Bronchopulmonary dysplasia: An update
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《美国医学杂志》
1 Division of Pediatric Pulmonology, Connecticut Children's Medical Center, Hartford, CT, USA
2 Division of Perinatal Medicine, Yale University School of Medicine, New Haven, CT, USA
Bronchopulmonary dysplasia (BPD) is a chronic lung disease associated with premature birth and characterized by early lung injury. Over the past 4 decades, there have been significant changes in its definition, pathology and radiological findings as well as management of BPD. Management of the acute phase and later stages of this lung disease continue to evolve. Use of non-invasive ventilatory techniques, recombinant human SOD and CC10 and inhaled NO are some novel approaches that are being studied. Adequate nutrition is vital to optimize lung growth and repair. The widely accepted practice of prophylaxis against viral infections has markedly decreased the rates of rehospitalization. Infants with BPD, however, continue to have significant pulmonary and neurodevelopmental sequelae. Unraveling the genetic contribution to BPD will potentially pave the way to improved preventive and therapeutic approaches.
Keywords: BPD; Prematurity; Chronic lung disease
The lack of a uniformly accepted definition of bronchopulmonary dysplasia (BPD) is related to the general disagreement amongst caregivers about the need for supplemental oxygen based on oxygen saturations on pulse oximetry. At a consensus meeting of National Institutes of Health in 2001, a new criteria for diagnosis and severity of BPD were proposed[1] which have been summarized in [Table - 1]. During this meeting, it was also recommended that the original nomenclature of BPD be reinstated instead of "chronic lung disease of infancy" since BPD is distinct from the numerous other chronic lung diseases in pediatric and adult age groups.[1]
Incidence
The incidence of BPD is difficult to assess given the lack of universally accepted definition of BPD. The "classic" BPD described by Northway in 1967[2] has now been replaced by less severe forms of "new" BPD, which are infrequently found in patients >30 weeks of gestation and birth weights >1200 grams. In a recent study, where BPD was defined as oxygen need at 36 weeks post menstrual age, the incidence was 52% in infants with birth weights of 501-750g, 34% in infants with birth weights of 751-1000g, 15% in infants with birth weights of 1001-1200g, and 7% in infants with birth weights of 1201-1500g.[3]
Pathology
The pathology of the BPD lung from the pre-surfactant era was remarkable for presence of severe airway injury, inflammation and parenchymal fibrosis and marked heterogeneity in lung pathology with severe alveolar septal fibrosis in some areas and presence of normally inflated and/or hyperinflated lung in the adjacent sub-lobule or lobe.[4],[5]
Pathological findings of the "new" BPD lung reveal more uniform inflation and less marked fibrosis and absence of both small and large airway epithelial metaplasia, smooth muscle hypertrophy and fibrosis, as compared to lungs of infants with "classic" BPD. Arrest of acinar development, resulting in decrease in alveolar number and a decrease in the arterial count with normal alveolar/arterial ratio was reported in the lungs of the patients with BPD regardless of whether the patients were treated with surfactant.[6] In addition to decreased alveolar number, various other abnormalities of distal microvasculature have been reported which include marked angiogenesis, proportionate to the growth of the air-exchanging lung parenchyma,[7] prominent corner vessels with variable capillary density in adjacent alveoli [8] or vessels that are more distant from the air surface.[7],[9] All this data suggests that prenatal and postnatal alveolar and vascular development are closely linked.
Pathogenesis
A proposed mechanism for the development of BPD has been shown in [Figure - 1]. An imbalance in the release of pro- and anti-inflammatory cytokines, occurring as a result of volu/baro trauma, hyperoxia, pulmonary edema, and/or sepsis, damages the immature lung. This is followed either by healing (resolution of injury) or repair of the lung (BPD).[10] Cytokine release and the responses of the immature lung are determined by allelic differences of the genes, creating a genetic susceptibility to BPD.[11]
Management
The principles of management, including pharmacotherapy, have been summarized in [Table - 2].
Outcomes in BPD
Pulmonary
Morbidity: There is significant pulmonary morbidity associated with BPD. Infants with BPD have higher rates of rehospitalizations, with up to 50% of very low birth weight (VLBW) infants with severe BPD needing re-hospitalization in the first year of life and 36% re-hospitalized the second year of life.[12] The commonest reasons for re-hospitalization in this population were reactive airway disease, pneumonia, respiratory syncytial virus (RSV) infection and worsening BPD. [12]
Radiological findings: Most studies show abnormal chest X-rays with subtle radiological abnormalities later in adolescence and adulthood.[13] Aquino et al[14] have reported a positive correlation between abnormal radiographic findings and pulmonary function.
Pulmonary Function: Most infants with BPD have decreased airway conductance and increased airway resistance which typically normalizes by 2-3 years of age.[15] Most children with history of BPD have significantly lower forced vital capacity (FVC), forced expiratory volume at 1 second (FEV 1), forced expiratory flow at 25% of FVC (FEF 25-75 ), and increased residual volume/total lung capacity (RV/TLC) when compared to normal full term infants and preterm controls without BPD.[13]
Small airway abnormalities and airway hyper-responsiveness are most likely to persist long-term in patients with BPD.[10],[13] Tracheomalacia and bronchomalacia result from prolonged endotracheal intubation and mechanical ventilation and are associated with increased airway compliance which predispose these infants to impaired airway clearance and acute episodes of cyanosis commonly referred to as "BPD spells". Other large airway problems commonly encountered are sub-glottic stenosis, airway granulomas and pseudopolyps and may require surgical intervention.
Mitchell et al[16] reported a decreased gas transfer and oxyhemoglobin saturations during exercise in school aged children (6-9 years) with past history of BPD when compared with full term controls and preterm children with no BPD, and attributed it to persistent lung structural abnormality or residual right ventricular dysfunction. Santuz et al[1 7] showed decrease in maximal exercise in capacity in BPD survivors aged 6-12 years when compared to healthy controls. Most studies, however, show no reduction in exercise capacity in children with BPD when compared to children with healthy term infants or preterm babies without lung disease.[10]
Neurodevelopmental
VLBW infants with BPD children have a greater fine and gross motor skill impairment as well as cognitive function and language delay as compared to VLBW infants without BPD.[18],[19]
Experimental Therapies
Use of early nasal continuous positive airway pressure (NCPAP)[20] or synchronized nasal intermittent positive pressure ventilation (SNIPPV)[21],[22] to minimize injury to the immature lung, has shown some benefit and large randomized clinical trials are currently underway.
Inhaled nitric oxide (iNO) may[23],[24] or may not[25],[26] be beneficial, and hence, more studies are needed to better identify the potential benefits to the target population that develop BPD.
Although the antioxidant recombinant Cu-Zn superoxide dismutase (SOD), did not show any difference in outcome,[27] infants <27 weeks of gestation that received SOD had decreased hospitalizations, emergency room visits and less frequent use of bronchodilator therapy at age 1 as compared to the infants that did not receive SOD,[28] suggesting that SOD may have interrupted an inflammatory cascade involving reactive oxygen reactive species and possibly conferring a long-term benefit.
Use of an anti-inflammatory protein, recombinant human Clara cell 10-kD protein (CC10) has shown some initial promise.[29]
Prevention
Prevention of BPD is obviously dependent on the prevention of premature labor and birth. Etiologies of preterm labor and premature rupture of membranes are currently being studied and a better understanding of these will likely impact on the incidence of preterm labor and hence, the number of infants at risk for development of BPD. The use of progesterone in prevention of premature labor has shown promise, although the prolongation of gestation as a result of use of progesterone, has yet to be shown to improve infant outcomes.[30] As far as prenatal lung maturation is concerned, antenatal steroids remain the single most effective intervention thus far.
Prevention, early diagnosis and treatment of sepsis, management of nutrition and fluid/electrolytes along with appropriate ventilatory management during the often stormy perinatal period remain of utmost importance to make an impact on the morbidity and mortality associated with BPD.[31],[32],[33],[34] Lastly, twin studies have shown a strong genetic susceptibility to BPD, and thus, further unraveling of the genetic contribution to BPD will potentially pave the way for gene specific therapies.[11]
Conclusion
BPD is a chronic lung disease associated with premature birth and early lung injury. Understanding of the various mechanisms of development of this lung disease has progressed dramatically over the last 4 decades. These 4 decades have also seen a change in its definition, pathology and radiological findings as well as management of BPD. Management of the acute phase and later stages of this lung disease as well as other co-morbidities in preterm infants continue to play a role in the resolution of BPD. Adequate nutrition is vital to optimize lung growth and repair. The widely accepted practice of prophylaxis against viral infections has markedly decreased the rates of rehospitalization. Infants with BPD, however, continue to have significant pulmonary and neurodevelopmental sequelae[42].
References
1.Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163 : 1723-1729.
2.Northway WH, Jr., Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 1967; 276 : 357-368.
3.Ehrenkranz RA, Walsh MC, Vohr BR et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116 : 1353-1360.
4.Rosan RC. Hyaline membrane disease and a related spectrum of neonatal pneumopathies. Perspect Pediatr Pathol 1975; 2 : 15-60. [PUBMED]
5.Stocker JT. Pathologic features of long-standing "healed" bronchopulmonary dysplasia: a study of 28 3- to 40-month-old infants. Hum Pathol 1986; 17 : 943-961. [PUBMED]
6.Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998; 29 : 710-717. [PUBMED]
7.De Paepe ME, Mao Q, Powell J et al. Growth of pulmonary microvasculature in ventilated preterm infants. Am J Respir Crit Care Med 2006; 173 : 204-211.
8.Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003; 8 : 73-81. [PUBMED] [FULLTEXT]
9.Thibeault DW, Mabry SM, Norberg M, Truog WE, Ekekezie, II. Lung microvascular adaptation in infants with chronic lung disease. Biol Neonate 2004; 85 : 273-282.
10.Bhandari A, Bhandari V. Pathogenesis, pathology and pathophysiology of pulmonary sequelae of bronchopulmonary dysplasia in premature infants. Front Biosci 2003; 8 : e370-380. [PUBMED] [FULLTEXT]
11.Bhandari V, Bizzarro MJ, Shetty AH et al. Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics 2006; 117 : 1901-1906.
12.Furman L, Baley J, Borawski-Clark E, Aucott S, Hack M. Hospitalization as a measure of morbidity among very low birth weight infants with chronic lung disease. J Pediatr 1996; 128 : 447-452. [PUBMED] [FULLTEXT]
13.Northway WH, Jr., Moss RB, Carlisle KB et al. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med 1990; 323 : 1793-1799.
14.Aquino SL, Schechter MS, Chiles C, Ablin DS, Chipps B, Webb WR. High-resolution inspiratory and expiratory CT in older children and adults with bronchopulmonary dysplasia. AJR Am J Roentgenol 1999; 173 : 963-967. [PUBMED]
15.Baraldi E, Filippone M, Trevisanuto D, Zanardo V, Zacchello F. Pulmonary function until two years of life in infants with bronchopulmonary dysplasia. Am J Respir Crit Care Med 1997; 155 : 149-155.
16.Mitchell SH, Teague WG. Reduced gas transfer at rest and during exercise in school-age survivors of bronchopulmonary dysplasia. Am J Respir Crit Care Med 1998; 157 : 1406-1412. [PUBMED] [FULLTEXT]
17.Santuz P, Baraldi E, Zaramella P, Filippone M, Zacchello F. Factors limiting exercise performance in long-term survivors of bronchopulmonary dysplasia. Am J Respir Crit Care Med 1995; 152 : 1284-1289. [PUBMED]
18.Short EJ, Klein NK, Lewis BA et al. Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes. Pediatrics 2003; 112:e359.
19.Lewis BA, Singer LT, Fulton S et al. Speech and language outcomes of children with bronchopulmonary dysplasia. J Commun Disord 2002; 35 : 393-406.
20.Verder H, Albertsen P, Ebbesen F et al. Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks' gestation. Pediatrics 1999; 103 : E24.
21.Khalaf MN, Brodsky N, Hurley J, Bhandari V. A prospective randomized, controlled trial comparing synchronized nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure as modes of extubation. Pediatrics 2001; 108:13-7.
22.Santin R, Brodsky N, Bhandari V. A prospective observational pilot study of synchronized nasal intermittent positive pressure ventilation (SNIPPV) as a primary mode of ventilation in infants > or = 28 weeks with respiratory distress syndrome (RDS). J Perinatol 2004; 24 : 487-493.
23.Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 2005; 353 : 23-32.
24.Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 2003; 349 : 2099-107.
25.Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatr 2005; 115: 926-936.
26.Hascoet JM, Fresson J, Claris O et al. The safety and efficacy of nitric oxide therapy in premature infants. J Pediatr 2005; 146 : 318-23.
27.Davis JM, Rosenfeld WN, Richter SE et al. Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome. Pediatrics 1997; 100 : 24-30.
28.Davis JM, Parad RB, Michele T, Allred E, Price A, Rosenfeld W. Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase. Pediatrics 2003; 111 : 469-476.
29.Levine CR, Gewolb IH, Allen K et al. The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatr Res 2005; 58 : 15-21.
30.Dodd JM, Crowther CA, Cincotta R, Flenady V, Robinson JS. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2005; 84 : 526-533.
31.Akram Khan M, Kuzma-O'reilly B, Brodsky NL, Bhandari V. Site-specific characteristics of infants developing bronchopulmonary dysplasia. J Perinatol 2006; 26 : 428-435.
32.Kulkarni A, Ehrenkranz RA, Bhandari V. Effect of introduction of synchronized nasal intermittent positive-pressure ventilation in a neonatal intensive care unit on bronchopulmonary dysplasia and growth in preterm infants. Am J Perinatol 2006; 23 : 233-240.
33.Bhandari V, Brodsky N, Porat R. Improved outcome of extremely low birth weight infants with Tegaderm application to skin. J Perinatol 2005; 25 : 276-281.
34.Bhandari V, Fall P, Raisz L, Rowe J. Potential biochemical growth markers in premature infants. Am J Perinatol 1999; 16 : 339-349.
35.Kamlin CO, Davis PG. Long versus short inspiratory times in neonates receiving mechanical ventilation. Cochrane Database Syst Rev 2004:CD004503.
36.Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 2000; CD001456.
37.Schmidt B, Roberts RS, Davis P et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006; 354 : 2112-2121.
38.Tyson JE, Wright LL, Oh W et al. Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med 1999; 340 : 1962-1968.
39.Halliday HL, Ehrenkranz RA, Doyle LW. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003 : CD001145.
40.Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003: CD001144.
41.Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003: CD001146.
42.Panitch HB, Keklikian EN, Motley RA, Wolfson MR, Schidlow DV. Effect of altering smooth muscle tone on maximal expiratory flows in patients with tracheomalacia. Pediatr Pulmonol 1990; 9 : 170-176.(Bhandari Anita, Bhandari Vineet)
2 Division of Perinatal Medicine, Yale University School of Medicine, New Haven, CT, USA
Bronchopulmonary dysplasia (BPD) is a chronic lung disease associated with premature birth and characterized by early lung injury. Over the past 4 decades, there have been significant changes in its definition, pathology and radiological findings as well as management of BPD. Management of the acute phase and later stages of this lung disease continue to evolve. Use of non-invasive ventilatory techniques, recombinant human SOD and CC10 and inhaled NO are some novel approaches that are being studied. Adequate nutrition is vital to optimize lung growth and repair. The widely accepted practice of prophylaxis against viral infections has markedly decreased the rates of rehospitalization. Infants with BPD, however, continue to have significant pulmonary and neurodevelopmental sequelae. Unraveling the genetic contribution to BPD will potentially pave the way to improved preventive and therapeutic approaches.
Keywords: BPD; Prematurity; Chronic lung disease
The lack of a uniformly accepted definition of bronchopulmonary dysplasia (BPD) is related to the general disagreement amongst caregivers about the need for supplemental oxygen based on oxygen saturations on pulse oximetry. At a consensus meeting of National Institutes of Health in 2001, a new criteria for diagnosis and severity of BPD were proposed[1] which have been summarized in [Table - 1]. During this meeting, it was also recommended that the original nomenclature of BPD be reinstated instead of "chronic lung disease of infancy" since BPD is distinct from the numerous other chronic lung diseases in pediatric and adult age groups.[1]
Incidence
The incidence of BPD is difficult to assess given the lack of universally accepted definition of BPD. The "classic" BPD described by Northway in 1967[2] has now been replaced by less severe forms of "new" BPD, which are infrequently found in patients >30 weeks of gestation and birth weights >1200 grams. In a recent study, where BPD was defined as oxygen need at 36 weeks post menstrual age, the incidence was 52% in infants with birth weights of 501-750g, 34% in infants with birth weights of 751-1000g, 15% in infants with birth weights of 1001-1200g, and 7% in infants with birth weights of 1201-1500g.[3]
Pathology
The pathology of the BPD lung from the pre-surfactant era was remarkable for presence of severe airway injury, inflammation and parenchymal fibrosis and marked heterogeneity in lung pathology with severe alveolar septal fibrosis in some areas and presence of normally inflated and/or hyperinflated lung in the adjacent sub-lobule or lobe.[4],[5]
Pathological findings of the "new" BPD lung reveal more uniform inflation and less marked fibrosis and absence of both small and large airway epithelial metaplasia, smooth muscle hypertrophy and fibrosis, as compared to lungs of infants with "classic" BPD. Arrest of acinar development, resulting in decrease in alveolar number and a decrease in the arterial count with normal alveolar/arterial ratio was reported in the lungs of the patients with BPD regardless of whether the patients were treated with surfactant.[6] In addition to decreased alveolar number, various other abnormalities of distal microvasculature have been reported which include marked angiogenesis, proportionate to the growth of the air-exchanging lung parenchyma,[7] prominent corner vessels with variable capillary density in adjacent alveoli [8] or vessels that are more distant from the air surface.[7],[9] All this data suggests that prenatal and postnatal alveolar and vascular development are closely linked.
Pathogenesis
A proposed mechanism for the development of BPD has been shown in [Figure - 1]. An imbalance in the release of pro- and anti-inflammatory cytokines, occurring as a result of volu/baro trauma, hyperoxia, pulmonary edema, and/or sepsis, damages the immature lung. This is followed either by healing (resolution of injury) or repair of the lung (BPD).[10] Cytokine release and the responses of the immature lung are determined by allelic differences of the genes, creating a genetic susceptibility to BPD.[11]
Management
The principles of management, including pharmacotherapy, have been summarized in [Table - 2].
Outcomes in BPD
Pulmonary
Morbidity: There is significant pulmonary morbidity associated with BPD. Infants with BPD have higher rates of rehospitalizations, with up to 50% of very low birth weight (VLBW) infants with severe BPD needing re-hospitalization in the first year of life and 36% re-hospitalized the second year of life.[12] The commonest reasons for re-hospitalization in this population were reactive airway disease, pneumonia, respiratory syncytial virus (RSV) infection and worsening BPD. [12]
Radiological findings: Most studies show abnormal chest X-rays with subtle radiological abnormalities later in adolescence and adulthood.[13] Aquino et al[14] have reported a positive correlation between abnormal radiographic findings and pulmonary function.
Pulmonary Function: Most infants with BPD have decreased airway conductance and increased airway resistance which typically normalizes by 2-3 years of age.[15] Most children with history of BPD have significantly lower forced vital capacity (FVC), forced expiratory volume at 1 second (FEV 1), forced expiratory flow at 25% of FVC (FEF 25-75 ), and increased residual volume/total lung capacity (RV/TLC) when compared to normal full term infants and preterm controls without BPD.[13]
Small airway abnormalities and airway hyper-responsiveness are most likely to persist long-term in patients with BPD.[10],[13] Tracheomalacia and bronchomalacia result from prolonged endotracheal intubation and mechanical ventilation and are associated with increased airway compliance which predispose these infants to impaired airway clearance and acute episodes of cyanosis commonly referred to as "BPD spells". Other large airway problems commonly encountered are sub-glottic stenosis, airway granulomas and pseudopolyps and may require surgical intervention.
Mitchell et al[16] reported a decreased gas transfer and oxyhemoglobin saturations during exercise in school aged children (6-9 years) with past history of BPD when compared with full term controls and preterm children with no BPD, and attributed it to persistent lung structural abnormality or residual right ventricular dysfunction. Santuz et al[1 7] showed decrease in maximal exercise in capacity in BPD survivors aged 6-12 years when compared to healthy controls. Most studies, however, show no reduction in exercise capacity in children with BPD when compared to children with healthy term infants or preterm babies without lung disease.[10]
Neurodevelopmental
VLBW infants with BPD children have a greater fine and gross motor skill impairment as well as cognitive function and language delay as compared to VLBW infants without BPD.[18],[19]
Experimental Therapies
Use of early nasal continuous positive airway pressure (NCPAP)[20] or synchronized nasal intermittent positive pressure ventilation (SNIPPV)[21],[22] to minimize injury to the immature lung, has shown some benefit and large randomized clinical trials are currently underway.
Inhaled nitric oxide (iNO) may[23],[24] or may not[25],[26] be beneficial, and hence, more studies are needed to better identify the potential benefits to the target population that develop BPD.
Although the antioxidant recombinant Cu-Zn superoxide dismutase (SOD), did not show any difference in outcome,[27] infants <27 weeks of gestation that received SOD had decreased hospitalizations, emergency room visits and less frequent use of bronchodilator therapy at age 1 as compared to the infants that did not receive SOD,[28] suggesting that SOD may have interrupted an inflammatory cascade involving reactive oxygen reactive species and possibly conferring a long-term benefit.
Use of an anti-inflammatory protein, recombinant human Clara cell 10-kD protein (CC10) has shown some initial promise.[29]
Prevention
Prevention of BPD is obviously dependent on the prevention of premature labor and birth. Etiologies of preterm labor and premature rupture of membranes are currently being studied and a better understanding of these will likely impact on the incidence of preterm labor and hence, the number of infants at risk for development of BPD. The use of progesterone in prevention of premature labor has shown promise, although the prolongation of gestation as a result of use of progesterone, has yet to be shown to improve infant outcomes.[30] As far as prenatal lung maturation is concerned, antenatal steroids remain the single most effective intervention thus far.
Prevention, early diagnosis and treatment of sepsis, management of nutrition and fluid/electrolytes along with appropriate ventilatory management during the often stormy perinatal period remain of utmost importance to make an impact on the morbidity and mortality associated with BPD.[31],[32],[33],[34] Lastly, twin studies have shown a strong genetic susceptibility to BPD, and thus, further unraveling of the genetic contribution to BPD will potentially pave the way for gene specific therapies.[11]
Conclusion
BPD is a chronic lung disease associated with premature birth and early lung injury. Understanding of the various mechanisms of development of this lung disease has progressed dramatically over the last 4 decades. These 4 decades have also seen a change in its definition, pathology and radiological findings as well as management of BPD. Management of the acute phase and later stages of this lung disease as well as other co-morbidities in preterm infants continue to play a role in the resolution of BPD. Adequate nutrition is vital to optimize lung growth and repair. The widely accepted practice of prophylaxis against viral infections has markedly decreased the rates of rehospitalization. Infants with BPD, however, continue to have significant pulmonary and neurodevelopmental sequelae[42].
References
1.Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163 : 1723-1729.
2.Northway WH, Jr., Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 1967; 276 : 357-368.
3.Ehrenkranz RA, Walsh MC, Vohr BR et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116 : 1353-1360.
4.Rosan RC. Hyaline membrane disease and a related spectrum of neonatal pneumopathies. Perspect Pediatr Pathol 1975; 2 : 15-60. [PUBMED]
5.Stocker JT. Pathologic features of long-standing "healed" bronchopulmonary dysplasia: a study of 28 3- to 40-month-old infants. Hum Pathol 1986; 17 : 943-961. [PUBMED]
6.Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998; 29 : 710-717. [PUBMED]
7.De Paepe ME, Mao Q, Powell J et al. Growth of pulmonary microvasculature in ventilated preterm infants. Am J Respir Crit Care Med 2006; 173 : 204-211.
8.Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003; 8 : 73-81. [PUBMED] [FULLTEXT]
9.Thibeault DW, Mabry SM, Norberg M, Truog WE, Ekekezie, II. Lung microvascular adaptation in infants with chronic lung disease. Biol Neonate 2004; 85 : 273-282.
10.Bhandari A, Bhandari V. Pathogenesis, pathology and pathophysiology of pulmonary sequelae of bronchopulmonary dysplasia in premature infants. Front Biosci 2003; 8 : e370-380. [PUBMED] [FULLTEXT]
11.Bhandari V, Bizzarro MJ, Shetty AH et al. Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics 2006; 117 : 1901-1906.
12.Furman L, Baley J, Borawski-Clark E, Aucott S, Hack M. Hospitalization as a measure of morbidity among very low birth weight infants with chronic lung disease. J Pediatr 1996; 128 : 447-452. [PUBMED] [FULLTEXT]
13.Northway WH, Jr., Moss RB, Carlisle KB et al. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med 1990; 323 : 1793-1799.
14.Aquino SL, Schechter MS, Chiles C, Ablin DS, Chipps B, Webb WR. High-resolution inspiratory and expiratory CT in older children and adults with bronchopulmonary dysplasia. AJR Am J Roentgenol 1999; 173 : 963-967. [PUBMED]
15.Baraldi E, Filippone M, Trevisanuto D, Zanardo V, Zacchello F. Pulmonary function until two years of life in infants with bronchopulmonary dysplasia. Am J Respir Crit Care Med 1997; 155 : 149-155.
16.Mitchell SH, Teague WG. Reduced gas transfer at rest and during exercise in school-age survivors of bronchopulmonary dysplasia. Am J Respir Crit Care Med 1998; 157 : 1406-1412. [PUBMED] [FULLTEXT]
17.Santuz P, Baraldi E, Zaramella P, Filippone M, Zacchello F. Factors limiting exercise performance in long-term survivors of bronchopulmonary dysplasia. Am J Respir Crit Care Med 1995; 152 : 1284-1289. [PUBMED]
18.Short EJ, Klein NK, Lewis BA et al. Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes. Pediatrics 2003; 112:e359.
19.Lewis BA, Singer LT, Fulton S et al. Speech and language outcomes of children with bronchopulmonary dysplasia. J Commun Disord 2002; 35 : 393-406.
20.Verder H, Albertsen P, Ebbesen F et al. Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks' gestation. Pediatrics 1999; 103 : E24.
21.Khalaf MN, Brodsky N, Hurley J, Bhandari V. A prospective randomized, controlled trial comparing synchronized nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure as modes of extubation. Pediatrics 2001; 108:13-7.
22.Santin R, Brodsky N, Bhandari V. A prospective observational pilot study of synchronized nasal intermittent positive pressure ventilation (SNIPPV) as a primary mode of ventilation in infants > or = 28 weeks with respiratory distress syndrome (RDS). J Perinatol 2004; 24 : 487-493.
23.Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 2005; 353 : 23-32.
24.Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 2003; 349 : 2099-107.
25.Field D, Elbourne D, Truesdale A et al. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatr 2005; 115: 926-936.
26.Hascoet JM, Fresson J, Claris O et al. The safety and efficacy of nitric oxide therapy in premature infants. J Pediatr 2005; 146 : 318-23.
27.Davis JM, Rosenfeld WN, Richter SE et al. Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome. Pediatrics 1997; 100 : 24-30.
28.Davis JM, Parad RB, Michele T, Allred E, Price A, Rosenfeld W. Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase. Pediatrics 2003; 111 : 469-476.
29.Levine CR, Gewolb IH, Allen K et al. The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatr Res 2005; 58 : 15-21.
30.Dodd JM, Crowther CA, Cincotta R, Flenady V, Robinson JS. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2005; 84 : 526-533.
31.Akram Khan M, Kuzma-O'reilly B, Brodsky NL, Bhandari V. Site-specific characteristics of infants developing bronchopulmonary dysplasia. J Perinatol 2006; 26 : 428-435.
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