Pediatrics

Bronchopulmonary dysplasia

Overview. What every practitioner needs to know.

Bronchopulmonary dysplasia (BPD) is diagnosed based on the need for supplemental oxygen at 36 weeks' postmenstrual age. The majority of infants diagnosed with BPD are born at less than 28 weeks' gestation.

Are you sure your patient has bronchopulmonary dysplasia? What are the typical findings for this disease?

Physical examination usually reveals signs of respiratory distress, including tachypnea, subcostal and intercostal retractions, and coarse breath sounds or rales on auscultation. In almost all cases, these signs will be accompanied by an abnormal chest radiograph (see imaging studies below). An arterial blood gas determination typically shows hypoxemia and hypercarbia, with later metabolic compensation for respiratory acidosis.

Pulmonary function testing typically shows increased respiratory system resistance and decreased dynamic compliance. More severe cases may be complicated by pulmonary hypertension, which can lead to the development of cor pulmonale.

Affected infants are more likely to have long-term pulmonary problems, to be rehospitalized during the first year of life, and to have delayed neurodevelopment. Sequelae of BPD may include pulmonary arterial hypertension and right-sided cardiac failure.Pathologic changes in long-term survivors include interstitial fibrosis, hyperinflation, reduced number of alveoli, reduction in alveolar surface area, arrested acinar development, pseudofissures, airway hyperplasia, and atelectasis. Tracheobronchomegaly, tracheobronchomalacia, and ciliary dysfunction are associated findings.

Definition of bronchopulmonary dysplasia

BPD is a chronic lung disease that affects newborn infants, predominantly those born prematurely. When first described in the 1960s, the diagnosis of BPD was assigned to infants who required supplemental oxygen and/or mechanical ventilation for at least 1 week and continued to require oxygen at 28 days' postnatal age. The definition has evolved as smaller and less mature infants have survived. Infants are now diagnosed with BPD if they need supplemental oxygen at 36 weeks' postmenstrual age (PMA).

A definition of BPD based on gestational age and severity was developed by a National Institutes of Health consensus conference and applies to infants who receive supplemental oxygen for the first 28 postnatal days. Infants born at less than 32 weeks' gestation are evaluated at 36 weeks' PMA: infants with mild BPD have no need for supplemental oxygen, those with moderate BPD require supplemental oxygen at less than 30%, and those with severe BPD need oxygen at greater than 30%, or positive pressure either as continuous positive airway pressure (CPAP) or mechanical ventilation.

For infants born at greater than 32 weeks' gestation, BPD severity is based on the receipt of oxygen at 56 days of age. This definition accounts for infants who are born at late preterm or term gestation who have severe lung disease at birth (e.g., pneumonia, meconium aspiration syndrome) requiring mechanical ventilation. However, most infants diagnosed with BPD are born at less than 28 weeks' gestation.

Since the definition of BPD is based on the receipt of supplemental oxygen, the diagnosis may be affected by the target oxygen saturations set by the clinician or by altitude. For this reason, a physiologic definition of BPD has been proposed, in part to achieve uniform diagnoses in clinical studies. Using this definition, an infant born at 36 weeks' PMA receiving effective supplemental oxygen of less than 30% would be classified as not having BPD if oxygen saturations could be maintained at greater than 90% in room air after supplemental oxygen was slowly withdrawn. Using a physiologic definition of BPD decreases its diagnosis by up to 20%.

What other disease/condition shares some of these symptoms?

The differential diagnosis includes congenital and acquired lung diseases. Congenital lobar emphysema, bronchogenic cyst, pulmonary lymphangiectasia, or bronchiectasis may mimic some of the radiographic changes seen in BPD.

Chronic aspiration pneumonia, unrepaired tracheal esophageal fistula, viral pneumonia, or idiopathic pulmonary fibrosis or pulmonary hypertension may also cause a persistent oxygen requirement in newborn infants and should be considered in infants with an atypical course for BPD.

What caused this disease to develop at this time?

The pathogenesis of BPD is multifactorial. Inflammation of the lung resulting from ventilator-induced mechanical injury, oxidant stress, and prenatal or postnatal infection all contribute to the pathogenesis. Elevated inflammatory markers (interleukin-8 and interleukin-6, tumor necrosis factor, and leukotrienes) in amniotic fluid, cord blood, and tracheal secretions of infants receiving mechanical ventilation have also been linked to the development of BPD. Nutritional deficiencies, genetic factors, and abnormal growth factor signaling also may play a role. Infants born before complete alveolarization of the lung (<26 weeks) are most at risk; lung injury at this stage may lead to an arrest of normal alveolarization, which occurs with lung growth.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Arterial or capillary blood gas analysis shows hypoxemia and hypercarbia, with metabolic compensation for the respiratory acidosis in the chronic phase of BPD. This may result in hypochloremia, a high total bicarbonate level, and a low serum potassium level on blood electrolyte determination.

Would imaging studies be helpful? If so, which ones?

Chest radiographs are almost always abnormal in infants with BPD (Figure 1). As smaller and less mature infants survive, the typical clinical presentation and radiographic findings of BPD have changed. In the "old" form of BPD, injury from mechanical ventilation predominated; chest radiographs showed evidence of interstitial scarring, with streaky densities, hyperlucencies, and hyperinflation. In the "new" BPD seen in extremely preterm infants, chest radiographs often show less evidence of lung injury, with diffuse haziness the predominant abnormality and normal to low lung volumes. In very severe cases, however, these changes may evolve as lung injury progresses.

Figure 1.

Bronchopulmonary dysplasia.

If you are able to confirm that the patient has bronchopulmonary dysplasia, what treatment should be initiated?

The goals of treatment during the neonatal intensive care unit course are to minimize additional lung injury and oxygen consumption and maximize nutritional support.

Many infants with developing BPD require positive pressure ventilation, either in the form of mechanical ventilation or CPAP. The goal is to use the minimum amount of support necessary to maintain adequate ventilation (PCO2 targets ~55 mm Hg, with pH >7.25). Synchronized intermittent mandatory ventilation with a time-cycled pressure-limited ventilator is the usual mode of mechanical support, although pressure-support ventilation may be useful in older infants with BPD. Mechanical support is slowly weaned as lung function and growth improve.

Supplemental oxygen is supplied to maintain the PaO2at greater than 55 mm Hg. Generally, this can be accomplished by maintaining oxygen saturations at 90%-95%, although higher targets may be used if an infant has echocardiographic evidence of pulmonary hypertension.

The presence of a symptomatic patent ductus arteriosus (PDA) is associated with a higher incidence of BPD. However, medical (indomethacin or ibuprofen) or surgical treatment, either prophylaxis or therapeutic, does not decrease the incidence of BPD. Appropriate management of a PDA in a premature infant with respiratory disease remains controversial.

Fluid restriction to as low as 120-130 mL/kg/d may be necessary to prevent pulmonary edema and increased oxygen needs. High caloric density feedings (up to 30 cal/oz) are usually needed for adequate nutritional support if fluids are significantly restricted.

Caffeine citrate may improve respiratory drive and facilitate earlier extubation. One randomized trial of caffeine started in the first 10 days after birth in infants weighing less than 1250 g at birth showed a decreased incidence of BPD in caffeine-treated infants.

Diuretics may be used to treat pulmonary fluid retention. Doses of furosemide (1-2 mg/kg enterally or 0.5-1 mg/kg intramuscularly or intravenously may acutely improve respiratory distress and decrease the oxygen requirement in infants with BPD, although chronic use should be avoided because of side effects. Thiazide diuretics (chlorothiazide or hydrochlorothiazide) are also used in BPD for chronic therapy. However, diuretics have not been shown to improve clinical outcomes, such as duration of ventilator dependence and oxygen therapy or hospital length of stay, and should be reserved for more severe cases. Infants receiving diuretics may need enteral supplementation with chloride in the form of potassium chloride to avoid hypochloremic metabolic alkalosis.

Some clinicians use bronchodilators, such as nebulized β-adrenergic agonists, if increased respiratory resistance or evidence of bronchospasm exists. No evidence exists for any benefit to this therapy other than mild transient acute improvements in resistance and compliance in some infants.

Systemic glucocorticoids (primarily dexamethasone) have been extensively studied in masked randomized trials to prevent BPD and treat established BPD. Infants treated with glucocorticoids are extubated sooner, but no substantial impact on long-term pulmonary outcomes has been observed.

Although neurodevelopmental follow-up was not performed in many studies of glucocorticoid treatment for BPD, data suggest that premature infants treated with dexamethasone may have a higher incidence of neurodevelopmental impairment, including the development of cerebral palsy. Because of this potential harm and lack of well-established long-term benefit, routine use of corticosteriods to treat BPD is discouraged. Hydrocortisone may have a better safety profile than dexamethasone and may be preferred if steroid treatment is considered in infants with severe respiratory that is refractory to other therapies.

Inhaled glucocorticoids have no short- or long-term benefit in infants with BPD.

What are the adverse effects associated with each treatment option?

Short- and long-term diuretic use may result in electrolyte disturbances, including hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis.These abnormalities may be partially ameliorated by electrolyte supplementation. Furosemide treatment increases urinary calcium excretion. Long-term use is associated with bone mineral loss and nephrocalcinosis.

Systemic glucocorticoid treatment may have short-term side effects, including hypertension, hyperglycemia, and spontaneous intestinal perforation (especially when given with indomethacin). As noted above, treatment with corticosteroids in preterm infants either at risk for or with established BPD is associated with a higher incidence of neurodevelopmental impairment.

What are the possible outcomes of bronchopulmonary dysplasia?

Infants with milder BPD gradually improve during the first year of life. Their dependence on supplemental oxygen resolves with continued lung growth. Infants with severe BPD may require supplemental oxygen for months to years. Pulmonary hypertension may develop in these infants, which if severe may result in right heart failure, and cor pulmonale.

Rarely, infants require tracheotomy for chronic long-term mechanical ventilation. This is more common in infants in whom tracheobronchomalacia develops as a complication of mechanical ventilation and airway injury.

Infants with BPD have a higher incidence of wheezing and reactive airway disease in childhood and may have diminished pulmonary function that persists into adulthood. Mortality is estimated at 10%-20% during the first year of life. However, most infants with BPD will recover lung function with growth over time.

Infants with BPD are at higher risk for respiratory infections (particularly from respiratory syncticial virus) and are more frequently rehospitalized in the first year after discharge from the hospital compared with premature infants without BPD.

Early growth failure may result from inadequate nutritional intake and increased energy expenditure, which may persist after clinical resolution of pulmonary disease.

The rate of cognitive, behavioral, and educational abnormalities is higher in children with BPD than in those without this disease.

What causes this disease and how frequent is it?

Approximately 15,000 new cases of BPD occur in the United States each year. Infants weighing less than 1250 g at birth, or birth at less than 28 weeks' gestation, are most at risk. The relative risk is less in African American and female infants.

The incidence of BPD varies widely among neonatal intensive care units, suggesting that local clinical practices may influence the development of BPD. In a report from the National Institute of Child Health & Human Development Neonatal Research Network, among infants of gestational age 22 to 28 weeks, 42% had BPD based on receipt of oxygen at 36 weeks' PMA, whereas 68% had BPD using the severity-based definition

Although data suggest a genetic component to the risk of BPD, specific genotypes or phenotypes have not been elucidated.

The pathogenesis of BPD is multifactorial. Inflammation of the lung resulting from ventilator-induced mechanical injury, oxidant stress, and prenatal or postnatal infection all contribute to the pathogenesis of BPD. Elevated inflammatory markers (interleukin-8 and interleukin-6, tumor necrosis factor, and leukotrienes) in amniotic fluid, cord blood, and tracheal secretions of infants receiving mechanical ventilation have also been linked to the development of BPD, suggesting a role for inflammation in its pathogenesis. Nutritional deficiencies, genetic factors, and abnormal growth factor signaling also may play a role.

Infants born before complete alveolarization of the lung (<26 weeks' gestation) are most at risk; lung injury at this stage may lead to an arrest of normal alveolarization, which occurs with lung growth.

How do these pathogens/genes/exposures cause the disease?

Mechanical injury to the developing lung by positive pressure ventilation is a major factor in the development of BPD. The preterm lung has diminished antioxidant defenses, which may result in oxygen toxicity in addition to mechanical injury to the lung. Prenatal infection may also lead to Inflammatory changes. However, the precise cause of BPD is unknown.

How can bronchopulmonary dysplasia be prevented?

Several strategies may reduce the development of BPD.

Judicious use/limitation of mechanical ventilation may help. Despite observational studies that suggest that early use of CPAP rather than mechanical ventilation is associated with a decreased risk of BPD in preterm infants with respiratory distress syndrome, randomized trials have not showed an effect on the incidence of BPD.

Supplemental vitamin A (1500 IU 3 times a week for 12 doses) was shown in a randomized trial to have a small benefit in the risk of BPD development in infants weighing less than 1000 g at birth.

Caffeine citrate treatment started in the first 10 days of life in infants weighing less than 1250 g reduced the rate of BPD in a randomized trial.

What is the evidence?

Schmidt, B, Roberts, RS, Davis, P. "Caffeine therapy for apnea of prematurity". N Engl J Med. vol. 354. 2006. pp. 2112-21.

Schmidt, B, Davis, P, Moddemann, D. "Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants". N Engl J Med. vol. 344. 2001. pp. 1966-72.

Watterberg, K. "Committee on Fetus and Newborn. Policy statement—postnatal corticosteroids to prevent or trreat bronchopulmonary dysplasia". Pediatrics. vol. 126. 2010. pp. 800-8.

Tyson, JE, Wright, LL, Oh, W. "Vitamin A supplementation for extremely-low-birth-weight infants". N Engl J Med. vol. 340. 1999. pp. 1962-8.

Ongoing controversies regarding etiology, diagnosis, treatment

Current controversies in the prevention and management of BPD include the optimal strategy for use of mechanical ventilation and/or CPAP in infants at risk; the role of a PDA in the pathogenesis of BPD and whether aggressive management of a symptomatic PDA improves outcome; the role of additional respiratory therapies, including inhaled nitric oxide or additional surfactant, in the prevention and management of BPD; and whether alternative corticosteroid treatments (other than dexamethasone) might decrease the risk of BPD without long-term adverse effects.

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