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This 3 month old, former 26 week gestation male, presents to his pediatrician's office with a 2 day history of cough and fever. He was stable until 3 days ago when he had an episode of emesis followed by choking. His parents witnessed the episode, patted him on the back, and increased his oxygen flow rate from 1/4 to 1/2 liter/min due to cyanosis during and after the event. His temperature peaked at 39.6 degrees C (103.4 F) today. There has been no diarrhea or rhinorrhea. Oxygen saturation readings (SpO2) at home have been in the mid 90s. His diet consists of BPD formula, thickened with rice cereal. He has a decreased appetite. He continues to have 1-2 episodes of emesis per day.
PMH is remarkable for delivery at 26 weeks gestation. His neonatal course was characterized by respiratory distress syndrome (RDS) treated with surfactant, a patent ductus arteriosus (PDA) requiring ligation at 5 days of age, coagulase negative staphylococcus bacteremia, and retinopathy of prematurity (ROP). He required mechanical ventilation for almost 5 weeks and was successfully extubated after a brief course of systemic corticosteroids. He was also diagnosed with gastroesophageal reflux (GER). He was discharged from the hospital 3 weeks ago at 36 weeks postconceptional age (PCA). His medications include: Albuterol aerosols 1.25 mg TID, furosemide 3 mg PO QD.
Exam: VS T 39.2, P 175, RR 73, BP 96/58, SpO2 94% on 1/2 liter/min O2 by nasal cannula. He is a pink, slightly pale infant in moderate respiratory distress with an intermittent cough. The remainder of his exam is remarkable for moderate subcostal, intercostal, and substernal retractions. Breath sounds demonstrate fair aeration throughout, but they are decreased in the right upper lung field. Diffuse, soft wheezing is heard bilaterally.
A chest x-ray shows bilateral interstitial infiltrates, flattened diaphragms, and consolidation of the right upper lobe.
Chronic lung disease (CLD) is a disorder that originates in the neonatal intensive care unit, but regularly presents in the outpatient arena. Therefore, knowledge of the clinical presentation, pathophysiology, management, and outcome of bronchopulmonary dysplasia (BPD) is equally essential to the intensivist as it is to the primary care physician. The case above underscores many of the common features of the infant with chronic lung disease or bronchopulmonary dysplasia. As discussed in detail below, BPD is a chronic illness that is seen primarily in preterm infants. Additional risk factors noted in this patient are biochemical immaturity (surfactant deficiency), patent ductus arteriosus, mechanical ventilation, and oxygen therapy (Table 1) (1). BPD is a serious and potentially life threatening disorder. Originally described in 1967 by Northway, a radiologist, radiographic findings remain a major feature of the diagnosis and staging of the disease process. The definition of chronic lung disease has changed over the years. The older definition describes infants who remain oxygen dependent at 28 days of age or more (typically following a course of mechanical ventilation) and with abnormal radiographic findings. The more recent definition uses oxygen dependency at 36 weeks postconceptional age (PCA) as opposed to 28 days postnatal age (age since birth) to identify infants with BPD. This change in definition reflects a change in the patient population that has occurred over the last 20 years with an increase in the survival of extremely low birth weight infants (ELBW, <1000 g). The need for respiratory support is common in ELBW infants at 28 days of age, often due to respiratory insufficiency/immature respiratory mechanics and not lung injury (BPD) per se.
Table 1. Major Risk Factors Associated with BPD
Prematurity (anatomical and biochemical lung immaturity; antioxidant insufficiency)
Patent ductus arteriosus
Mechanical ventilation (barotrauma, volutrauma)
The incidence of BPD increases with decreasing birth weight and gestational age such that approximately 15% of infants <1500 grams (g) and 50% of infants <1000 g are diagnosed with the disorder (1). The pathophysiology is based on the developing lung's vulnerability to various forms of injury. With the understanding that it is not "normal" for a 26 week gestation fetus to be outside of a fluid filled intrauterine environment, it is easy to appreciate how endotracheal intubation and mechanical ventilation can "do harm". This is, indeed, the neonatologist's major dilemma; providing support to an infant with immature respiratory physiology while minimizing iatrogenic injury. All aspects of patient care, nutrition, fluid administration, respiratory, infectious disease, etc., must be meticulously managed to curb the incidence and severity of chronic lung disease. Early in the disease process there is injury, inflammation, and capillary leak. Ongoing inflammation leads to fibroblast proliferation and scarring. Barotrauma or volutrauma causes airway epithelial and alveolar necrosis. If continued unchecked, the final outcome is a chronic pulmonary condition with features that include increased airway resistance and reactivity, mucous production, cystic emphysema, scarring, and atelectasis.
The clinical manifestations of chronic lung disease also evolve over time. In the early stages, tachypnea, retractions, cyanosis, and occasional grunting are seen. Later, reactive airway disease associated with wheezing and hypercarbia develops. Coexisting conditions such as feeding difficulties, poor growth, and gastroesophageal reflux (GER) may further complicate the clinical picture making these infants uniquely challenging and often frustrating to manage.
Prevention strategies are by far the most effective and satisfying in decreasing the incidence and reducing the severity of chronic lung disease. It is reasonable, based on the pathophysiology of BPD, that one approach might be to reduce an infant's exposure to mechanical ventilation and oxygen. Nasal continuous positive airway pressure (NCPAP) has been increasingly used to provide non-invasive respiratory support in the preterm infant. In addition, non-invasive means of monitoring oxygenation through the use of pulse oximetry allows for titration and reduction of supplemental oxygen to meet the infant's needs. Permissive hypercapnia, accepting higher levels of CO2, is also employed to reduce (wean or discontinue) ventilator support. Other approaches to prevention are listed in Table 2 (2), the most recent of which has been vitamin A supplementation. Vitamin A, necessary for epithelial integrity and healing, is often deficient in preterm infants, (as are other cofactors, antioxidants, minerals, and trace elements). Recent studies have shown that vitamin A supplementation is beneficial in ameliorating the development and progression of chronic lung disease (3).
Table 2. Prevention Strategies for BPD
Alternative ventilation strategies (synchronized, high frequency)
Balanced nutritional support
Various therapies have been developed to reduce symptom severity in the infant with BPD (Table 3). It is, indeed, the infant's good fortune that time is on his/her side! Because lung growth and development continues throughout infancy and early childhood, this is a disease process that the patient literally (completely or partially) outgrows. The goals of effective supportive therapy are to achieve adequate nutrition and growth while limiting episodes of disease exacerbation. It is, therefore, easy to understand why nutritional support serves as the mainstay of treatment. Caloric requirements for these infants sometimes exceed 140-150 kcals/kg/day. Increased metabolic demands coupled with feeding problems and GER, make this an especially challenging aspect of care. Parents share in the frustration of providing these infants with enough calories to grow and often suffer feelings of guilt in the process. Special formulas have been developed to increase caloric density (and intake), provide a proper balance of carbohydrate, protein, and fat, and limit free water. Preterm infant formulas (already 24 kcals/oz) are commonly used as the "base" which is further supplemented with protein, polycose (carbohydrate) and medium chain triglyceride (MCT) oil or vegetable oil to provide 30 kcals/oz. Indwelling nasogastric feeding tubes, and in some cases, gastrostomy tubes, are placed to provide enteral calories in infants with varying degrees of feeding difficulties. Close monitoring of an infant's growth is critical and, like all children, growth charts should be meticulously kept.
Table 3. BPD Treatment Strategies
Immunization (specifically, against RSV, respiratory syncytial virus)
Respiratory support (oxygen, CPAP, mechanical ventilation)
Diuretic therapy is common in the treatment of chronic lung disease of infancy. The rationale for diuretic use early in the disease process is to treat the pulmonary edema that accompanies inflammation and capillary leak. Later in the course, the lungs of BPD patients remain hydrophilic due to impaired lymphatic drainage from distorted architecture and decreased plasma oncotic pressure related to malnutrition and/or fluid overload (1). Cor pulmonale (right ventricular hypertrophy secondary to pulmonary hypertension), an end stage complication of severe BPD, also responds to diuretic therapy. Furosemide is the first line and most popular diuretic due to its additional benefits of venodilation and diminished airway reactivity. However, because of the multiple untoward side effects of furosemide, chlorothiazide (with or without spironolactone) is frequently used in "maintenance" therapy. Careful monitoring of electrolytes is essential with diuretic use. Bronchodilators are widely used to treat the reactive airway component of BPD. Inhaled agents include albuterol and ipratropium bromide. Rarely, in the most severe cases, theophylline may be employed as an adjunct to inhaled agents. Wheezing and CO2 retention are two of the major clinical manifestations of reactive airway disease. It is often beneficial to auscultate the chest before and several minutes following an inhalation treatment to determine its clinical efficacy. Confirming therapeutic benefit in the individual patient is important for determining ongoing management. Airway disease in these infants may sometimes be unresponsive to bronchodilator therapy.
The most controversial, but most effective short term treatment for CLD is dexamethasone. Clinical trials of dexamethasone treatment began in the early to mid 80s (4,5). The anti-inflammatory and pro-surfactant properties of corticosteroids made them a logical focus of study. These and subsequent studies have repeatedly demonstrated the positive short term benefits of corticosteroids as manifested by dramatic weaning of ventilator and oxygen support. As with many clinical trials, dosing amount, frequency, and treatment duration varied widely among studies. Adverse side effects, including hyperglycemia and hypertension, have also been documented. Subsequent trials of early dexamethasone use (within the 1st week of life) have shown greater risk than benefit (6,7). Therefore, if dexamethasone therapy is being considered, its use should be reserved for those patients with established chronic lung disease or prolonged ventilator dependency, typically older than 1 week of age (8,9). Of great concern is evidence suggesting that dexamethasone treatment is associated with an increase in developmental disability and cerebral palsy. It is the knowledge of the many serious side effects associated with systemic dexamethasone that has prompted clinicians and investigators to consider the use of hydrocortisone and inhaled corticosteroids in the prevention and treatment of chronic lung disease. Inhaled corticosteroids have been used in the treatment of adult and childhood asthma for many years. Limited studies in neonates have demonstrated no significant benefit beyond a reduction in the need for systemic steroid therapy (10). Logistical issues surrounding dosing and drug delivery in infants has further complicated this matter. Inhaled steroids are safer, but not without serious systemic side effects, especially at higher doses. Further information is needed before inhaled steroids become incorporated into the routine treatment of CLD.
The prognosis for BPD is largely dependent on its severity and the coexistence of other morbidities of prematurity (intraventricular hemorrhage/periventricular leukomalacia, short bowel syndrome, GER, and failure to thrive). As mentioned above, most infants outgrow their disease at varying rates. Despite the lack of clinical symptomatology in older children and adolescents, abnormalities often persist on pulmonary function testing. Less than 1% of ventilated preterm infants remain ventilator dependent for months or years. Aggressive measures to prevent and treat acute (respiratory) infections (hand washing, immunization, prompt use of antibiotics) must be instituted for an optimal outcome. Outside of the concerns regarding dexamethasone, it has long been recognized that infants with CLD are at high risk for neurodevelopmental delay and cerebral palsy which may occur in up to 28% of the time (1).
Infants with BPD are at risk for serious infections when they encounter respiratory viruses. A good example is respiratory syncytial virus (RSV), which typically presents as an upper respiratory infection in older children and adults and bronchiolitis in healthy infants. However, in infants with BPD, RSV pneumonia often occurs, which may result in apnea and respiratory failure. Prophylaxis against RSV has been available for the last 5 years to reduce the severity of infection. Passive immunization is available in two forms, a monoclonal antibody (palivizumab) and RSV immune globulin (RSV-IGIV). Palivizumab is administered monthly to high risk infants as an IM injection during the peak of the RSV season (November thru March) (11).
In summary, BPD or chronic lung disease of infancy is a disorder with a multi-factorial etiology. The smallest preterm infants are at highest risk due to the anatomical and biochemical immaturity of their respiratory, antioxidant, and immune systems. Prevention is the key to dealing with this disorder, however, once BPD develops, nutritional, respiratory, and developmental supportive therapies are critical to the successful management of these patients. Research is ongoing to further characterize the pathogenesis and explore safer and more effective options for prevention and treatment.
1. True/False: BPD is a common condition affecting most preterm infants requiring mechanical ventilation.
2. All of the following factors are included in the pathogenesis of chronic lung disease except:
. . . . . a. infection
. . . . . b. antenatal corticosteroids
. . . . . c. oxygen toxicity
. . . . . d. patent ductus arteriosus
3. Chronic lung disease is defined as:
. . . . . a. ventilator dependency at 2 weeks of age
. . . . . b. oxygen dependency at 36 weeks postconceptional age
. . . . . c. oxygen dependency at 28 days postconceptional age
. . . . . d. oxygen dependency at 28 days postnatal age
. . . . . e. b and d
4. An effective prevention measure for BPD is:
. . . . . a. surfactant therapy
. . . . . b. vitamin A supplementation
. . . . . c. fluid management
. . . . . d. management of patent ductus arteriosus
. . . . . e. all of the above
5. For adequate growth, infants with chronic lung disease frequently require a caloric intake of:
. . . . . a. 80 kcals/kg/day
. . . . . b. 100 kcals/kg/day
. . . . . c. 120 kcals/kg/day
. . . . . d. 140 kcals/kg/day
6. True/False: Inhaled corticosteroids are as effective as systemic steroids in the treatment of BPD, but with reduced side effects.
Severe BPD case: Yamamoto LG. Severe Chronic Lung Disease and Respiratory Distress. In: Yamamoto LG, Inaba AS, DiMauro R (eds). Radiology Cases In Pediatric Emergency Medicine, 1995, volume 3, case 2. Available online at: www.hawaii.edu/medicine/pediatrics/pemxray/v3c02.html
Miscellaneous chest x-rays: Yamamoto LG. Test Your Skill In Reading More Pediatric Chest Radiographs. In: Yamamoto LG, Inaba AS, DiMauro R (eds). Radiology Cases In Pediatric Emergency Medicine, 1996, volume 5, case 5. Available online at: www.hawaii.edu/medicine/pediatrics/pemxray/v4c05.html
1. Gerdes JS. Chapter 9-Bronchopulmonary Dysplasia. In: Polin RA, Yoder ML, Burg FD (eds). Workbook in Practical Neonatology, 3rd edition. 2001, Philadelphia: W. B. Saunders Company, pp. 185-202.
2. Barrington KJ, Finer NN. Treatment of Bronchopulmonary Dysplasia. Clinics in Perinatology 1998;25(1):177-202.
3. Hazinski TA. Vitamin A Treatment for the Infant at Risk for Bronchopulmonary Dysplasia. NeoReviews 2000;1(1):e11-14.
4. Mammel MC, Johnson DE, Green TP, Thompson TT. Controlled trial of Dexamethasone Therapy in Infants with Bronchopulmonary Dysplasia. Lancet 1983;1:1356-1358.
5. Avery GB, Fletcher AB, Kaplan M, et al. Pediatrics 1985;75(1):106-111.
6. Stark AR, Carlo WA, Tyson JF, et al. Adverse effects of early dexamethasone in extremely low-birth-weight infants. NICHD and Human Development Neonatal Research Network. New Engl J Med 2001;344(2):95-101.
7. Halliday HL, Ehrenkranz RA. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2000;(2)CD001146. Review
8. Halliday HL, Ehrenkranz RA. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2000;(2):CD001144. Review
9. Halliday HL, Ehrenkranz RA. Delayed (> 3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2000;(2):CD001145. Review
10. Cole CH. Inhaled Glucocorticoid Therapy in Infants at Risk for Neonatal Chronic Lung Disease. J Asthma 2000;37(7):533-542.
11. American Academy of Pediatrics, Disease. Prevention of Respiratory Syncytial Virus Infections: Indications for the Use of Palivizumab and Update on the Use of RSV-IGIV. Pediatrics 1998;102(5):1211-1216
Answers to questions
1. False, 2. b, 3. e, 4. e, 5. d, 6. False