Bronchopulmonary Dysplasia: Clinical Perspective Deepak Jain and Eduardo Bancalari*
Since Northway’s original description of BPD almost 45 years ago, the clinical presentation of BPD has evolved into a disease process, which mostly involves extremely premature infants. This new form of BPD is the result of multiple antenatal and postnatal factors that can cause injury to the developing lung leading to altered alveolar and vascular development. Over the years, there has been considerable increase in knowledge of factors that contribute to the development of BPD. This has led to different strategies for prevention as well as management of BPD. Some of these strategies have been successful and have withstood the test of clinical trials, such as vitamin A supplementation, post-natal steroids, caffeine, and volume targeted ventilation. The evidence for other interventions has been weak or negative.
Introduction There have been significant advancements in the field of neonatal and perinatal medicine since Northway and colleagues described “bronchopulmonary dysplasia” in their original study almost 45 years ago. Although these advancements have markedly increased survival rates of extremely premature infants, BPD continues to be one of the most common complications in these infants with incidence ranging from 25 to 42% in very low birth weight infants (Walsh et al., 2004; Stoll et al., 2010). Since its description, the clinical presentation of BPD has changed significantly with the original severe BPD in relatively bigger infants being replaced by a milder form in extremely preterm infants with a very different clinical and radiographic course. There has also been significant progress in the understanding of factors contributing to lung injury and repair, which can lead to development of preventive and therapeutic strategies in the near future.
Clinical Presentation When Northway and colleagues first introduced the term BPD, they described the clinical, radiographic, and pathologic course of a group of infants with severe respiratory distress syndrome (RDS). All of these infants had severe respiratory failure and were ventilated with high pressures and high oxygen concentrations. They had a high mortality rate (59%), and a significant number developed cor pulmonale. The respiratory course of these infants was described in different stages evolving from initial RDS to a final stage of chronic lung disease at approximately 1 month of age.
University of Miami, Miami, Florida *Correspondence to: Eduardo Bancalari, University of Miami, PO Box 016960 (R-131), Miami, FL 33101. E-mail: [email protected] Published online 27 February 2014 in Wiley Online Library (wileyonlinelibrary. com). Doi: 10.1002/bdra.23229
C 2014 Wiley Periodicals, Inc. V
With better understanding of the complex and multifactorial pathogenesis of BPD, it is quite clear that any single therapy is very unlikely to eliminate this problem unless it reduces prematurity. Further development in prevention and treatment of BPD will likely need a multi-pronged strategy with novel therapeutic agents acting at various stages of the disease process. Birth Defects Research (Part A) 100:134–144, 2014. C 2014 Wiley Periodicals, Inc. V
Key words: BPD; clinical presentation; prevention; management; premature
This final stage consisted of severe respiratory failure with a radiographic picture characterized by increased densities secondary to fibrosis and atelectasis and adjacent large emphysematous areas (Northway et al., 1967) (Fig. 1). NEW BPD
Over the years with increasing use of antenatal steroids, surfactant replacement therapy, and refinement in assisted ventilation methods, the severe form of BPD has become less frequent. As more immature preterm infants are surviving and care of preterm infants is improving, BPD now is seen most commonly in extremely low birth weight infants with structurally immature lungs and underdeveloped pulmonary vasculature. These infants typically have mild initial respiratory disease, which improves quickly with noninvasive respiratory support or surfactant treatment. Within a few days, they are with minimal ventilator settings requiring low FiO2 or are extubated to noninvasive respiratory support. A large proportion of these infants subsequently have progressive respiratory deterioration requiring increasing respiratory support, which may be due to development of a symptomatic patent ductus arteriosus (PDA) or pulmonary infections. These infants may go on to require mechanical ventilation and oxygen for several weeks or months but a large majority of them are essentially symptom free at the time of discharge (Bancalari et al., 2003). This chronic lung disease process has been termed as “New BPD” to differentiate from the process described by Northway, “Original BPD.” The radiographic picture in infants with “New BPD” usually progress from hazy ground glass-opacity, which clears after surfactant treatment to a hazy opacification by 1 to 2 weeks of age and eventually to a relatively uniform pattern of coarse interstitial opacities (Fig. 2) (Agrons et al., 2005). SEVERE BPD
There remains a small group of preterm infants who have severe initial RDS, lung hypoplasia, or pneumonia who do
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(Abman et al., 2008). These infants have increased pulmonary vascular resistance and abnormal vascular reactivity, leading to excessive vasoconstrictor response to acute hypoxia (Abman et al., 1985; Mourani et al., 2004). Clinically these changes in lung architecture lead to a varying degree of hypoxemia, which increases during the periods of physical activity, feeding, or pulmonary infections and edema. They also commonly have hypercapnia secondary to alveolar hypoventilation and ventilationperfusion mismatch. This leads to compensatory metabolic alkalosis, which is often exaggerated by the use of loop diuretics.
Prevention of BPD
FIGURE 1. Original BPD with areas of hyperinflation and emphysema with adjacent dense areas of atelectasis.
not respond adequately to surfactant administration. These infants continue to require mechanical ventilation with high airway pressure and inspired oxygen concentration. Many of these infants develop air leak syndrome, secondary lung infections, and pulmonary edema secondary to inflammation or a PDA further aggravating the lung damage. These infants sometimes develop a radiographic picture characteristic of “Original BPD” and are more likely to develop pulmonary hypertension and signs of right heart failure. Except for a minority, most of these infants can eventually be weaned off from respiratory support but require supplemental oxygen for prolonged periods of time and many are discharged home on oxygen.
Bronchopulmonary dysplasia is the end result of multiple factors that lead to injury to the developing lung and pulmonary vasculature. Therefore, effective prevention of BPD requires a multifactorial approach, which avoids factors that are injurious to the lung and vasculature and promotes normal growth and development of the lung. Over the years, multiple strategies have been tried for decreasing the incidence of BPD with variable success (Table 1). Some of them, which have been more successful, are discussed here. ANTENATAL STEROIDS
Corticosteroids are given prenatally to promote maturation of the surfactant system and reduce the incidence and severity of RDS (NIH Consensus Development Panel, 1995). Treatment with antenatal corticosteroids has been associated with overall reduction in RDS (relative risk [RR], 0.66; 95% confidence interval [CI], 0.59–0.73), and moderate to severe RDS (RR, 0.55; 95% CI, 0.43–0.71). However, treatment with antenatal steroids has failed to show statistically significant reduction in BPD (RR, 0.86;
PULMONARY FUNCTION IN BPD
Infants with established BPD have varying degrees of altered lung architecture due to disrupted alveolar and vascular development. The infants with severe BPD commonly have increased airway resistance due to mucosal hyperplasia, tracheomalacia, and bronchomalacia, resulting in increased time constant and dead space ventilation. There is heterogeneous damage to distal airways and distal airspaces, resulting in variable time constant for different parts of the lungs. This can lead to areas of over inflation and atelectasis and ventilation-perfusion mismatch. These infants also have decreased functional residual capacity and lung compliance. One of the major factors leading to pulmonary morbidities associated with BPD is decreased pulmonary vascular growth and excessive pulmonary vascular remodeling
FIGURE 2. New BPD with generalized homogenous opacities with an interstitial pattern.
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TABLE 1. Strategies for Prevention of BPD Proven strategies from randomized clinical trials:
BRONCHOPULMONARY DYSPLASIA
approaches, early surfactant administration should be considered in all extremely low birth weight infants with RDS, who require endotracheal intubation for management of respiratory failure.
1. Caffeine 2. Vitamin A 3. Volume targeted ventilation 4. Postnatal Steroids Strategies with equivocal evidence from clinical studies: 1. Antenatal steroids 2. Exogenous surfactant 3. Early PDA closure 4. High frequency ventilation 5. Non invasive respiratory support 6. Inhaled nitric oxide 7. Reduced oxygen exposure
95% CI, 0.61–1.22) (Roberts and Dalziel, 2006). This could be due to increased number of preterm infants at risk of BPD being salvaged with use of antenatal steroids. There has been conflicting evidence regarding the advantage of multiple courses of antenatal steroids against single course. There are some animal data suggesting that repeated glucocorticoid administration may inhibit lung growth and development (Massaro and Massaro, 1992, Tschanz et al., 1995). A recent Cochrane review comparing multiple courses of antenatal steroids with single course showed reduced RDS but no improvement in BPD with multiple courses (Crowther et al., 2011). SURFACTANT TREATMENT
Surfactant treatment has improved survival of extremely preterm infants reducing the severity of RDS, need for aggressive ventilation and prolonged oxygen therapy. However, multiple randomized controlled trials (RCTs) have failed to show a statistically significant effect of surfactant on BPD, which may partly be due to increased survival of the more immature infants resulting from surfactant treatment. With the increasing use of nasal continuous positive airway pressure (NCPAP) and noninvasive ventilation, there have arisen new questions regarding need and timing of surfactant use. A recent meta-analysis comparing prophylactic vs. selective surfactant use concluded that a prophylactic approach was associated with increased risk of BPD (RR, 1.13; 95% CI, 1.00–1.28) (Rojas-Reyes et al., 2012). One of the areas that have generated interest in recent years is less invasive methods for administration of surfactant with multiple approaches being currently evaluated (Finer et al., 2010b; Dargaville et al., 2011). Until there is robust evidence on effectiveness and safety of these
NONINVASIVE VENTILATION
One of the major contributing factors for development of BPD is injury to the premature lung due to respiratory support required to sustain life. Therefore, use of noninvasive ventilation, if it can provide adequate gas exchange, may decrease the incidence of BPD. This was first shown by Avery et al. who described a lower incidence of BPD in centers with highest use of continuous positive airway pressure (CPAP) and avoidance of mechanical ventilation (Avery et al., 1987). Since then, numerous clinical trials have examined use of early CPAP instead of mechanical ventilation on incidence of BPD with no significant reduction in incidence of BPD with use of early CPAP (Verder et al., 1994; Morley et al., 2008). Recently, a meta-analysis of studies evaluating strategies to avoid endotracheal mechanical ventilation did show a small but statistically significant reduction in incidence of BPD or death (odds ratio, 0.83; 95% CI, 0.71–0.96) by avoiding endotracheal mechanical ventilation (Fischer and Buhrer, 2013). Most clinical trials performed to evaluate use of early CPAP have shown that 50 to 80% of these infants develop respiratory failure that requires endotracheal intubation (Morley et al., 2008; Finer et al., 2010a). High failure rate of NCPAP has led to studies evaluating use of nasal intermittent positive pressure ventilation (NIPPV) as the initial mode of respiratory support and its effect on BPD. These studies have provided conflicting results with one study of 43 infants showing reduction in BPD (5% vs. 33%, p < 0.05, for infants with birth weight 7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 1:CD001145. Halliday HL, Ehrenkranz RA, Doyle LW. 2010. Early (
Since Northway’s original description of BPD almost 45 years ago, the clinical presentation of BPD has evolved into a disease process, which mostly involves extremely premature infants. This new form of BPD is the result of multiple antenatal and postnatal factors that can cause injury to the developing lung leading to altered alveolar and vascular development. Over the years, there has been considerable increase in knowledge of factors that contribute to the development of BPD. This has led to different strategies for prevention as well as management of BPD. Some of these strategies have been successful and have withstood the test of clinical trials, such as vitamin A supplementation, post-natal steroids, caffeine, and volume targeted ventilation. The evidence for other interventions has been weak or negative.
Introduction There have been significant advancements in the field of neonatal and perinatal medicine since Northway and colleagues described “bronchopulmonary dysplasia” in their original study almost 45 years ago. Although these advancements have markedly increased survival rates of extremely premature infants, BPD continues to be one of the most common complications in these infants with incidence ranging from 25 to 42% in very low birth weight infants (Walsh et al., 2004; Stoll et al., 2010). Since its description, the clinical presentation of BPD has changed significantly with the original severe BPD in relatively bigger infants being replaced by a milder form in extremely preterm infants with a very different clinical and radiographic course. There has also been significant progress in the understanding of factors contributing to lung injury and repair, which can lead to development of preventive and therapeutic strategies in the near future.
Clinical Presentation When Northway and colleagues first introduced the term BPD, they described the clinical, radiographic, and pathologic course of a group of infants with severe respiratory distress syndrome (RDS). All of these infants had severe respiratory failure and were ventilated with high pressures and high oxygen concentrations. They had a high mortality rate (59%), and a significant number developed cor pulmonale. The respiratory course of these infants was described in different stages evolving from initial RDS to a final stage of chronic lung disease at approximately 1 month of age.
University of Miami, Miami, Florida *Correspondence to: Eduardo Bancalari, University of Miami, PO Box 016960 (R-131), Miami, FL 33101. E-mail: [email protected] Published online 27 February 2014 in Wiley Online Library (wileyonlinelibrary. com). Doi: 10.1002/bdra.23229
C 2014 Wiley Periodicals, Inc. V
With better understanding of the complex and multifactorial pathogenesis of BPD, it is quite clear that any single therapy is very unlikely to eliminate this problem unless it reduces prematurity. Further development in prevention and treatment of BPD will likely need a multi-pronged strategy with novel therapeutic agents acting at various stages of the disease process. Birth Defects Research (Part A) 100:134–144, 2014. C 2014 Wiley Periodicals, Inc. V
Key words: BPD; clinical presentation; prevention; management; premature
This final stage consisted of severe respiratory failure with a radiographic picture characterized by increased densities secondary to fibrosis and atelectasis and adjacent large emphysematous areas (Northway et al., 1967) (Fig. 1). NEW BPD
Over the years with increasing use of antenatal steroids, surfactant replacement therapy, and refinement in assisted ventilation methods, the severe form of BPD has become less frequent. As more immature preterm infants are surviving and care of preterm infants is improving, BPD now is seen most commonly in extremely low birth weight infants with structurally immature lungs and underdeveloped pulmonary vasculature. These infants typically have mild initial respiratory disease, which improves quickly with noninvasive respiratory support or surfactant treatment. Within a few days, they are with minimal ventilator settings requiring low FiO2 or are extubated to noninvasive respiratory support. A large proportion of these infants subsequently have progressive respiratory deterioration requiring increasing respiratory support, which may be due to development of a symptomatic patent ductus arteriosus (PDA) or pulmonary infections. These infants may go on to require mechanical ventilation and oxygen for several weeks or months but a large majority of them are essentially symptom free at the time of discharge (Bancalari et al., 2003). This chronic lung disease process has been termed as “New BPD” to differentiate from the process described by Northway, “Original BPD.” The radiographic picture in infants with “New BPD” usually progress from hazy ground glass-opacity, which clears after surfactant treatment to a hazy opacification by 1 to 2 weeks of age and eventually to a relatively uniform pattern of coarse interstitial opacities (Fig. 2) (Agrons et al., 2005). SEVERE BPD
There remains a small group of preterm infants who have severe initial RDS, lung hypoplasia, or pneumonia who do
BIRTH DEFECTS RESEARCH (PART A) 100:134–144 (2014)
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(Abman et al., 2008). These infants have increased pulmonary vascular resistance and abnormal vascular reactivity, leading to excessive vasoconstrictor response to acute hypoxia (Abman et al., 1985; Mourani et al., 2004). Clinically these changes in lung architecture lead to a varying degree of hypoxemia, which increases during the periods of physical activity, feeding, or pulmonary infections and edema. They also commonly have hypercapnia secondary to alveolar hypoventilation and ventilationperfusion mismatch. This leads to compensatory metabolic alkalosis, which is often exaggerated by the use of loop diuretics.
Prevention of BPD
FIGURE 1. Original BPD with areas of hyperinflation and emphysema with adjacent dense areas of atelectasis.
not respond adequately to surfactant administration. These infants continue to require mechanical ventilation with high airway pressure and inspired oxygen concentration. Many of these infants develop air leak syndrome, secondary lung infections, and pulmonary edema secondary to inflammation or a PDA further aggravating the lung damage. These infants sometimes develop a radiographic picture characteristic of “Original BPD” and are more likely to develop pulmonary hypertension and signs of right heart failure. Except for a minority, most of these infants can eventually be weaned off from respiratory support but require supplemental oxygen for prolonged periods of time and many are discharged home on oxygen.
Bronchopulmonary dysplasia is the end result of multiple factors that lead to injury to the developing lung and pulmonary vasculature. Therefore, effective prevention of BPD requires a multifactorial approach, which avoids factors that are injurious to the lung and vasculature and promotes normal growth and development of the lung. Over the years, multiple strategies have been tried for decreasing the incidence of BPD with variable success (Table 1). Some of them, which have been more successful, are discussed here. ANTENATAL STEROIDS
Corticosteroids are given prenatally to promote maturation of the surfactant system and reduce the incidence and severity of RDS (NIH Consensus Development Panel, 1995). Treatment with antenatal corticosteroids has been associated with overall reduction in RDS (relative risk [RR], 0.66; 95% confidence interval [CI], 0.59–0.73), and moderate to severe RDS (RR, 0.55; 95% CI, 0.43–0.71). However, treatment with antenatal steroids has failed to show statistically significant reduction in BPD (RR, 0.86;
PULMONARY FUNCTION IN BPD
Infants with established BPD have varying degrees of altered lung architecture due to disrupted alveolar and vascular development. The infants with severe BPD commonly have increased airway resistance due to mucosal hyperplasia, tracheomalacia, and bronchomalacia, resulting in increased time constant and dead space ventilation. There is heterogeneous damage to distal airways and distal airspaces, resulting in variable time constant for different parts of the lungs. This can lead to areas of over inflation and atelectasis and ventilation-perfusion mismatch. These infants also have decreased functional residual capacity and lung compliance. One of the major factors leading to pulmonary morbidities associated with BPD is decreased pulmonary vascular growth and excessive pulmonary vascular remodeling
FIGURE 2. New BPD with generalized homogenous opacities with an interstitial pattern.
136
TABLE 1. Strategies for Prevention of BPD Proven strategies from randomized clinical trials:
BRONCHOPULMONARY DYSPLASIA
approaches, early surfactant administration should be considered in all extremely low birth weight infants with RDS, who require endotracheal intubation for management of respiratory failure.
1. Caffeine 2. Vitamin A 3. Volume targeted ventilation 4. Postnatal Steroids Strategies with equivocal evidence from clinical studies: 1. Antenatal steroids 2. Exogenous surfactant 3. Early PDA closure 4. High frequency ventilation 5. Non invasive respiratory support 6. Inhaled nitric oxide 7. Reduced oxygen exposure
95% CI, 0.61–1.22) (Roberts and Dalziel, 2006). This could be due to increased number of preterm infants at risk of BPD being salvaged with use of antenatal steroids. There has been conflicting evidence regarding the advantage of multiple courses of antenatal steroids against single course. There are some animal data suggesting that repeated glucocorticoid administration may inhibit lung growth and development (Massaro and Massaro, 1992, Tschanz et al., 1995). A recent Cochrane review comparing multiple courses of antenatal steroids with single course showed reduced RDS but no improvement in BPD with multiple courses (Crowther et al., 2011). SURFACTANT TREATMENT
Surfactant treatment has improved survival of extremely preterm infants reducing the severity of RDS, need for aggressive ventilation and prolonged oxygen therapy. However, multiple randomized controlled trials (RCTs) have failed to show a statistically significant effect of surfactant on BPD, which may partly be due to increased survival of the more immature infants resulting from surfactant treatment. With the increasing use of nasal continuous positive airway pressure (NCPAP) and noninvasive ventilation, there have arisen new questions regarding need and timing of surfactant use. A recent meta-analysis comparing prophylactic vs. selective surfactant use concluded that a prophylactic approach was associated with increased risk of BPD (RR, 1.13; 95% CI, 1.00–1.28) (Rojas-Reyes et al., 2012). One of the areas that have generated interest in recent years is less invasive methods for administration of surfactant with multiple approaches being currently evaluated (Finer et al., 2010b; Dargaville et al., 2011). Until there is robust evidence on effectiveness and safety of these
NONINVASIVE VENTILATION
One of the major contributing factors for development of BPD is injury to the premature lung due to respiratory support required to sustain life. Therefore, use of noninvasive ventilation, if it can provide adequate gas exchange, may decrease the incidence of BPD. This was first shown by Avery et al. who described a lower incidence of BPD in centers with highest use of continuous positive airway pressure (CPAP) and avoidance of mechanical ventilation (Avery et al., 1987). Since then, numerous clinical trials have examined use of early CPAP instead of mechanical ventilation on incidence of BPD with no significant reduction in incidence of BPD with use of early CPAP (Verder et al., 1994; Morley et al., 2008). Recently, a meta-analysis of studies evaluating strategies to avoid endotracheal mechanical ventilation did show a small but statistically significant reduction in incidence of BPD or death (odds ratio, 0.83; 95% CI, 0.71–0.96) by avoiding endotracheal mechanical ventilation (Fischer and Buhrer, 2013). Most clinical trials performed to evaluate use of early CPAP have shown that 50 to 80% of these infants develop respiratory failure that requires endotracheal intubation (Morley et al., 2008; Finer et al., 2010a). High failure rate of NCPAP has led to studies evaluating use of nasal intermittent positive pressure ventilation (NIPPV) as the initial mode of respiratory support and its effect on BPD. These studies have provided conflicting results with one study of 43 infants showing reduction in BPD (5% vs. 33%, p < 0.05, for infants with birth weight 7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 1:CD001145. Halliday HL, Ehrenkranz RA, Doyle LW. 2010. Early (
