatively deficient antioxidant defenses and worsen bronchopulmonary dysplasia. The patient's oxygen requirements are frequently increased during stressful procedures and feedings. Caregivers are more likely to follow wide guidelines for ranges of oxygen saturation than narrow ones. Some infants, especially those living at high altitudes, may require oxygen therapy for many months.

Transfusion of packed RBCs may increase oxygen-carrying capacity in preterm infants who have anemia (hematocrit < 30% [0.30]), but transfusion may further increase complication rates. The ideal hemoglobin level in critically ill neonates is not well established. Hemoglobin levels are not well correlated with oxygen transport, although it has been shown that oxygen content and systemic oxygen transport increased and that oxygen consumption and requirements decreased in infants with bronchopulmonary dysplasia after blood transfusion.

The need for multiple transfusions and donor exposures can be minimized by using iron supplementation, a reduction in phlebotomy requirements, and by use of erythropoietin administration.

Treatment of inflammation

Chorioamnionitis is associated with a higher risk of development of bronchopulmonary dysplasia.[1] Elevated levels of interleukin-6 and placental growth factor in the umbilical venous blood of preterm neonates are associated with increased incidence of bronchopulmonary dysplasia. This inflammation likely affects alveolarization and vascularization of the pulmonary system of the second-trimester fetus.

Fetal sheep exposed to inflammatory mediators or endotoxin develop inflammation and abnormal lung development. Activation of inflammatory mediators has been demonstrated in humans and animal models of acute lung injury. Activation of leukocytes after cell injury caused by oxygen free radicals, barotrauma, infection, and other stimuli may begin the process of destruction and abnormal lung repair that results in acute lung injury then bronchopulmonary dysplasia.

Radiolabeled activated leukocytes have been recovered by means of bronchoalveolar lavage (BAL) in preterm neonates receiving oxygen and PPV. These leukocytes, as well as lipid byproducts of cell-membrane destruction, activate the inflammatory cascade and are metabolized to arachidonic acid and lysoplatelet factor. Lipoxygenase catabolizes arachidonic acid, resulting in the production of cytokines and leukotrienes. Cyclooxygenase may also metabolize these byproducts to produce thromboxane, prostaglandin, or prostacyclin. All of these substances have potent vasoactive and inflammatory properties. levels of these substances are elevated in the first days of life, as measured in tracheal aspirates of preterm infants who subsequently develop bronchopulmonary dysplasia.

Metabolites of arachidonic acid, lysoplatelet factor, prostaglandin, and prostacyclin may cause vasodilatation, increase capillary permeability with subsequent albumin leakage, and inhibit surfactant function. This effects increase oxygenation and ventilation requirements and potentially increase rates of bronchopulmonary dysplasia Activation of transcription factors such as nuclear factor-kappa B in early postnatal life is associated with death or bronchopulmonary dysplasia.

Collagenase and elastase are released from activated neutrophils. These enzymes may directly destroy lung tissue because hydroxyproline and elastin (breakdown products of collagen and elastin) have been recovered in the urine of preterm infants who develop bronchopulmonary dysplasia.

Alpha1-proteinase inhibitor mitigates the action of elastases and is activated by oxygen free radicals. Increased activity and decreased function of alpha1-proteinase inhibitor may worsen lung injury in neonates. A decrease in bronchopulmonary dysplasia and in the need for continued ventilator support is found in neonates given supplemental alpha1-proteinase inhibitor.

All these findings suggest the fetal inflammatory response effects pulmonary development and substantially contributes to the development of bronchopulmonary dysplasia. The self-perpetuating cycle of lung injury is accentuated in the extremely preterm neonate with immature lungs.

Management of infection

Maternal cervical colonization and/or colonization in the neonate with Ureaplasma urealyticum has been implicated in the development of bronchopulmonary dysplasia. Viscardi and colleagues found that persistent lung infection with U urealyticum may contribute to chronic inflammation and early fibrosis in the preterm lung, leading to pathology consistent with clinically significant bronchopulmonary dysplasia.[2]

Systematic reviews have concluded that infection with U urealyticum is associated with increased rates of bronchopulmonary dysplasia. Infection—either antenatal chorioamnionitis and funisitis or postnatal infection—may activate the inflammatory cascade and damage the preterm lung, resulting in bronchopulmonary dysplasia. In fact, any clinically significant episode of sepsis in the vulnerable preterm neonate greatly increases his or her risk of bronchopulmonary dysplasia, especially if the infection increases the baby's requirement for oxygen and mechanical ventilation.

Future management

Future management of bronchopulmonary dysplasia will involve strategies that emphasize prevention. Because few accepted therapies currently prevent bronchopulmonary dysplasia, many therapeutic modalities (eg, mechanical ventilation, oxygen therapy, nutritional support, medication) are used to treat bronchopulmonary dysplasia. Practicing neonatologists have observed reduced severities of bronchopulmonary dysplasia in the postsurfactant era. Maintaining PPV and oxygen therapy for longer than 4 months and discharging patients to facilities for prolonged mechanical ventilation is now unusual.

Infants with bronchopulmonary dysplasia have multisystem involvement. Therefore, various pediatric subspecialists should be consulted: cardiologist, pulmonologist, gastroenterologist, developmentalist, ophthalmologist, neurologist, physical therapist, and nutritionist.

Pharmacists who have specialized in pediatrics and neonatal care are invaluable in guiding therapy and providing in-patient and outpatient support for these fragile infants. They may also assist with ongoing care after patients are discharged from the hospital.

Infants with bronchopulmonary dysplasia have increased energy requirements. Early parenteral nutrition is often used to ameliorate the catabolic state of the preterm infant, although excessive fluid administration (and failure to lose weight) in the first week of life may increase the risk for patent ductus arteriosus (PDA) and bronchopulmonary dysplasia. Maximizing the patient's intake of protein, carbohydrates, fat, vitamins, and trace metals is critical to prevent further lung injury and augment tissue repair. However, excessive administration of non-nitrogen calories should be avoided because this may lead to excessive formation of carbon dioxide and complicate weaning.

Antioxidant enzymes may protect the lung and help prevent or mitigate bronchopulmonary dysplasia. In preterm neonates, deficiency of trace element such as copper, zinc, and manganese may predispose them to lung injury, and supplementation may provide protection.

Vitamins A and E are nutritional antioxidants that may help prevent lipid peroxidation and maintain cell integrity. However, supplementation of vitamin E in preterm neonates does not prevent bronchopulmonary dysplasia. Preterm neonates may be deficient in vitamin A, and many trials of vitamin A supplementation to prevent bronchopulmonary dysplasia in preterm infants have been completed. Data from meta-analyses reported in a Cochrane Database review of vitamin A supplementation indicate that vitamin A supplementation reduces the risk of bronchopulmonary dysplasia in premature neonates.

Extremely preterm infants may require large amounts of free water because of increased insensible water loss through their thin, immature skin. Excessive administration of fluid increases the risk of symptomatic PDA and pulmonary edema (PE). The increased ventilator settings and oxygen requirements necessary to treat PDA and PE may worsen pulmonary injury and increase the risk of bronchopulmonary dysplasia. Early PDA treatment may improve pulmonary function but does not affect the incidence of bronchopulmonary dysplasia. A retrospective study by Oh et al revealed that lowered fluid intake soon after birth helped reduce the risk of death and oxygen requirement at 36 weeks' corrected gestational age.[26]

Protein and fat supplementation is progressively increased to provide approximately 3-3.5 g/kg/day. Rapid and early administration of high concentrations of lipids may possibly worsen bronchopulmonary dysplasia by depleting pulmonary vascular lipid. Excessive glucose loads may increase oxygen consumption, the respiratory drive, and glucosuria. Calcium and phosphorus requirements are greatly increased in preterm infants. Most mineral stores in the fetus are collected during the third trimester, leaving the extremely preterm infant deficient in calcium and phosphorus and at increased risk of rickets. Furosemide therapy and limited intravenous administration of calcium may worsen bone mineralization and cause secondary hyperparathyroidism.

Vitamin A supplementation decreases the incidence of bronchopulmonary dysplasia. Supplementation of trace minerals (eg, copper, zinc, manganese) are needed because they are essential cofactors in antioxidant enzymes.

Early insertion of percutaneous central venous lines may aid the administration of parenteral nutrition.

Early enteral feeding of small amounts (even if umbilical lines are in place) followed by slow, steady increases in volume appears to optimize tolerance of feeds and nutritional support. The most immature and unstable preterm infant often has a difficult transition to complete enteral nutrition. Frequent interruption of feedings because of intolerance or illness can complicate the care of patients. Enteral feedings of breast milk provides the best nutrition while preventing feeding complications (eg, sepsis, necrotizing enterocolitis). The energy content of expressed breast milk and formulas can be enhanced to increase energy intake while minimizing fluid intake. Infants may require 120-150 kcal/kg/day to gain weight.

Diuretics are often used to treat fluid overload, but initially avoiding excessive fluid administration is preferred.

Postnatal growth failure is common and may have considerable effects on long-term developmental outcomes. Strategies to optimize postnatal weight gain are important to improve pulmonary, retinal, and neurologic development.

The multifactorial etiology of bronchopulmonary dysplasia complicates its prevention. Note the following:

• Prenatal steroid therapy and postnatal surfactant has improved survival and mitigated the severity of bronchopulmonary dysplasia. Prevention of preterm birth and chorioamnionitis should reduce the incidence of bronchopulmonary dysplasia.

• Meticulous attention to optimal oxygenation, ventilation (early extubation, increased use of continuous positive airway pressure [CPAP]), and fluid management may decrease the incidence and severity of bronchopulmonary dysplasia.

• Maximizing nutritional support, careful monitoring of fluid intake, and judicious use of diuretics promote lung healing.

• Evidence regarding the use of high-frequency ventilation, inhaled nitric oxide (iNO), and antioxidants (other than vitamin A) to prevent bronchopulmonary dysplasia is inconclusive.

Infection

Infants with bronchopulmonary dysplasia (BPD) are at high risk of respiratory infections in the first 2 years of life. Note the following:

• In infants with bronchopulmonary dysplasia, infection with a respiratory syncytial virus (RSV) may cause severe illness and even death.

• Monthly injections of RSV antibody may prevent or reduce the risk of rehospitalization in infants with bronchopulmonary dysplasia and may mitigate the severity of illness.

• The American Academy of Pediatrics (AAP) has issued a policy statement about the use of RSV antibody injections during RSV season (November to March) in preterm infants discharged from the NICU.

Growth and development

Poor growth and delayed development are frequently observed in infants with bronchopulmonary dysplasia, especially those with markedly abnormal pulmonary function. In addition, many infants may have worsening pulmonary function with liberalization of fluid intake and repeated pulmonary infections. Use of diuretics, high-energy formulas, and breast-milk additives are the mainstays of treatment in and out of the hospital.

Infants with bronchopulmonary dysplasia are at high risk for abnormal neurodevelopment.

At 18-22 months' corrected age in extremely low birth weight infants, abnormal growth occurred in 50-60% of infants with bronchopulmonary dysplasia. The risk of neurodevelopmental impairment, cerebral palsy, and low intelligent quotient (IQ) more than doubled in infants with severe bronchopulmonary dysplasia compared with infants with mild bronchopulmonary dysplasia.

Many drug therapies are used to treat infants with severe bronchopulmonary dysplasia (BPD). The efficacy, exact mechanisms of action, and potential adverse effects of these drugs have not been definitively established. A study group from the NICHD and US Food and Drug Administration (FDA) reviewed many of the drugs used to prevent and treat bronchopulmonary dysplasia. Walsh and colleagues concluded that detailed analyses of many of these treatments, as well as long-term follow-up, are needed.[27]

Vitamin A supplementation

Seven trials of vitamin A supplementation in preterm neonates to prevent bronchopulmonary dysplasia were analyzed for the Cochrane Collaborative Neonatal review. Vitamin A supplementation reduced bronchopulmonary dysplasia and death at 36 weeks' postmenstrual age.

Diuretics

Furosemide (Lasix) is the treatment of choice for fluid overload in infants with bronchopulmonary dysplasia. It is a loop diuretic that improves clinical pulmonary status and function and decreases pulmonary vascular resistance. Daily or alternate-day furosemide therapy may facilitate weaning from positive pressure ventilation (PPV), oxygenation, or both. Adverse effects of long-term therapy are frequent and include hyponatremia, hypokalemia, contraction alkalosis, hypocalcemia, hypercalciuria, renal stones, nephrocalcinosis, and ototoxicity. Careful parenteral and enteral nutritional supplementation is required to maximize the benefits instead of exacerbating the adverse effects.

Thiazide diuretics plus aldosterone inhibitors (eg, spironolactone [Aldactone]) have also been used in infants with bronchopulmonary dysplasia. In several trials of infants with bronchopulmonary dysplasia, thiazide diuretics combined with spironolactone increased urine output with or without improvement in pulmonary mechanics. Hoffman et al reported that spironolactone did not reduce the need for supplemental electrolytes in preterm infants with bronchopulmonary dysplasia.[28] To the present authors' knowledge, long-term studies to compare the efficacy of furosemide with those of thiazide and spironolactone therapy have not been performed.

Bronchodilators

Albuterol is a specific beta2-agonist used to treat bronchospasm in infants with bronchopulmonary dysplasia. Albuterol may improve lung compliance by decreasing airway resistance by relaxing smooth muscle cell. Changes in pulmonary mechanics may last as long as 4-6 hours. Adverse effects include increased blood pressure (BP) and heart rate. Ipratropium bromide is a muscarinic antagonist that is related to atropine; however, it may have bronchodilator effects more potent than those of albuterol. Improvements in pulmonary mechanics were demonstrated in patients with bronchopulmonary dysplasia after they received ipratropium bromide by inhalation. Combined therapy with albuterol and ipratropium bromide may be more effective than either agent alone. Few adverse effects are noted.

Methylxanthines are used to increase respiratory drive, decrease apnea, and improve diaphragmatic contractility. These substances may also decrease pulmonary vascular resistance and increase lung compliance in infants with bronchopulmonary dysplasia, probably by directly causing smooth muscle to relax. Methylxanthines also have diuretic effects. All of these effects may increase success in weaning patients from mechanical ventilation.

Synergy between theophylline and diuretics has been demonstrated. Theophylline has a half-life of 30-40 hours. It is metabolized primarily to caffeine in the liver and may result in adverse effects such as increase in heart rate, gastroesophageal reflux, agitation, and seizures. The half-life of caffeine is approximately 90-100 hours, and caffeine is excreted unchanged in the urine. Both agents are available in intravenous and enteral formulations. Caffeine has fewer adverse effects than theophylline. Schmidt and colleagues reported that the early use of caffeine to treat apnea of prematurity appeared to reduce ventilatory requirements and that it may decrease the incidence of bronchopulmonary dysplasia.[29]

Corticosteroids

Systemic and inhaled corticosteroids have been studied extensively in preterm infants to prevent and treat bronchopulmonary dysplasia.

Dexamethasone is the primary systemic synthetic corticosteroid studied in preterm neonates. Dexamethasone has many pharmacologic benefits but clinically significant adverse effects. This drug stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, inhibits prostaglandin and leukotriene, decreases pulmonary edema (PE), breaks down granulocyte aggregates, and improves pulmonary microcirculation. Its adverse effects are hyperglycemia, hypertension, weight loss, GI bleeding or perforation, cerebral palsy, adrenal suppression, and death.

Many researchers have evaluated the effects of early administration of dexamethasone to prevent bronchopulmonary dysplasia, often demonstrating short-term improvements in clinical outcome. However, Papile and associates reported that early use of dexamethasone during the first 2 weeks of life did not prevent bronchopulmonary dysplasia and may worsen neurologic outcome.[30] Infants who received a combination of dexamethasone and indomethacin were at increased risk of spontaneous intestinal perforation. Neurodevelopmental follow-up studies of infants treated with prolonged and high-dose dexamethasone suggest that, though this therapy improves short-term pulmonary outcome, long-term outcome appears to considerably worsen.

The routine use of dexamethasone in infants with bronchopulmonary dysplasia is currently not recommended. The American Academy of Pediatrics and the Canadian Society of Pediatrics do not advocate the routine use of corticosteroids in preterm neonates to treat bronchopulmonary dysplasia.[31, 32] Despite these recommendations, dexamethasone is still used in carefully selected patients who have substantially increased ventilatory requirements at about 1 month of age.

Studies of inhaled glucocorticoid therapy have suggested that the only beneficial effect was a reduction in the use of systemic corticosteroids in infants receiving inhaled steroids. A recent randomized trial by Bassler et al indicates that inhaled budesonide as a long-term therapy reduces BPD, but at the expense of a small increase in mortality.[33]

Vasodilators

Inhaled nitric oxide (iNO) is a short-acting gas that relaxes the pulmonary vasculature. It may also act as an anti-inflammatory agent at low concentrations.

Multiple randomized controlled trials of iNO in preterm infants have been performed using varying entry criteria and outcomes. The results are mixed. Although certain selected subgroups may benefit, whether the sickest and smallest infants at greatest risk of bronchopulmonary dysplasia benefit from iNO remains unclear.

Class Summary

Diuretics promote excretion of water and electrolytes by the kidneys. They are used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention results in edema or ascites.

Furosemide (Lasix)

Loop diuretic often used for fluid overload in infants with BPD. Therapy qd or qod improves respiratory function and may facilitate weaning from PPV, oxygen, or both. Increases excretion of water by interfering with chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.

Class Summary

Bronchodilators decrease muscle tone in both the small and large airways in the lungs, increasing ventilation. This category includes beta-adrenergic agents, methylxanthines, and anticholinergics.

Albuterol (Proventil, Ventolin)

Specific beta2-agonist used to treat bronchospasm in infants with BPD. May improve lung compliance by decreasing airway resistance secondary to smooth muscle cell relaxation. With current strategies for aerosol administration, exactly how much is delivered to airways and lungs of infants with BPD (especially if ventilator dependent) is unclear. Because clinically significant smooth muscle relaxation does not appear to occur in first few weeks of life, do not start aerosol therapy before this time unless patient has profound respiratory illness.

Caffeine citrate (Cafcit)

CNS stimulant used to treat infants with apnea of prematurity and infants with BPD. Caffeine may facilitate weaning from ventilator.

Theophylline (Elixophyllin, Theo-Dur)

Systemic bronchodilator. Used to treat apnea of prematurity. May improve contractility of skeletal muscle and decrease diaphragmatic fatigue in infants with BPD. May facilitate weaning infant with BPD from continuous mechanical ventilation.

Monitor serum levels and adjust on basis of infant's response; therapeutic levels approximately 5-12 mcg/mL. IV dose based on theophylline equivalent.

Ipratropium bromide (Atrovent)

Muscarinic antagonist with potent bronchodilating effects. May improve pulmonary mechanics in infants with BPD. Inhaled drug poorly absorbed systemically.

Class Summary

Corticosteroids are produced by the adrenal gland. Mineralocorticoids are produced in the adrenal medulla and primarily affect fluid and electrolyte balance. Glucocorticoids possess strong anti-inflammatory properties and affect the metabolism of many tissues.

Dexamethasone (Decadron)

Stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, inhibits prostaglandin and leukotriene, breaks down granulocyte aggregates, and improves pulmonary microcirculation. Has many pharmacologic benefits but clinically significant adverse effects: hyperglycemia, hypertension, weight loss, GI bleeding or perforation, cerebral palsy, adrenal suppression, and death.

Class Summary

Preterm infants are deficient in vitamin A.

Vitamin A (Palmitate-A 5000)

Intramuscular vitamin A supplementation reduces incidence of BPD. Firm dosing guidelines not established; most centers use the NICHD NRN protocol of 5000 IU three times per week for the first four weeks (total 12 doses).