Bronchopulmonary dysplasia (BPD), also called chronic lung disease of prematurity, was first described a little over a quarter century ago,1 soon after the development of mechanical ventilation for the treatment of respiratory distress syndrome (RDS). Thus, BPD has been a reminder of both the triumph and the cost of neonatology. While advances in neonatal care have given infants weighing less than 750 g a better than 60% chance of survival, the incidence of BPD has increased at the same time.2 In feet, BPD ranks with cystic fibrosis as the two most common causes of chronic lung disease in children. The general pediatrician is seeing infants with BPD in his or her office with increasing frequency for acute and longitudinal care. These infants also create a large emotional and financial burden for their parents, caregivers, and society with their increased need for prolonged hospitalization, home care, and associated problems.
This article reviews recent information regarding aspects of the epidemiology and pathophysiology of BPD, especially in light of the widespread use of surfactant replacement therapy for RDS. After a brief review of the hospital course of these babies, the focus will switch to the impact of BPD on long-term outcome, specifically in areas such as growth, development, and respiratory function.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
Determining the exact incidence of BPD has been difficult due to the continuing evolution of the definition of the condition. Bancalari's criteria of 19793 included exposure of premature infants to mechanical ventilation within the first 2 weeks of life, evidence of poor compliance and oxygen need by 4 weeks of life, and characteristic chest radiographic changes. With the increase in survival of premature infants as young as 24 weeks gestation, using this definition has led to the overdiagnosis of BPD in such extremely premature infants at 4 weeks of age. A newer definition, based on the need for oxygen at 36 weeks postconceptional age, has been shown to correlate with long-term pulmonary morbidity.4 This definition is being included in more recent articles about BPD.
Risk Factors for Bronchopulmonary Dysplasia
The most significant risk factor for the development of BPD is the degree of prematurity (Table). While surfactant replacement has improved the survival rate for premature infants, and its use is associated with a decreased need for oxygen and high ventilator pressures, its impact on the incidence of BPD has been less dramatic.
The combined results of eight placebo-controlled studies of prophylactic surfactant therapy indicate that while the overall survival rate rose from 79 to 85/100 high-risk births (P<-05), the BPD rate was equal in the two groups at 29 cases/100 births.5"12 In babies with the lowest birth weight, BPD rates were even higher in the surfactant-treated infants (Figure 1). It is estimated that there are 15 000 new cases of BPD each year.
Besides oxygen and positive pressure ventilation, other factors, relating to the degree of prematurity, are undergoing increasing scrutiny. Premature infants are deficient in their anti-oxidant defenses. It remains to be determined whether lung supplementation with antioxidants will alter the incidence or severity of BPD.
Clinically, it is becoming apparent that infection increases the chances of developing BPD. In our neonatal intensive care unit, 70% of infants with moderate to severe BPD had bacterial sepsis before day 14 of life, compared with 31% of those who did not have chronic lung disease (P<.002). Several studies also have examined the relationship between low grade or asymptomatic infection of the lower respiratory tract with a mycoplasma, Ureaplasma urealyticum, and the subsequent development of BPD.13
Figure 1. Survival rate and bronchopulmonary dysplasia (BPD) rate based on combined results of eight placebocontrolled randomized clinical trials of surfactant therapy for prevention of respiratory distress syndrome (all patients) and of results from Survanta trial for infants weighing <750 g.5
Figure 2 presents a summary of the cunent understanding of the pathogenesis of BPD. The relative duration and severity of each step will vary in each patient. The overall sequence is: 1) exposure to damaging stimuli, 2) direct local damage by these agents (eg, oxygen radicals), 3) signals that turn on lung inflammation and edema, 4) resolution of the alveolitis in those who recover or persistence in infants who develop BPD, 5) influx of mononuclear cells and a proliferation of fibroblasts with subsequent fibrosis, and 6) simultaneous airway changes with epithelial metaplasia and inflammation followed by smooth-muscle hypertrophy. Clinically, these infants can act like children with asthma.
Newly described intercellular signalling molecules, called cytokines, may play a role in the pathogenesis of BPD. For example, two studies have found that levels of inflammatory cytokines are elevated in the first day of life in premature babies who go on to develop BPD.1415 Their results are illustrated in Figure 3. These studies are a portion of the efforts cunentiy underway to determine if changes in the behavior of these and other cytokines can help explain why babies develop BPD. For example, alveolar macrophages from newborn rabbits elaborate more IL·! than cells from their adult counterparts. Results from these investigations should become available in the next 3 to 5 years.
By some estimates, up to 10% of those babies diagnosed with BPD do not survive their initial hospitalization. On the other hand, more than one third of those infants who are receiving oxygen therapy at 28 days of life no longer require extra oxygen by 36 weeks postconceptional age. The majority of patients with BPD, however, spend extra weeks and months in the intensive care nursery compared to their unaffected counterparts. This small group of patients consume a disproportionately large amount of the resources used in neonatal intensive care.
Figure 2. Outline of pathophysiology of BPD. The sequence of events, their duration and magnitude, and the specific components of each step vary markedly among different populations and individuals.
The most important factor favoring the eventual recovery of these BPD babies is that their lungs are continuing to grow and develop. It is estimated that the normal term infant has an average of 24 million alveoli and that by 4 years of age this has increased at least tenfold.16 Significantly damaged lung tissue may not recover, but the ratio of healthy to damaged lung should steadily improve. Recovery involves the provision of enough respiratory support to allow for pulmonary growth but not so much as to cause ongoing pulmonary damage. Many neonatologists will allow the blood PCO2 to be in the 50-mm Hg to 60-mm Hg range in these babies, arguing that the cost in barotrauma of trying to achieve a "normal" blood PCO2 is not worth any benefits gained. Sufficient supplemental oxygen should be given to maintain oxygen saturation above at least 88% to 90%, while avoiding prolonged hyperoxia. Another major requirement for recovery is assuring adequate nutritional support so that lung growth and cellular repair can occur.
Diuretics such as furosemide or thiazides are often employed in the pharmacotherapy of BPD. They act to decrease the extra accumulation of lung water due to disrupted lymphatic drainage and increased capillary permeability. By giving a large dose of furosemide every other day, many of the electrolyte and mineral side effects associated with long-term use of this drug can be avoided, though nephrocalcinosis remains a concern. To help dilate reactive airways, many of the same medications used for asthma are employed, including theophylline and aerosolized beta agonists such as albuterol and terbutaline.17
Figure 3. Levels of pro-inflammatory cytokines IL-1ß14 and IL-615 in lung lavage obtained on day 1 of life from intubated newborns. Infants who go on to develop BPD have significantly higher levels compared with those who recover from their lung disease.
The most recent addition to the pharmacological armamentarium for BPD has been a prolonged course of systemic corticosteroids. While clinically effective at reducing oxygen and ventilator needs in high-risk infants, the drug is associated with several side effects and should be used with caution. There are active efforts to improve the ratio of benefits to side effects by several different strategies, including using shorter courses of the drug earlier in the disease18 or by delivering smaller doses of steroid directly into the lungs of affected babies.19
With careful management and treatment, the majority of infants with BPD show a slow and steady recovery during their initial hospitalization, if complications such as severe infection do not supervene.
Another potential complication of BPD that can have a significant impact on the long-term ventilator care of these children is that of airway damage such as tracheal stenosis or malacia. Tracheostomy or reconstructive procedures such as a cricoid split may be necessary for the long-term management of these infants.
When an infant is born very prematurely, there is an increased risk that he or she will develop BPD. The vast majority of these babies will eventually recover from their chronic lung disease to be well enough to go home. But for some of them and for their families, their time in the hospital can be long and arduous. And after their discharge, their pulmonary disease can impact many aspects of their health and development.
DISCHARGE PLANNING AND FOLLOW-UP
Discharge planning should begin several weeks before the infant leaves the hospital. Several key steps must be taken before discharge occurs:
* One or more primary caregivers at home must be identified. Parents usually take on this role, but family or friends may fill the role as well.
* Some member of the neonatal staff must be the coordinator of the discharge plan and act as the key person to shepherd the infant through the transition from nursery to home.
* A physician in the community will be required to be the primary care physician for the infant. He or she must be apprised as to the status of the infant and be given a full account of the child's hospitalization, treatment, and follow-up plans.
* All the elements for home care must be lined up before discharge. This may include home nurses, nursing assistants, public health nursing, respiratory therapy, occupational and physical therapy, and social services. The numbers and complexity of services will depend on the severity of the infant's illness and the support required to maintain that child outside of the nursery.20
The primary caregivers must demonstrate their ability to provide all the care the child will require in the home setting before leaving the hospital. This may include feeding, adjusting O2 support, suctioning and airway management, bathing, giving medications, and monitoring. Caregivers should be taught how to assess the infant's respiratory condition and understand the baseline respiratory pattern of the BPD patient (frequency of respiration, rhythm, degree of retractions, and color of skin and mucous membranes).
Infants with BPD need careful primary care followup. They should be seen by their primary care pediatrician within a day or two of discharge (if not before discharge) so that a baseline assessment of their condition may be established by these important physicians. These children should receive immunizations on schedule, and careful attention should be given to their nutritional status and growth. It is important that good communications be established between the primary care physician and other specialists who also are seeing the patient. Medication adjustments and altered treatment plans should be communicated to the primary care pediatrician, and this physician should be included in major medical decisions regarding the patient.
Probably one of the most important roles of the pediatrician, aside from providing acute medical care, is the provision of emotional support for the parents or caregiver. Caring for a BPD infant at home can be quite stressful and the pediatrician must be mindful of this when dealing with the parents. Extra praise goes a long way when the parents are doing a good job. If it appears that the stress is not well handled, then the pediatrician should be aware of this and suggest alternatives to care that may reduce the stress to both the parent and child. The primary care pediatrician is in a unique position to provide long-term care management, preventive care, and acute care to a patient with many medical, social, and emotional challenges.
Growth delays are not uncommon in BPD infants. When BPD babies are compared with control infants of like gestational age and birth weight, they do not grow as well. Some catch-up growth occurs when the respiratory status of the infants improves, but growth delay often extends into the second year of life.21
One element of growth delay may be due to poor nutrition. Every effort should be made to provide adequate caloric intake in order to achieve reasonable weight gain and linear growth. Supplemental calories may be required because of the increased caloric need due in part to the increased work of breathing. Supplemental calories can be provided by dietary adjustments that will increase the caloric density of feedings. A pediatric nutritionist well trained in the medical conditions related to prematurity and BPD can be very helpful in designing a diet that will yield optimal growth for the BPD infant. Careful monitoring of growth and nutrition will be required throughout infancy and early childhood. Ongoing dietary adjustments will be required as the patient ages and medical conditions change.
However, some BPD patients can receive calories at high levels (180 to 200 Kcal/kg/day) and not achieve adequate growth. Chronic hypoxia may be a reason that these patients grow poorly. Many BPD patients require supplemental O2 to maintain O2 Sat 88% to 90%. Supplemental oxygen should be provided until the O2 saturation stabilizes at 88% to 90% in room air. New data indicate that even these patients may become desaturated during times of stress (as in after feeding), and they may require several hours to return back to baseline O2 saturation values.22 Repeated episodes of hypoxia during these stress times may be a factor in poor growth.
A third factor that affects growth is that of recurrent infections. Infants with BPD have an increase in the incidence of upper and lower respiratory infections. Prompt treatment of these infections along with the use of supplemental O2 when indicated is important.
Finally, BPD infants are at risk for growth failure due to poor parental bonding and dysfunctional family situations. Every effort must be made to provide adequate bonding opportunities during the initial hospitalization and the use of inhospital and community social service agencies when indicated.
Infants with BPD grow best when optimal nutritional support and excellent medical care are provided in the setting of a warm nurturing family. Much effort is often required in order to provide these components for the BPD infant.
Earlier reports of BPD survivors seemed to indicate that respiratory function was near normal by the second or third birthday. Clinical evidence of residual respiratory disease disappeared in most children before school age. More recent reports would indicate that surviving children with BPD have abnormal lungs and abnormal pulmonary function. The recognition of altered pulmonary function may be due to either a change in the BPD population (now that premature infants of lower gestational age are surviving after mechanical ventilation) or the development of precise instruments for the measurement of pulmonary functions.
It appears that many older school-age and teenage children who had BPD now have serious pulmonary dysfunction.23 When tested and compared with agematched controls, the BPD children showed airway obstruction, airway hyperactivity and hyperinflation. Over 60% of BPD children have abnormal pulmonary function, and over 50% have reactive airway response when challenged with exercise, methacholine, or a bronchodilator. These children are at an increased risk for readmission to the hospital during early childhood (up to 60% of BPD infants in one study) because of infection or reactive airway disease.
Aggressive treatment of acute pulmonary problems such as bronchiolitis, reactive airway disease, and pneumonia is required in BPD infants and children. Physicians who care for these patients must be aware that they have little pulmonary reserve and can develop respiratory failure easily. Bronchopulmonary dysplasia patients seem to have a poor tolerance to viral infections such as adenovirus and respiratory syncytial virus (RSV). The use of specific antiviral treatment for RSV infection is advocated by some but effectiveness of antiviral treatment is unclear.
What will happen to the pulmonary status of BPD survivors as they approach middle age and beyond is uncertain. It would seem prudent that they avoid smoking (active and passive smoke) and occupational exposure to pulmonary toxins. Education as to the possibility of future pulmonary injury from these environmental hazards should begin at school age and continue for a lifetime. Careful follow-up will be required in an attempt to learn the natural outcome of BPD infants as they move into young adulthood and middle age.
PREVENTION OF BPD
Prevention of BPD has been a goal ever since this disease was first recognized. Initially, various ventilator modifications and ventilation techniques were tried in an attempt to lower the incidence of BPD. Likewise, a variety of pharmacologic agents including vitamin E and superoxide dismutase (to reduce oxygenfree radicals), vitamin A (to promote healing), and corticosteroids (to reduce inflammation) have been used in an attempt to prevent or alter this disease. None of these interventions have been uniformly successful.
Prevention of preterm birth appears to be the key to reducing the incidence of BPD. While it is unlikely that prematurity can be totally eliminated, even the delay of the delivery of premature infants until after the 32nd week of gestation would be effective in reducing the incidence of BPD. No simple solution to the elimination of premature labor and delivery is expected in the near future since epidemiologic studies have shown that premature delivery is associated with a wide variety of social conditions and maternal medical or obstetrical problems. Additional research into the triggers of premature labor must be completed before there is a better understanding of how to prevent or stop premature labor. Until that happens, BPD will continue to be a major source of morbidity of prematurity.
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Risk Factors for Bronchopulmonary Dysplasia