Bronchopulmonary Dysplasia:
Beyond the Neonatal Period

Bonnie B. Hudak, M.D.

 

Introduction

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in infants with a history of extreme prematurity. It was first described in 1967, shortly after the onset of mechanical ventilation of preterm infants. Unfortunately, it remains a significant cause of morbidity among neonatal intensive care unit (NICU) survivors. BPD is characterized by structural changes in the lungs that appear to persist for many years. While it is usually thought of as a disease of infants, long-term follow-up data indicate that the sequelae of BPD persist into childhood and even into adulthood1.

When BPD was first described, it was thought to be secondary to injury of the immature lung by barotrauma and oxygen toxicity. However, 30 years later, the etiology of BPD remains elusive. In fact, the mechanism and type of lung injury are probably somewhat different. Neonatology is vastly different today than in the 1960's. In addition, the limit of viability has steadily declined to its present lower limit of 23 weeks gestation. The most important factor in the development of BPD appears to be the marked structural, biochemical and physiologic immaturity of the premature lung. Incomplete pulmonary development, inadequate antioxidant defenses, surfactant deficiency, inflammatory mediators, infections, and congestive heart failure probably all play a role.

The pathologic changes of BPD are of particular concern when speculating on the long- term pulmonary outcome of infants developing BPD today. Recent pathology studies are characterized by an arrest of alveolar development resulting in fewer and larger alveoli2. Since alveolar development only occurs throughout early childhood, the consequences of this diminished alveolarization are unclear but of great concern. Will these children have a permanent loss of alveoli and surface area for gas exchange? If so, they would be expected to have life-long pulmonary abnormalities.

Therapies to prevent BPD

Over the years many therapies have been tried to prevent BPD. These have included surfactant replacement therapy, nutritional and antioxidant supplementation, mechanical ventilation strategies and corticosteroids. However, prevention of preterm birth remains the only truly effective therapy for preventing BPD.

Surfactant replacement therapy has had an impact on BPD by increasing survival among extremely preterm infants. Unfortunately, it has not been shown to decrease the incidence of BPD3. The incidence of BPD remains high, with the majority of survivors born at 23-25 weeks gestation being affected4. Clinical trials of vitamin A, vitamin E, and superoxide dismutase have not proved to be of marked benefit.

The role of steroids in the prevention and treatment of BPD remains controversial. Data supports the use of systemic corticosteroids in the first 2-4 weeks of life to facilitate weaning from mechanical ventilation5. however, most steroid-treated infants still require prolonged oxygen therapy after extubation. Steroid therapy has not improved survival or decreased the incidence of BPD in most studies. In addition, there is a growing body of evidence supporting the association of adverse neurodevelopmental outcome with the use of corticosteroids in the neonatal period6. Similarly, there are concerns that early steroid therapy may alter lung development in these very immature infants2. While inhaled corticosteroids are safer than oral corticosteroids in older children and adults, few data support either their safety or efficacy in preventing BPD5.

Outcome

Numerous studies have identified long-term pulmonary function, gas exchange and exercise abnormalities in children with a history of BPD1. A particularly interesting study of pulmonary follow-up in BPD is that done by Northway and colleagues7. This group evaluated pulmonary function in older teens and young adults, some of which were included in Northway's original description of BPD in 1967. Of the 25 patients studied, 68% had some abnormality of pulmonary function, primarily small airways obstruction. In most, these abnormalities tended to be mild. However, 24% had moderate to severe small airways obstruction. In addition, 24% of the patients had fixed small airways obstruction, that is, it was not reversible with a bronchodilator. It is difficult to speculate on the relevance of these findings to the infants diagnosed with BPD today given the enormous differences in gestational age, birth weight and neonatal care. On the other hand, it clearly points out the "graduation" of this form of lung disease from the pediatric to the adult patient population.

Studies of respiratory outcome done in children born more recently have shown the persistence of pulmonary problems throughout infancy and into childhood. Up to 50% of infants with BPD are hospitalized in the first 2 years of life for respiratory causes. They have increased pulmonary symptoms including cough and wheeze. Pulmonary function studies continue to show an increase in small airways obstruction and an increase in airway responsiveness that persists into adolescence. Interestingly, studies of exercise performance have shown normal exercise capacity in survivors of BPD. However, some had a decrease in oxygen saturation and/or an increase in small airways obstruction with exercise8-10.

Children with a history of BPD tend to be smaller than either children born at term or those with a history of prematurity without BPD. However, they do achieve normal growth rates with median values plotting between the 30-40th percentiles on standard growth curves1,11.

Infants with BPD are also at increased risk for neurodevelopmental disability. Studies have shown infants with BPD to have increased developmental delay when compared to term infants12,13. In general, studies have shown infants with BPD to have a higher rate of cognitive and motor disabilities than preterm infants without BPD.

Pulmonary Management of BPD

The management of BPD, once established, has not changed dramatically in the past 20 years. The key elements of BPD management continue to be maintaining adequate oxygenation and providing sufficient nutrition for growth. Although firm data are lacking, maintaining oxygen saturations of 92% or greater appears to allow adequate growth without the development of cor pulmonale. Attaining an adequate growth rate is often difficult. Poor growth may be multifactorial (TABLE 1).


Increasing the caloric density of the formula is often sufficient to allow good growth. Some infants may benefit from diuretic therapy. Chlorothiazide and spironolactone will often provide adequate diuresis without adversely affecting electrolytes. Furosemide can provide a more vigorous diuresis but is more likely to require electrolyte replacement and can be complicated by nephrocalcinosis or hearing loss. Infants with BPD have been shown to have increased responsivity to bronchodilators early in life. Beta-agonist therapy may result in improvement in pulmonary function in some infants, even in the absence of wheezing. Once again, the role of inhaled corticosteroids is unclear.

Infants with BPD: Primary Care

Growth is extremely important in the pulmonary recovery of an infant with BPD. These infants have been shown to attain normal growth rates and often demonstrate some "catch-up" growth. Frequent assessment of weight gain is helpful. Prompt evaluation and intervention is necessary for infants who are not gaining weight well. Causes of poor growth are listed in (TABLE 2).

The most common cause of poor growth is inadequate intake. An infant with BPD may require a caloric intake that is 50% greater than that of a healthy infant. Caloric intake can be increased by concentrating the formula to 24-26 calories per ounce. The caloric density of the formula can be further increased by the addition of oil or polycose to the formula. However, if this is necessary, further evaluation into the need for this concentrated formula is indicated.

Babies with BPD require the same health care maintenance as do healthy infants. Immunizations, including the pneumococcal vaccine, should be given at the usual times based on chronologic age (uncorrected for prematurity). In addition, BPD infants should receive influenza vaccines at the appropriate time of year once they reach 6 months of age. The majority of infants with BPD should be placed on their backs for sleep. Those with significant upper airway obstruction or gastroesophageal reflux may be candidates for prone sleep position.

Tobacco smoke exposure poses a threat to survivors of BPD at all ages. Parents should be counseled to smoke in well-ventilated areas outside the home and never in the home or car. Preteens with a history of BPD should be vigorously advised of the additional dangers of tobacco smoke.

Developmental screening is also important in the primary care of infants with BPD. As noted above, they are at increased risk for neurodevelopmental disability. An infant who fails to meet milestones for corrected age, or who has tone abnormalities or other evidence of disability, should be referred to an early intervention program for further evaluation and management.

One relatively new addition to the pharmacology of BPD is palivizumab (Synagis), a monoclonal antibody to the respiratory syncytial (RSV) virus. RSV is a major cause of morbidity in infants with BPD. It is ubiquitous, with most infants developing RSV infection within the first 2 years of life. About 13% of infants with BPD are hospitalized with RSV. Palivizumab is available for the prevention of RSV as a monthly injection given during the epidemic season. Studies have shown that it reduces the incidence of infection and hospitalization due to RSV in preterm infants (<35 weeks gestation). In infants with BPD, the rate of hospitalization due to RSV was reduced by 39%, from 12.8 to 7.9%. Recommendations for the use or palivizumab are available in the American Academy of Pediatrics Red Book14.

Implications for adult care providers

Survivors of prematurity are now reaching adulthood. This poses a new challenge for the adult care provider. A birth history should be included in a new patient history. Pulmonary function should be assessed in adults with a history of prematurity and pulmonary symptoms. Appropriate counseling should be given regarding tobacco smoke avoidance or smoking cessation.

References

  1. Eber E and Zach MS. Long term sequelae of bronchopulmonary dysplasia (chronic lung disease of infancy). Thorax 36:317-323, 2001.
  2. Jobe AJ. The New BPD: An arrest of lung development. Pediatr Res 46:641-643, 1999.
  3. Hudak BB and Egan EA. Impact of lung surfactant therapy on chronic lung diseases in premature infants. Clinics in Perinatology 19:591-602, 1992.
  4. Allen MC, Donohue PK, Dusman AE. The limit of viability _ Neonatal outcome of infants born at 22-25 weeks gestation. NEJM 329:597-601, 1993.
  5. Crowley P. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972-1994. Am J Obstet Gynecol 173:372-335, 1995.
  6. Cole CH, Frantz ID III. Role of post-natal steroids for chronic lung disease. In: Hansen TN, McIntosh N, eds, Current Topics in Neonatology, number 2. London: W.B. Saunders, 1997:256-80.
  7. Northway WH, Moss RB, Carlisle KB, Parker BR et al. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med 1990; 323:1793-9.
  8. Jacob SV, Coates AL, Lands LC, MacNeish CF et al. Long-term pulmonary sequelae of severe bronchopulmonary dysplasia. J Pediatr 1998;133:193-200.
  9. Gross SJ, Iannuzzi DM, Kveselis DA and Anbar RD. Effect of preterm birth on pulmonary function at school age: a prospective controlled study. J Pediatr 1998;133:188-92.
  10. Giacoia GP, Venkataraman PS, West-Wilson KI, and Faulkner MJ. Follow-up of school-age children with bronchopulmonary dysplasia. J Pediatr 1997;130:400-8.
  11. Vrlenich LA, Bozynski MEA, Shyr Y, Schork MA et al. The effect of bronchopulmonary dysplasia on growth at school age. Pediatrics 1995;95:855-9.
  12. Robertson CMT, Etches PC, Goldson E and Kyle JM. Eight-year school performance, neurodevelopmental, and growth outcome of neonates with bronchopulmonary dysplasia: a comparative study. Pediatrics 1992;89:365-72.
  13. Gray PH, Burns YR, Mohay HA, O'Callaghan MJ, et al. Neurodevelopmental outcome of preterm infants with bronchopulmonary dysplasia. Arch Dis Child 1995;73:F128-F134.
  14. American Academy of Pediatrics. Section 3: Respiratory Syncytial Virus. In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Disease. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000: 483-7.
December, 2001/ Jacksonville Medicine

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