BRONCHOPULMONARY DYSPLASIA TREATMENT

Medical Care: Future management of BPD will involve strategies stressing prevention. Because few accepted therapies currently exist that can significantly prevent the development of BPD, many different therapeutic modalities (ie, mechanical ventilation, oxygen therapy, nutritional support, medications) are employed to treat BPD. Fortunately, the practicing neonatologist has observed a reduced severity of BPD in the postsurfactant era. Maintaining infants on PPV and oxygen therapy for longer than 4 months and discharging them to long-term care facilities for prolonged mechanical ventilation is now unusual.

• Mechanical ventilation
o Oxygen and PPV frequently are life-saving in extremely preterm infants; however, the early and aggressive use of nasal CPAP may eliminate the need for PPV and exogenous surfactant in some infants or facilitate weaning from PPV in other infants. Other investigators recommend brief periods of intubation primarily for exogenous surfactant administration followed quickly by extubation and nasal CPAP as a method of minimizing the need for prolonged PPV.

o In infants requiring oxygen and PPV, minimize oxygen toxicity and barotrauma/volutrauma by careful and meticulous management. Monitor pH, partial pressure of carbon dioxide, and partial pressure of oxygen carefully; maintain pH at 7.20-7.40, partial pressure of carbon dioxide at 45-65 mm Hg, and partial pressure of oxygen at 50-70 mm Hg. Assessment of blood gases requires arterial, venous, or capillary blood samples. Indwelling arterial lines are often employed early in the acute management of RDS, and they provide the most accurate information about pulmonary function. Arterial puncture may not provide completely accurate samples secondary to patient agitation and discomfort. Capillary blood gases, if properly obtained, may correlate with arterial values; however, capillary samples may suffer from wide variability and poor carbon dioxide correlation.

o Pulse oximetry and transcutaneous carbon dioxide measurement may provide useful information on assessing adequate ventilation and oxygenation with minimal patient discomfort. Many new synchronized ventilators may provide important information regarding tidal and minute volumes and flow volume loops. Proper interpretation of this information may help to improve gas exchange and minimize oxygen toxicity and barotrauma/volutrauma. Humidify and warm inspired gas and appropriately note the continuous monitoring of inhaled oxygen in patient records. Synchronized ventilators often allow infants to set their own inspiratory time as well as rate in dynamic fashion to minimize infant discomfort.

o Weaning from mechanical ventilation and oxygen is often difficult in infants with moderate-to-severe BPD, and few criteria have been defined to enhance the chances of successful extubation. When adequate tidal volumes and low inspired oxygen concentrations are noted, a trial of extubation and nasal CPAP may be indicated. Not uncommonly, atrophy and fatigue of respiratory muscles may result in extubation failure. A trial of endotracheal CPAP prior to extubation is controversial because of increased work of breathing and airway resistance. Optimization of methylxanthines, diuretics, and adequate nutrition all support and facilitate weaning the infant from mechanical ventilation. Meticulous primary nursing care is essential to ensure airway patency and facilitate extubation. Prolonged and repeated intubations, as well as mechanical ventilation, may be associated with severe upper airway abnormalities, such as vocal cord paralysis, subglottic stenosis, and laryngotracheomalacia.

o Consider bronchoscopic evaluation in infants with BPD in whom extubation is repeatedly unsuccessful despite optimization of nutrition, medications, and ventilator settings. Surgical interventions (cricoid split, tracheostomy) for severe structural abnormalities are less frequently employed today than in the past.

• Oxygen therapy
o Pulmonary hypertension and cor pulmonale may result from chronic hypoxia and airway remodeling in infants with severe BPD. Oxygen is a potent pulmonary vasodilator acting through the stimulation of NO production, which causes smooth muscle cell relaxation via activation of cyclic guanosine monophosphate (GMP). Currently, pulse oximetry is the mainstay of noninvasive oxygen monitoring. Repeated episodes of desaturation and hypoxia may occur in infants with BPD on mechanical ventilation as a result of a decrease in respiratory drive, alterations in pulmonary mechanics, excessive stimulation, and bronchospasm.

o Hyperoxia may overwhelm the neonate's relatively deficient AO defenses and worsen BPD. Increased oxygen requirements are frequently needed during stressful procedures as well as during feedings. Wean oxygen slowly. The optimal range of oxygen saturation in BPD is controversial, but maintain saturation of arterial oxygen (SaO2) at 90-95%. Some infants, especially those living at high altitudes, may require oxygen therapy for many months. Transfusion of packed RBCs may increase oxygen carrying capacity of preterm infants who are anemic (hematocrit [Hct] <30), but transfusion may further increase complication rates. The ideal hemoglobin level in critically ill neonates has not been well established.

o In 1988, Alverson and colleagues demonstrated increases in oxygen content and systemic oxygen transport and decreases in oxygen consumption and oxygen requirements in infants with BPD after blood transfusion. Hemoglobin levels do not correlate well with oxygen transport. Minimize the need for multiple transfusions and donor exposures by the use of erythropoietin therapy, iron supplementation, and a reduction in phlebotomy requirements.

• Nutritional support
o Infants with BPD have increased energy requirements. Early parenteral nutrition is often used to ameliorate the catabolic state of the preterm infant. Maximizing parenteral protein, carbohydrate, fat, vitamin, and trace metal intake is critical to prevent further lung injury and augment tissue repair. However, take care to avoid excessive nonnitrogen calories because this may lead to excessive carbon dioxide formation and complicate weaning. Early insertion of percutaneous central venous lines may help to improve the energy density of parenteral nutrition. Accomplish progressive increases in protein and fat supplementation to provide approximately 3-3.5 g/kg of body weight per day. Rapid and early administration of high concentrations of lipids may worsen hyperbilirubinemia and BPD through pulmonary vascular lipid deposition and bilirubin displacement from albumin.

o Excessive glucose loads may increase oxygen consumption, respiratory drive, and glucosuria. Calcium and phosphorus requirements are greatly increased in preterm infants. Most mineral stores in the fetus occur during the third trimester, leaving the extremely preterm infant calcium and phosphorus deficient and at increased risk of rickets. Supplemental furosemide therapy and limited intravenous calcium use may worsen bone mineralization and secondary hyperparathyroidism. Vitamin A supplementation may improve lung repair and decrease incidence of BPD. Supplement trace minerals (ie, copper, zinc, and manganese) because they are essential cofactors in the AO defenses.

o Early initiation of small amounts of enteral feeds (even if umbilical lines are in place) followed by slow steady increases in volume appears to facilitate tolerance of feeds. The most immature and unstable preterm infant often experiences a difficult transition to complete enteral nutrition. Frequent interruption of feedings secondary to intolerance or instability complicates the management of these patients. Enteral feeding of breast milk provides the best nutrition while preventing feeding complications (ie, sepsis, necrotizing enterocolitis). The energy content of expressed breast milk and formulas can be enhanced to provide increased energy intake, while minimizing fluid intake. Infants may require 120-150 kcal/kg of body weight per day to gain weight. Diuretics may often be used to prevent or treat fluid overload.

• Medical therapies: Often, many different drug therapies are employed to treat infants with severe BPD. The efficacy, exact mechanisms of action, and potential adverse effects of these medications have not been definitively established.
o Diuretics
􀂃 Furosemide (Lasix) is the treatment of choice for fluid overload in infants with BPD. It is a loop diuretic that has been demonstrated to decrease PIE and pulmonary vascular resistance (VR), improving pulmonary function. Daily or alternate day furosemide therapy improves respiratory function and may facilitate weaning from PPV, oxygen, or both.

􀂃 Adverse effects of long-term Lasix therapy are frequent and include hyponatremia, hypokalemia, contraction alkalosis, hypocalcemia, hypercalciuria, cholelithiasis, renal stones, nephrocalcinosis, and ototoxicity. Careful parenteral and enteral nutritional supplementation is required to maximize the benefits instead of exacerbating the adverse effects of furosemide. Potassium chloride supplementation is favored over sodium chloride supplementation in cases of mild hyponatremia or hypokalemia.

􀂃 Thiazide diuretics with inhibitors of Aldactone have also been used in infants with BPD. Several trials of thiazide diuretics combined with spironolactone have shown increased urine output with or without improvement in pulmonary mechanics in infants with BPD. In 2000, Hoffman reported that spironolactone administration does not reduce the need for supplemental electrolyte administration in preterm infants with BPD. In 1989, Englehardt and colleagues found no effect in pulmonary mechanics in infants with BPD. Adverse effects include electrolyte imbalance. Long-term efficacy studies comparing furosemide with thiazide and spironolactone therapy have not been performed to date.

o Smooth muscle agents (bronchodilators)
􀂃 Albuterol is a specific beta2-agonist used to treat bronchospasm in infants with BPD. Albuterol may improve lung compliance by decreasing airway resistance secondary to smooth muscle cell relaxation. Changes in pulmonary mechanics may last as long as 4-6 hours.

􀂃 Adverse effects include increases in BP and heart rate. Ipratropium bromide is a muscarinic antagonist that is related to atropine but may have more potent bronchodilator effects. Improvements in pulmonary mechanics have been demonstrated in BPD after ipratropium bromide inhalation. Combination therapy of albuterol and ipratropium bromide may be more effective than either agent alone. Few adverse effects are noted.

􀂃 Cromolyn sodium inhibits release of inflammatory mediators from mast cells. Some studies have shown a decrease in inflammatory mediators in tracheobronchial aspirates of infants with BPD who were treated with this drug. Do not use cromolyn to treat acute bronchospasm; however, it may be used as an agent to prevent bronchospasm from occurring. With current aerosol administration strategies, exactly how much medication is delivered to the airways and lungs of infants with BPD (especially if they are ventilator dependent) is unclear. Because significant smooth muscle relaxation does not appear to occur within the first few weeks of life, do not initiate aerosol therapy before this time unless profound respiratory illness exists.

o Systemic bronchodilators
􀂃 Methylxanthines are used to increase respiratory drive, decrease apnea, and improve diaphragmatic contractility. These substances may also decrease pulmonary VR and increase lung compliance in infants with BPD, probably through direct smooth muscle relaxation. They also exhibit diuretic effects.

􀂃 All of the above effects may increase success at weaning from mechanical ventilation. Synergy between theophylline and diuretics has been demonstrated. Theophylline has a half-life of 30-40 hours, is metabolized primarily to caffeine in the liver, and may include adverse effects, such as increase in heart rate, gastroesophageal reflux, agitation, and seizures. Caffeine has a longer half-life than theophylline (approximately 90-100 h) and is excreted unchanged in the urine. Both are available in intravenous and enteral formulations. Caffeine has fewer adverse effects than theophylline.

􀂃 Long-term comparison studies of these 2 agents are needed. Oral albuterol and subcutaneous terbutaline have also been used to treat infants with BPD but appear to offer no therapeutic advantage when compared to the methylxanthines.

o Corticosteroids: These are produced by the adrenal gland. Mineralocorticoids are produced in the adrenal medulla and primarily affect fluid and electrolyte balance. Glucocorticoids possess strong anti-inflammatory properties and affect the metabolism of many tissues. Systemic and inhaled corticosteroids have been studied extensively in preterm infants to prevent and treat BPD.

􀂃 Seven studies have evaluated the effect of dexamethasone versus placebo during the first 2 weeks of life to prevent BPD. Original work by Cummings et al in 1989 revealed that a 42-day course of dexamethasone resulted in a decrease need for oxygen and improved neurologic outcome compared to control subjects aged 6 and 15 months. In 1998, Papile et al reported on the effects of dexamethasone treatment at 2 weeks versus 4 weeks in 371 preterm infants.

􀂃 Dexamethasone treatment initiated at 14 days reduced 28-day mortality and oxygen requirement at 1 month; however, Koroco et al found no difference in CLD at 36 weeks corrected age in 60 infants who received systemic and inhaled corticosteroids or saline placebo beginning at 7 days of life. In 1999, Garland et al reported findings on very early use of a 3-day course of dexamethasone begun within 48 hours of life to prevent BPD. He found that infants treated with dexamethasone had less BPD but noticed an increase in early intestinal perforations. The difference in intestinal perforations between groups prompted a dosage adjustment after the first interim analysis.

􀂃 Dexamethasone has also been administered to preterm infants older than 3 weeks to treat presumed CLD (ie, 28-d oxygen requirement). The largest collaborative dexamethasone trial revealed a decrease in ventilator requirements but no difference in supplemental oxygen usage. Outcomes at age 3 years were similar. 􀂃 Dexamethasone is the primary systemic synthetic corticosteroid that has been studied in preterm neonates. Dexamethasone has many pharmacologic benefits but significant adverse effects. Dexamethasone stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, inhibits prostaglandin and leukotriene, decreases PE, breaks down granulocyte aggregates, and improves pulmonary microcirculation. The adverse effects are hyperglycemia, hypertension, weight loss, GI bleeding or perforation synthesis, cerebral palsy, adrenal suppression, and death.

􀂃 Neurodevelopmental follow-up studies of infants treated with dexamethasone suggest that although this therapy improves short-term pulmonary outcome, long-term outcome appears significantly worse.

􀂃 The routine use of dexamethasone in infants with BPD is not currently recommended unless severe pulmonary disease exists. A rapid tapering course starting at 0.25 mg/kg/d and lasting for 5-7 days appears to be adequate. If no response is observed after 3 days, then discontinue dexamethasone. Inhaled glucocorticoid therapy has been studied in neonates to prevent BPD. In 1999, Cole and colleagues found that early therapy with beclomethasone did not prevent BPD, but it did decrease the need for systemic steroids. Further studies and the development of more efficient aerosol delivery systems are definitely needed.

o Vasodilators: NO is a short-acting inhaled gas that relaxes the pulmonary vasculature. NO is metabolized rapidly by RBCs, thereby minimizing systemic hypotension. NO in vitro may have direct effects on the tracheobronchial tree. In 1999, Banks and colleagues studied the effect of inhaled NO in 16 preterm infants with severe BPD. Eleven of 16 infants had improved oxygenation after 1 hour of inhalation, an effect that persisted in some infants. Further controlled studies are necessary to define the use of NO in the prevention and treatment of BPD.

• Because the routine use of surfactant replacement has begun, survival of the most immature infants has improved. Along with other advances in technology and improved understanding of neonatal physiology, infants with BPD now appear to have less severe disease. Infants with severe BPD remain at high risk for pulmonary morbidity and mortality during the first 2 years of life.

• Fortunately, pulmonary function slowly improves in most survivors with BPD, likely secondary to continued lung and airway growth and healing. Northway followed the cases of patients with BPD to adulthood. In 1992, Northway reported that these patients had airway hyperreactivity, abnormal pulmonary function, and hyperinflation noted on chest radiography. Rehospitalization for impaired pulmonary function is most common during the first 2 years of life. In 1990, Hakulinen et al found a gradual decrease in symptom frequency in children aged 6-9 years as compared to the first 2 years of life. Bader in 1987 and Blayney et al in 1991 found persistence of respiratory symptoms and abnormal PFT results in children aged 7 and 10 years. High-resolution chest CT scanning or MRI studies in children and adults with a history of BPD reveal lung abnormalities that correlate directly with the degree of pulmonary function abnormality.

Consultations: Infants with BPD have multisystem involvement. Therefore, consultations should be obtained from various pediatric subspecialists. They include a cardiologist, pulmonologist, gastroenterologist, developmental pediatrician, ophthalmologist, neurologist, physical therapist, and nutritionist. They may also assist the pediatrician with the ongoing care of these infants after patients are discharged from the hospital.

Diet: Infants with BPD have increased energy requirements.
• Early parenteral nutrition is often used to minimize the catabolic state of the preterm infant. The most immature and unstable preterm infant often has a difficult transition to complete enteral nutrition. Frequent interruption of feedings secondary to intolerance or patient instability complicates the management of these patients. Enteral feeding of breast milk may provide the best nutrition, while possibly preventing feeding complications (eg, sepsis, necrotizing enterocolitis).

• The energy content of expressed breast milk and formulas can be enhanced to provide increased energy intake, while minimizing fluid intake. Infants may require 120-150 kcal/kg of body weight per day to adequately gain weight.

• Diuretics may often be used to prevent or treat fluid overload. • Early insertion of percutaneous central venous lines may help to improve energy density of parenteral nutrition. Accomplish progressive increases in protein and fat supplementation to provide approximately 3-3.5 g/kg of body weight per day and 3 g/kg of body weight per day.

• Rapid and early administration of high concentrations of lipids may worsen hyperbilirubinemia and BPD through pulmonary vascular lipid deposition and bilirubin displacement from albumin.

• Excessive glucose loads may increase oxygen consumption, respiratory drive, carbon dioxide production, and glucosuria.

• Calcium and phosphorus requirements greatly increase in preterm infants. Most mineral stores in the fetus occur during the third trimester, leaving the extremely preterm infant calcium and phosphorus deficient and at increased risk of rickets. Supplemental furosemide therapy and limited intravenous calcium use may worsen bone mineralization and secondary hyperparathyroidism.

• Vitamin A supplementation may improve lung repair and decrease incidence of BPD.

• Trace mineral supplementations (ie, copper, zinc, manganese) are essential cofactors in the AO defenses.