84: Bronchopulmonary Dysplasia/Chronic Lung Disease

Classic bronchopulmonary dysplasia (BPD) is a neonatal form of chronic pulmonary disorder that follows a primary course of respiratory failure (eg, respiratory distress syndrome [RDS], meconium aspiration syndrome) in the first days of life. It is sometimes referred to as chronic lung disease (CLD) of prematurity. A “new” form of BPD has been described in extremely low birthweight infants. This occurs in infants who initially had none or modest initial ventilatory and oxygen needs. BPD is defined as persistent oxygen dependency up to 28 days of life. The severity of BPD-related pulmonary dysfunction in early childhood is more accurately predicted by an oxygen dependence at 36 weeks' postmenstrual age (PMA) in infants <32 weeks' gestational age (GA) and at 56 days of age in infants with older GA. BPD is thus classified at this later postnatal age according to the type of respiratory support required to maintain a normal arterial oxygen saturation (89%).

1. Mild BPD. Infants who have been weaned from any supplemental oxygen.

2. Moderate BPD. Infants who continue to need up to 30% oxygen.

3. Severe BPD. Infants whose requirements exceed 30% and/or include continuous positive airway pressure or mechanical ventilation.

The incidence of BPD is influenced by many risk factors, the most important of which is lung maturity. The incidence of BPD increases with decreasing birth- weight and affects ∼30% of infants with birthweights <1000 g. The large variability in rates among centers is partly related to differences in clinical practices, such as criteria used for the management of mechanical ventilation.

A primary lung injury is not always evident at birth. The secondary development of a persistent lung injury is associated with an abnormal repair process and leads to structural changes such as arrested alveolarization and pulmonary vascular dysgenesis.

1. The major factors contributing to BPD are as follows:

   1. Inflammation. Central to the development of BPD. An exaggerated inflammatory response (alveolar influx of numerous proinflammatory cytokines as well as macrophages and leukocytes) occurs in the first few days of life in infants in whom BPD subsequently develops.

   2. Mechanical ventilation. Volutrauma/barotrauma is one of the key risk factors for the development of BPD. Minimizing the use of mechanical ventilation by the use of early nasal continuous positive airway pressure, noninvasive ventilatory support (nasal intermittent positive pressure ventilation), and early use of methylxanthines (caffeine) has led to fewer days of mechanical ventilation and to lesser use of postnatal steroids.

   3. Oxygen exposure. Classic BPD observed before the availability of exogenous surfactant treatment was always associated with prolonged exposure (>150 hours) to an Fio₂ >60%. Hyperoxia can have major effects on lung tissue, such as proliferation of alveolar type II cells and fibroblast, alterations in the surfactant system, increases in inflammatory cells and cytokines, increased collagen deposition, and decreased alveolarization and microvascular density. Today, in the postsurfactant era, exposure to prolonged high oxygen is limited, and a new form of BPD is being observed. For this “new” BPD, the association between persistent need for mechanical ventilation and supplemental oxygen in the first 2 weeks of life is not as dominant as in the past. For instance, a third of the preterm infants receiving either supplemental oxygen or intermittent positive pressure ventilation at 14 days did not develop BPD, whereas 17% of the infants in room air at 14 days of age did. Nevertheless, aiming for Spo₂ in the range of 85–93% rather than >92% has led to a decrease in the need for supplemental oxygen at 36 weeks' PMA in this postsurfactant era. The advantages off keeping Spo₂ at the lower range, for BPD (and retinopathy of prematurity) prevention, needs to be carefully weighed against the possibility that keeping Spo₂ in the range of 85–89% may be associated with higher mortality.

2. Pathologic changes. Compared with the presurfactant era, lungs of infants currently dying from BPD have normal-appearing airways, less fibrosis, and more uniform inflation. However, these lungs have deficient septation, leading to fewer and larger alveoli with possible reduced pulmonary capillarization that may lead to pulmonary hypertension.

Major risk factors are prematurity, white race, male sex, chorioamnionitis, tracheal colonization with Ureaplasma, and the increased survival of the extremely low birthweight infant. Other risk factors are RDS, excessive early intravenous fluid administration, symptomatic patent ductus arteriosus (PDA), sepsis, oxygen therapy, vitamin A deficiency, and a family history of atopic disease.

BPD is usually suspected in infants with progressive and idiopathic deterioration of pulmonary function. Infants in whom BPD develops often require oxygen therapy or mechanical ventilation beyond the first week of life. Severe cases of BPD are usually associated with poor growth, pulmonary edema, and a hyperreactive airway.

1. Physical examination

   1. General signs. Worsening respiratory status is manifested by an increase in the work of breathing, in oxygen requirement, or in apnea-bradycardia, or in a combination of these signs.

   2. Pulmonary examination. Retractions and diffuse fine rales are common. Wheezing or prolongation of expiration may also be noted.

   3. Cardiovascular examination. A right ventricular heave, single S₂, or prominent P₂ may accompany cor pulmonale.

   4. Abdominal examination. The liver may be enlarged secondary to right-sided heart failure or may be displaced downward into the abdomen secondary to lung hyperinflation.

2. Laboratory studies. These studies are intended to rule out differential diagnosis such as sepsis or PDA during the acute nature of the disease and to detect problems related to BPD or its therapy.

   1. Arterial blood gas levels. Frequently reveal carbon dioxide retention. However, if the respiratory difficulties are chronic and stable, the pH is usually subnormal (pH ≥7.25).

   2. Electrolytes. Abnormalities of electrolytes may result from chronic carbon dioxide retention (elevated serum bicarbonate), diuretic therapy (hyponatremia, hypokalemia, or hypochloremia), or fluid restriction (elevated urea nitrogen and creatinine), or all 3.

   3. Complete blood count and differential. To diagnose neutropenia or an elevated white blood count in sepsis.

   4. Urinalysis. Microscopic examination may reveal the presence of red blood cells, indicating a possible nephrocalcinosis as a result of prolonged diuretic treatment.

3. Imaging and other studies. To detect problems related to BPD or its therapy.

   1. Chest radiograph. Radiographic findings may be quite variable. Most frequently, BPD appears as diffuse haziness and lung hypoinflation in infants who were very immature at birth and have persistent oxygen requirements. In other infants, a different picture is seen, reminiscent of that originally described by Northway: streaky interstitial markings, patchy atelectasis intermingled with cystic area, and severe overall lung hyperinflation. Because those findings persist for a prolonged period, new changes (eg, a secondary infection) are difficult to detect without the benefit of comparison to previous radiographs. (See Figure 11–17 for an example of BPD.)

   2. Renal ultrasonography. Radiologic studies of the abdomen should be considered during diuretic therapy to detect the presence of nephrocalcinosis. It should be performed when red blood cells are present in the urine.

   3. Electrocardiography and echocardiography. Indicated in nonimproving or worsening BPD. Electrocardiograms and echocardiograms could detect cor pulmonale and/or pulmonary hypertension, manifested by right ventricular hypertrophy and elevation of pulmonary artery pressure with right axis deviation, increased right systolic time intervals, thickening of the right ventricular wall, and abnormal right ventricular geometry.

1. Prevention of BPD

   1. Prevention of prematurity and RDS. Therapies directed toward decreasing the risk of prematurity and lowering the incidence of RDS include improving prenatal care and antenatal corticosteroids.

   2. Reducing exposure to risk factors. Successful measures should include minimizing exposure to oxygen by limiting SpaO2 to 90–95%, ventilation strategies that minimize the use of excessive tidal volume (above 4–6 mL/kg), prudent administration of fluids, aggressive closure of PDA (controversial), and adequate nutrition. Early surfactant replacement therapy may be beneficial, but the avoidance of intubation and mechanical ventilation with the initiation of continuous positive airway pressure (CPAP) shortly after birth may prove to be an effective preventive strategy.

   3. Vitamin A. Low blood levels of vitamin A seen in extremely low birthweight infants have been associated with increased risk of BPD. Vitamin A supplementation, 5000 IU administered intramuscularly 3 times per week for 4 weeks, significantly reduced the rate of BPD. Its effects were modest. One additional infant survived without BPD for every 15 extremely low birthweight infants treated; however, no long-term beneficial respiratory or neurodevelopmental outcomes have been found.

   4. Caffeine. Methylxanthines decrease the frequency of apnea and allow for shorter duration of mechanical ventilation, leading to a reduced rate of BPD.

   5. Inhaled nitric oxide (iNO). Its use to prevent BPD remains controversial. Although inhaled nitric oxide has been shown in animal models to reduce pulmonary vascular tone and prevent lung inflammation, its clinical benefits remain equivocal and do not justify the cost. At present, routine use of iNO for preterm infants at risk for BPD is not recommended.

2. Treatment of BPD. Once BPD is present, the goal of management is to prevent further injury by minimizing respiratory support, improving pulmonary function, preventing cor pulmonale, and emphasizing growth and nutrition.

   1. Respiratory support

      1. Supplemental oxygen. Maintaining adequate oxygenation is important in the infant with BPD to prevent hypoxia-induced pulmonary hypertension, bronchospasm, cor pulmonale, and growth failure. However, the least-required oxygen should be delivered to minimize oxygen toxicity. Spo₂ should be monitored during the infant's various activities, including rest, sleep, and feeding, and should be maintained in the range of 90–95%. Infrequent blood gas measurements are important for the assessment of trends in pH, Paco₂, and serum bicarbonate, but they are of limited use in monitoring oxygenation because they provide information about only one point in time.

      2. Positive-pressure ventilation. Mechanical ventilation should be used only when clearly indicated. Similarly, inspiratory pressure needs to be limited at the expense of tolerating Paco₂ of 50–60 mm Hg (controversial). Nasal CPAP can be useful as an adjunctive therapy after extubation.

   2. Improving lung function

      1. Fluid restriction. Restricting fluid to 120 mL/kg/d is often required. It can be accomplished by concentrating proprietary formulas to 24 cal/oz. Increasing the caloric density further to 27–30 cal/oz may require the addition of fat (eg, medium-chain triglyceride oil or corn oil) and carbohydrate (eg, Polycose) to avoid excessive protein intake.

      2. Diuretic therapy. See Chapter 148 for dosing.

         1. Furosemide. Furosemide (1–2 mg/kg every 12 hours, orally or intravenously) is a potent diuretic that is particularly useful for rapid diuresis. It is associated with side effects such as electrolyte abnormalities, interference with bilirubin-albumin binding capacity, calciuria with bone demineralization and renal stone formation, and ototoxicity. When used as a chronic medication, Na⁺ and K⁺ supplementation are often required.

         2. Bumetanide. Bumetanide 0.015–0.1 mg/kg daily or every other day, orally or intravenously. When administered orally, 1 mg of bumetanide (Bumex) has a diuretic effect similar to that of 40 mg of furosemide. Whereas furosemide's bioavailability is 30–70%, bumetanide's bioavailability is >90%. Bumetanide produces side effects similar to those of furosemide, except that it may produce less ototoxicity and less interference with bilirubin-albumin binding.

         3. Chlorothiazide and spironolactone. When used in doses of 20 mg/kg/d (chlorothiazide) and 2 mg/kg/d (spironolactone), a good diuretic response can often be achieved. Although less potent than furosemide, this combination is often better suited for chronic management because it has relatively fewer side effects. It may be the diuretic combination of choice when the calciuric effect of furosemide has led to the development of nephrocalcinosis.

      3. Bronchodilators. See doses in Table 8–3.

         1. β₂-Agonists. Inhaled β₂-agonists (eg, albuterol) produce measurable acute improvements in lung mechanics and gas exchange in infants with BPD exhibiting symptoms of increased airway tone. Their effect is usually time limited. Because of their side effects (eg, tachycardia, hypertension, hyperglycemia, and possible arrhythmia), their use should be limited to the management of acute exacerbations of BPD. Xopenex (levalbuterol) is a nonracemic form of albuterol recently introduced in pediatric and adult populations. Its experience in newborns is limited. Its potential advantages are better and it has longer efficacy; hence lower doses have a therapeutic effect, enabling a significant reduction in the adverse effects associated with racemic albuterol. If bronchodilators are being used long term, a frequent reevaluation of their benefit is essential.

         2. Anticholinergic agents. The best studied and most available inhaled quaternary anticholinergic is ipratropium bromide (nebulized Atrovent). Its bronchodilatory effect is more potent than that of atropine and similar to that of albuterol. Combined albuterol and ipratropium therapy has a larger effect than either agent alone. Unlike atropine, systemic effects do not occur because of its poor systemic absorption.

         3. Methylxanthine. The beneficial actions of theophylline include smooth airway muscle dilation, improved diaphragmatic contractility, central respiratory stimulation, and mild diuretic effects. It appears to improve lung function in BPD when levels are maintained at >10 mcg/mL. Side effects are fairly common and may include central nervous system (CNS) irritability, gastroesophageal reflux, and gastrointestinal irritation. Prevention of apnea rather than bronchodilation is the major reason for infants with BPD to receive a methylxanthine treatment (mostly caffeine).

      4. Corticosteroids. Although very efficient, the use of postnatal steroids should be limited to infants who are at high risk for mortality secondary to severe lung disease and who cannot be weaned from mechanical ventilation after 7 days of age. Parents should be informed that the use of postnatal steroids could be associated with impaired brain and somatic growth and increased incidence of cerebral palsy. Although dexamethasone has been the most studied postnatal steroids to treat BPD, various therapy regimens using milder types of steroids have been proposed, hoping to decrease the observed adverse effects. However, the beneficial effects of these mild steroids on extubation, duration of mechanical ventilation, BPD, and death have not been prospectively studied.

         1. Dexamethasone. Initiate at >7 days of age at 0.25 mg/kg twice daily for 3 days and then gradually taper by 10% every 3 days for a total course of 42 days. It is one of the original regimens that have proven efficacious in the treatment of BPD. Decrease brain growth and increased incidence of cerebral palsy has been associated with dexamethasone treatment. Its early use (<7 days) increases the risk of spontaneous gastrointestinal perforation, in particular when used in conjunction with prostaglandins inhibitor such as indomethacin. Other side effects include infection, hypertension, gastric ulcer, hyperglycemia, adrenocortical suppression, lung growth suppression, and hypertrophic cardiomyopathy. Lower doses and shorter duration of dexamethasone have been attempted to decrease its undesirable effects.

         2. Methylprednisolone (Solu-Medrol). A corticosteroid with much weaker genomic activity than dexamethasone, methylprednisolone has almost similar nongenomic activity and thus possibly fewer CNS and somatic side effects. In a pilot study, methylprednisolone, 0.6, 0.4, 0.2 mg/kg/dose every 6 hours, respectively, for 3 consecutive days, followed by betamethasone, 0.1 mg/kg orally every other day for a total of 21 days, was found to have similar beneficial effects and fewer side effects (eg, periventricular leukomalacia, hyperglycemia) than dexamethasone. These findings still need to be confirmed by large randomized controlled trials.

         3. Hydrocortisone. Hydrocortisone 5 mg/kg/d divided every 6 hours for 1 week, and then gradually tapered for the following 2–5 weeks. In contrast to infants treated with dexamethasone, when compared with controls, hydrocortisone therapy has not been associated with adverse neurodevelopmental outcome or with brain abnormalities on magnetic resonance imaging in long-term follow-up studies up to 5–8 years of age.

         4. Prednisolone. Prednisolone 2 mg/kg/d orally divided twice per day for 5 days, then 1 mg/kg/dose orally daily for 3 days, and then 1 mg/kg/dose every other day for 3 doses has been used to wean from oxygen therapy before discharge home.

         5. Nebulized corticosteroids. Nebulized corticosteroids (eg, beclomethasone, 100–200 mcg 4 times/day) produced fewer side effects than oral or parenteral forms but are much less efficacious in the treatment of BPD.

   3. Growth and nutrition. Because growth is essential for recovery from BPD, adequate nutritional intake is crucial. Infants with BPD frequently have high caloric needs (120–150 kcal/kg/d or more) because of increased metabolic expenditures. Concentrated formula is often necessary to provide sufficient calories and prevent pulmonary edema. In addition, specific micronutrient supplementation, such as antioxidant therapy, may also enhance pulmonary and nutritional status.

3. Discharge planning. Oxygen can often be discontinued before discharge from the neonatal intensive care unit. However, home oxygen therapy can be a safe alternative to long-term hospitalization. The need for home respiratory, heart rate, and oxygen monitoring must be decided on an individual basis but is generally recommended for infants discharged home on oxygen. Synagis (palivizumab, humanized monoclonal antibodies against respiratory syncytial virus [RSV]) should be given monthly (15 mg/kg administered intramuscularly) throughout the RSV season. All parents should be instructed in cardiopulmonary resuscitation.

4. General care. Care plans for older infants with BPD should include adapting their routine for home life and involving the parents in their care. Immunizations should be given at the appropriate chronologic age. Periodic screening for chemical evidence of rickets and echocardiographic evidence of pulmonary hypertension is recommended. Assessment by a developmental specialist and occupational or physical therapist, or both, can be useful for prognostic and therapeutic purposes.

The prognosis for infants with BPD depends on the degree of pulmonary dysfunction and the presence of other medical conditions. Most deaths occur in the first year of life as a result of cardiorespiratory failure, sepsis, or respiratory infection or as a sudden, unexplained death.

1. Pulmonary outcome. The short-term outcome of infants with BPD, including those requiring oxygen at home, is surprisingly good. Weaning from oxygen is usually possible before their first birthday, and they demonstrate catch-up growth as their pulmonary status improves. However, in the first year of life, rehospitalization is necessary for ∼30% of patients for treatment of wheezing, respiratory infections, or both. Although upper respiratory tract infections are probably no more common in infants with BPD than in normal infants, they are more likely to be associated with significant respiratory symptoms. Most adolescents and young adults who had moderate to severe BPD in infancy have some degree of pulmonary dysfunction, consisting of airway obstruction, reactive airway disease, and hyperinflation.

2. Neurodevelopmental outcome. Children with moderate to severe BPD appear to be at an increased risk for adverse neurodevelopmental outcome compared with comparable infants without BPD. Neuromotor and cognitive dysfunction appears to be more common. In addition, children with BPD may be at higher risk for significant hearing impairment and retinopathy of prematurity. They are also at risk for later problems, including learning disabilities, attention deficits, and behavior problems.