Pulmonary Care and Adjunctive Therapies for Prevention and Amelioration of Bronchopulmonary Dysplasia Robert H.

Pfister and Roger F. Soll Neoreviews 2011;12;e635 DOI: 10.1542/neo.12-11-e635

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Pulmonary Care and Adjunctive Therapies for Prevention and Amelioration of Bronchopulmonary Dysplasia
Robert H. Pster, MD,* Roger F. Soll, MD

Abstract
Shortly after the introduction of assisted ventilation in the newborn, bronchopulmonary dysplasia (BPD) was rst described. Northway and coworkers described a group of preterm infants who developed chronic respiratory failure and characteristic radiographic changes after prolonged mechanical ventilation. The prevention and management of BPD in infants at risk is challenging due to the complex pathogenesis of multiple contributing factors that include prematurity, supplemental oxygen exposure, mechanical ventilation, patent ductus arterious, inammation, genetic predisposition and postnatal infection. Treatment of existing BPD requires a coordinated approach including optimal nutrition, careful uid management, evidence-based drug therapy, and gentle respiratory techniques aimed at minimizing lung injury. The best respiratory support strategy remains unclear and requires further investigation but includes avoidance of ventilator-induced lung injury (barotraumas and volutrauma), hyperoxemia, and hypocapnea. Among the available interventions antenatal steroids, caffeine, and surfactant have the best risk-benet prole. Systemic postnatal corticosteroids should be used only in ventilated infants unable to be weaned from the ventilator. Quality improvement techniques may have a role towards improvement of hospital systems geared toward reduction of BPD.

Author Disclosure: Drs Pster and Soll have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Objectives:

After completing this article, readers should be able to:

1. Understand the changing denition of BPD. 2. Understand the changing appreciation of the pathophysiology of the new BPD. 3. Understand the relative efcacy and limitations of many of our therapeutic interventions have in decreasing the risk of BPD. 4. Understand the role of quality improvement in reducing complex multifactorial outcomes such as BPD.

Introduction
The introduction of mechanical ventilation in the newborn led to remarkable changes in survival, particularly among very low birthweight infants. Shortly after the introduction of this new technology, Northway et al (1) described a new respiratory disease termed BPD that developed in these infants. Northway et al (1) described a group of preterm infants who developed chronic respiratory failure and characteristic radiographic changes after prolonged mechanical ventilation. The lung damage that was seen in these infants was Abbreviations thought to be due to the impact of mechanical ventilation and the attendant barotrauma as well as the toxic effects of BPD: bronchopulmonary dysplasia high inspired oxygen concentrations. Northway et al (1) CI: condence interval originally described four stages of the disease: an early stage, CPAP: continuous positive airway pressure involving necrosis; a second phase, involving repair and iNO: inhaled nitric oxide inammation; a third phase, involving dysplastic change; and INSURE: Intubate Surfactant Extubate a fourth phase, occurring after many weeks, of severe cystic PDA: patent ductus arteriosus change and cor pulmonale. Many factors contribute to BPD; RDS: respiratory distress syndrome clearly, prematurity and the need for ventilator support lead RR: relative risk the list. However, a variety of other issues, such as genetic
*Assistant Professor of Pediatrics, The University of Vermont, Burlington, VT. Professor of Pediatrics, The University of Vermont, Burlington, VT. NeoReviews Vol.12 No.11 November 2011 e635

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predisposition, perinatal asphyxia, perinatal infection, and inammation, may all contribute to the process. Since Northway et als (1) rst description of BPD, our understanding of the pathophysiology of BPD and even the way we dene BPD has evolved.

Pathophysiology
Classical BPD was noted during an era when mechanical ventilation was just beginning to be employed and was characterized by airway injury, smooth muscle hypertrophy, and areas of parenchymal lung brosis alternating with areas with emphysematous changes. Over several decades of improvements in respiratory care, a new BPD has emerged that often occurs after little initial acute lung injury and is thought to be affected by other factors such as inammation (secondary to sepsis or chorioamnionitis) and the presence of a patent ductus arteriosus (PDA). (5)(6) As compared with classic BPD, preterm infants who have new BPD have decreased brosis and emphysema but also have a marked decrease in alveolar septation and microvascular development. The heterogeneous damage to airways and lungs results in unstable time constants and marked ventilationperfusion mismatch. Lung compliance is reduced secondary to brosis and edema. Tracheolaryngomalacia and increased airway resistance of both small and larger airways is common. As the course of BPD progresses, initial low lung volumes secondary to atelectasis are often at least partially replaced by hyperination. BPD is marked by abnormal structure and function of the pulmonary circulation in parallel to pulmonary parenchymal injury. Of note, epithelial lesions, broblast proliferation, and smooth muscle hyperplasia have all been observed and result in a pulmonary vascular bed that is markedly reduced compared with normal. Marked, abnormal vasoconstriction in response to hypoxia often accompanies these anatomic changes, further increasing pulmonary vascular resistance and in some cases progressive pulmonary hypertension. (7) Other cardiovascular abnormalities associated with BPD include systemic hypertension, left ventricular hypertrophy, and development of systemic-pulmonary collateral vessels. (8)

Denition
The infants originally described by Northway et al (1) presented within the rst month after birth. Based on the original description of the disease, most of the denitions of BPD originally focused on the neonatal period. The rst standard denition was proposed by the National Institutes of Health sponsored workshop in 1979. BPD was dened as continued oxygen dependency during the rst 28 days plus compatible clinical and radiographic changes. (2) This denition, although useful in the initial categorization of BPD, fails when we consider the very low birthweight that is currently managed in the neonatal intensive care unit. If a denition of oxygen requirement at 28 days is used, well over 70% of extremely low birthweight infants would be categorized as having BPD. Shennan et al (3) demonstrated that simply being in oxygen at 28 days did not routinely identify increased risk of abnormal pulmonary follow-up. Instead of using a xed time point at 28 days, Shennan et al (3) looked at corrected or adjusted gestational age. If infants between 25 and 32 weeks gestation were still in oxygen at 36 weeks postmenstrual gestational age, over 50% were noted to have abnormal pulmonary follow-up. This became a useful denition as it identied fewer infants who were at measurable risk. Newer denitions have tried to rene this approach. In 2001 the National Institutes of Health developed a consensus denition of BPD to help compare the incidence of the disease among institutions and evaluate potential preventive strategies and treatments. This definition was based on gestational age at birth, time of assessment, and severity of disease. (2) More recently, a simple physiologic description has been proposed: the inability to maintain an oxygen saturation of 88% or greater in room air for 60 minutes at 36 weeks postmenstrual age. (4) This denition is particularly useful because of its objectivity and has been shown to decrease variation in reported rates of BPD. However, such testing is problematic in that many infants will no longer be available for assessment by individual institutions at this point in time as many infants will have been transferred or discharged from the hospital.
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Factors That Affect Pathogenesis

BPD has a complex multifactorial etiology. In their original description, Northway et al (1) demonstrated the presence of oxygen-free radicals and posited that oxygen toxicity was a major cause of BPD. Barotrauma and volutrauma combined with oxygen toxicity contribute to inammatory reactions that are implicated in the development of BPD. (9)(10)(11) Chorioamnionitis, fetal infection, sepsis, and pneumonia may also contribute or amplify the development of BPD via inammatory pathways. An association between uid overload and the presence of a symptomatic PDA with BPD can poten-

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tially be explained by increased need for mechanical ventilation in these infants. (5) Genetic factors have been implicated in the severity of acute respiratory disease as well as the development of BPD. (12)(13) Finally, inadequate nutrition is believed to lead to decreased alveolar development, impaired surfactant production, and a catabolic state that inhibits growth and repair of the premature lung.

ford Network Annual Report 2009). Antenatal betamethasone is preferred over dexamethasone. (20)

Postnatal Interventions
Nutrition
Optimizing nutrition is key to all aspects of recuperation and growth in preterm infants. It is known that BPD is more common in extremely low birthweight infants with the poorest growth. (21) However, few studies have focused directly on the impact of nutrition on BPD and those that have do not show signicant differences, with the possible exception of studies of vitamin A and inositol. Inositol is incorporated into cell membranes of the lung and serves as a precursor for synthesis of pulmonary surfactant. Small trials have demonstrated a signicant reduction in death or BPD in infants who received inositol. (22) These ndings remain to be repeated in larger trials. Vitamin A plays an important role in the differentiation and maintenance of the integrity of the epithelial cells in the conducting airways. Several trials have tested vitamin A in the prevention of BPD and demonstrated a small but meaningful improvement in the rates of BPD development (typical relative risk [RR]0.87, 95% condence interval [CI]0.77 to 0.98; typical risk difference0.08, 95% CI0.14 to 0.01; number needed to treat 13, 95% CI7 to 100). (23)

Antenatal Interventions to Prevent Bronchopulmonary Dysplasia

Prevention of Preterm Birth
In our efforts to prevent BPD, multiple interventions have been considered, both before and after birth. Any intervention that prevents preterm birth would be an important improvement in decreasing the risk of development of BPD. Unfortunately, few therapies have been shown to prevent or postpone preterm delivery. Berkman et al (14) systematically reviewed the effectiveness of tocolytics to stop uterine contractions or maintain quiescence. Studies of rst-line tocolysis reported a small improvement in pregnancy prolongation and birth at term relative to placebo; however, data were insufcient to demonstrate a decrease in neonatal morbidity or mortality. These short-term benets offer little meaningful improvement to neonatal outcome except that the few days gained may act as a window in which to administer antenatal steroids. As mentioned above, infection and inammation have been implicated in the cause of BPD. Efforts to treat mothers with urinary tract infection or bacterial colonization have been, in general, unsuccessful in minimizing the rate of preterm labor or BPD. (15)

Postnatal Glucocorticosteroids
No interventions for BPD have created more controversy than the administration of postnatal corticosteroids to preterm infants. Studies have demonstrated that both inhaled and systemic steroids improve lung function and gas exchange as well as reduce inammation. (24)(25) Steroid use either as an early/preventative strategy (beginning at 7 d) or as a later/treatment strategy (beginning at 7 d) signicantly reduces the incidence of BPD; however, no difference in mortality was reported. (26)(27) Although immediate pulmonary benet is realized, increased alveolar simplication is reported. Other side effects of corticosteroids include systemic hypertension, cardiomyopathy, infection, hyperglycemia, gastrointestinal bleeding, and perforation. More worrisome is the potential for adverse neurologic outcomes. Longterm follow-up studies of infants who received high dosage, early steroids reveal an increased risk of neurodevelopmental delay and cerebral palsy. (26) However, major neurosensory disability and the combined rate of death or major neurosensory disability were not signicantly different between steroid and control groups in
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Antenatal Glucocorticosteroids
Administration of glucocorticosteroids is one of the few antenatal interventions that lead to meaningful improvements in neonatal outcome. Antenatal administration of glucocorticosteroids leads to a decrease in respiratory distress syndrome (RDS), a decrease in respiratory support, and a decrease in mortality but only a modest decline in BPD. (16)(17)(18) One explanation for this is that the protective effect of antenatal steroids may be keeping patients alive who would have otherwise died and who go on to develop BPD. Another explanation is that antenatal steroids may promote alveolar oversimplication. (19) Rates of the use of antenatal steroids have risen dramatically over the past several decades. Currently, well over 70% of all very low birthweight infants are exposed to antenatal steroid therapy (Vermont Ox-

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infants randomized to receive late steroids. (27) Due to concerns regarding these adverse events, the American Academy of Pediatrics recommended against the routine use of high-dose systemic steroids to treat or prevent BPD. (28) A meta-regression of the studies of postnatal steroids has revealed that in certain infants at extremely high risk of developing BPD and its associated morbidity, the benets of postnatal steroids may outweigh the deleterious affects. (29) Clinicians must weigh the potential risks of steroids versus the potential benets of facilitating extubation in those infants who are still ventilator dependent or on high concentrations of inspired oxygen after several weeks of therapy. Inhaled steroids have been tested and found to have no signicant advantage with respect to prevention or treatment of BPD when compared with systemic steroids. (30)(31) No long-term outcome data are available regarding inhaled steroids.

ing patients alive who would have otherwise died and who are at increased risk of BPD. Although BPD is not reduced, prophylactic surfactant has been shown to be benecial in increasing survival without BPD (typical RR0.85, 95% CI0.76 to 0.95). (38) Specic approaches or strategies to the use of surfactant may impact on BPD. There is a slight decrease in pneumothorax associated with the use of animal derived products. Earlier treatment (within the rst 2 h after birth) to infants at risk for or having RDS may also improve outcome. However, in the age of increased antenatal steroids and increased knowledge of less invasive support (use of early nasal continuous positive airway pressure), these therapies have been questioned.

Oxygen Therapy
Given the toxicity associated with supplemental oxygen, attempts to target lower saturations for oxygen are an attractive approach to decreasing BPD. Observational studies have suggested that lower saturation shortly after birth is associated with better short-term outcomes. In a study of four neonatal units, Tin et al (39) found that a lower saturation correlated with improved short-term outcomes in infants less than 28 weeks gestation. Practice in these units varied greatly, ranging from saturation targets of 80% to 90% to 94% to 98%. Surviving infants in units that targeted the lower saturation range were ventilated for a shorter time and needed less oxygen at 36 weeks postmenstrual age (18% versus 46%). Survival rates and cerebral palsy rates at 1 year follow-up were similar. The Surfactant Positive Airway Pressure and Pulse Oximetry Trial in extremely low birthweight infants was a randomized, multicenter trial conducted by the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network. (40) One arm of this 22 factorial design trial compared target ranges of oxygen saturation of 85% to 89% or 91% to 95% among 1,316 infants who were born between 24 and 276 weeks gestation. Death before discharge occurred more frequently in the 85% to 89% saturation group (RR1.27, 95% CI1.01 to 1.60), whereas severe retinopathy among survivors occurred less often in this group (RR0.52, 95% CI0.37 to 0.73). The rate of oxygen use at 36 weeks was reduced in the 85% to 89% saturation group as compared with the 91% to 95% saturation group (RR0.82, 95% CI0.79 to 0.93); however, the rates of BPD among survivors, as determined by the physiologic test of oxygen saturation at 36 weeks, and the composite outcome of BPD or death by 36 weeks did not differ signicantly between the

Other Anti-inammatory Therapy

Outside of corticosteroids, a variety of agents that might decrease the inammatory response in the lung have been tested including vitamin E, alpha-1 protease inhibitor, and superoxide dismutase. Unfortunately, none of these have had an impact on BPD. (32)(33)(34) Other novel anti-inammatory agents that have promise include nebulized pentoxifylline and budesonide administered intratracheally by using surfactant as a carrier and have been tested in ventilated preterm infants. (35)(36) Both approaches are promising, revealing decreased BPD without adverse events and may be a potential alternative to steroids. Further investigation in larger clinical trials is indicated.

Surfactant Therapy
The introduction of surfactant therapy has reduced incidence of pneumothorax and death in infants at risk for or having RDS. (37) Whether used as a preventive strategy or as treatment of established RDS, there is an approximately 30% decrease in the risk of pneumothorax and death. Given the fact that surfactant therapy decreases the need for inspired oxygen, decreases the need for ventilator support, decreases acute lung injury as reected by pneumothorax, and leads to improved survival, one would have assumed that there would be a decrease in BPD. However, the situation is not that straightforward. The absolute risk of developing BPD (dened in most of the surfactant trials as oxygen requirement at 28 d) is unchanged with therapy. Similar to the observed effect of antenatal steroids, perhaps the protective effect of surfactant may be keepe638 NeoReviews Vol.12 No.11 November 2011

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treatment groups. There were no signicant differences in the rates of other adverse events. Other trials of oxygen saturation targeting have recently been halted due to similar concerning ndings regarding increased mortality in the group managed with lower saturation limits. The impact of lower saturation targeting on BPD has not as yet been reported.

Assisted Ventilation
All types of mechanical ventilation injure the premature lung. When using conventional ventilation, one common strategy to decrease pulmonary damage is to limit the duration of mechanical ventilation outright. While on the ventilator, a variety of approaches to minimizing lung injury while on respiratory support have been tested. The use of patient-triggered ventilation is now virtually omnipresent in neonatal intensive care. Based on animal data, it was thought that this innovation would decrease lung trauma and when used in the recovery phase of infants with RDS, this technology signicantly shortens the weaning from mechanical ventilation. However, clinical trials show a marginal effect on BPD and no effect on survival. (41) Another conventional ventilator strategy provides optimal lung volumes by using gentle ventilation techniques, as reected by moderate permissive hypercapnia. Practically speaking, this entails optimal positive end expiratory pressure (42) for lung recruitment and ventilation with low lung tidal volumes (4 to 6 mL/kg). Permissive hypercapnia is unproven but popular. One small study demonstrated that ventilation strategies for very low birthweight infants that had received surfactant and were maintained mildly hypercapnic (PaCO2 45 to 55 mm Hg) were safe (ie, no increased rates of IVH [intraventricular hemorrhage] or PVL [periventricular leukomalacia]) and reduced the duration of mechanical ventilation. (43) A larger, multicenter, randomized trial revealed that targeting a PaCO2 of 52 mm Hg resulted in a reduction in mechanical ventilation at 36 weeks postmenstrual age but did not decrease death or BPD. (44) Volume-targeted ventilation allows for the peak inating pressure to adjust in a breath-to-breath manner to changes in lung compliance and a patients spontaneous respiratory effort. These modalities may deliver desired tidal volumes more consistently at lower pressures thereby avoiding injurious overdistention. Importantly, a recent systematic review of studies comparing volumetargeted ventilation compared with pressure-limited ventilation demonstrated that infants ventilated by using volume-targeted modes had reduced death and BPD

(typical RR0.73, 95% CI0.57 to 0.93; number needed to treat 8, 95% CI5 to 33). (45) High frequency ventilation has also been extensively tested. Despite promising results in animal models, this technique of ventilation does little in increasing survival or preventing BPD. Recent meta-analyses show marginal improvements in these outcomes, with some risk of increased severe intraventricular hemorrhage.

Avoidance of Mechanical Ventilation

Some of the strongest evidence for an effective prevention strategy to decrease BPD includes limiting the duration of or avoiding altogether mechanical ventilation. (6) Noninvasive ventilation techniques and methylxanthine administration are two techniques effective at limiting time spent on the ventilator.

Nasal Continuous Positive Airway Pressure

In the study of Avery et al (46) it was reported that, in the National Institute of Child Health and Human Development lung centers, one center had a remarkably lower rate of BPD (dened as oxygen in survivors at 28 d). This center was in Columbia, New York City. One obvious difference in their approach to care was the routine and aggressive use of nasal continuous positive airway pressure (CPAP). Multiple trials have now looked at stabilization on nasal CPAP. Recent trials suggest that nasal CPAP may be an effective way to stabilize infants without exposing them to mechanical ventilation. (47)(48)(49)(50) Although statistically signicant differences did not emerge, the fact that this less invasive approach appears to be of equal benet may well signal an era of less aggressive ventilator support. Nasal intermittent positive pressure ventilation has been shown to improve the effectiveness of CPAP in extubated infants, leading to a decrease in reintubation rates and a reduced risk of BPD. (51) Surfactant administration followed by extubation to nasal intermittent positive pressure ventilation has been suggested to be synergistic in decreasing BPD. (52) Another promising approach has been developed, called INSURE (Intubation Surfactant Extubation). In this approach, surfactant is administered during a brief intubation followed by immediate extubation to CPAP. INSURE has been reported to reduce the need for mechanical ventilation. (53) Although these ndings are promising, larger additional studies are needed to clarify and rene this method.
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Methylxanthines
Perhaps one of the most overlooked therapies in the prevention of BPD has been the use of methylxanthines. These agents function as a phosphodiesterase inhibitor, which plays a role in regulating intracellular concentrations of second messenger cyclic AMP (adenosine monophosphate) and cyclic GMP (guanosine monophosphate). Caffeine citrate has frequently been used to reduce apnea in preterm infants. Schmidt et al. (54)(55) reported the effect of caffeine citrate, administered to infants 1,250 grams, demonstrated decreased time on the ventilator, decreased oxygen use, decreased corticosteroid administration, and decreased need for transfusions. More importantly, a signicant reduction in the rate of development of BPD (adjusted odds ratio0.64, 95% CI0.52 to 0.78) and a composite outcome of death, cerebral palsy, and cognitive delay (adjusted odds ratio0.77, 95% CI0.64 to 0.93) was noted in the treatment group. (54)(55)

Avoiding Nosocomial Infection

Nosocomial bacteremia and pneumonia contribute to increased lung injury and BPD secondary to inammation, polymorphonuclear leukocyte inltration, and release of protelolytic enzymes. (63) Prevention of sepsis or pneumonia will result in decreased inammation and decreased time on mechanical ventilation and should be a goal of every center. Programs to reduce ventilatorassociated pneumonia have been advocated and commercial intervention bundles are marketed; however, no data have shown these programs reduce the incidence of BPD.

Bronchodilators
Commonly used bronchodilators dilate small airways with muscle hypertrophy in young children with hyperactive airway disease. Improved compliance and decreased pulmonary resistance are reported with use of bronchodilators in infants with BPD. A systematic review of short-term studies demonstrated improved pulmonary compliance and reduced resistance after bronchodilator treatment in infants with established and evolving BPD, but these short-term benets did not translate to decreased need for systemic steroids or in rates of mortality or BPD. (64)

Treatment of Pulmonary Edema

Excessive intravenous uid administration increases the risk of BPD, and infants who lose less weight and receive more intravenous uids immediately after birth have an increased risk for development of BPD. (56)(57)(58) It is not clear, however, that uid restriction reduces the incidence of BPD. (59) Diuretics continue to be commonly used in the treatment of BPD. These therapies may lead to measurable short-term changes in lung compliance and pulmonary function, but little has been demonstrated regarding any long-term improvement in reducing BPD or mortality. Given these data, careful restriction of water intake so physiologic needs are met without allowing signicant dehydration seems prudent.

Pulmonary Bed Vasodilators

Inhaled nitric oxide (iNO) has been tested, both early in the course of respiratory distress (on infants at risk for respiratory distress and in infants with serious respiratory insufciency) and in infants with early BPD. (65) The rationale for the use of iNO in preterm infants includes the cardiovascular effects of iNO (decreased pulmonary hypertension) as well as many primary effects of iNO on lung development. None of the trials of iNO administered early in the course of respiratory distress have demonstrated any clinical benet; only the trial of Ballard et al. (66) has demonstrated a small improvement in BPD in infants given a prolonged course of iNO beginning at around 1 to 2 weeks after birth. (66) iNO as rescue therapy for the very ill preterm infant does not appear to be effective. Early routine use of iNO in preterm infants with respiratory disease does not improve survival without BPD or improve neurodevelopmental outcomes. Later use of iNO to prevent BPD might be effective but needs further study. Oral agents that reduce pulmonary vascular resistance including sildenal, prostacyclin, and bosentan have promise in infants with established BPD, but these treatments have yet to be studied in randomized controlled trials. (67)(68)

Patent Ductus Arteriosus Treatment

The presence of a symptomatic PDA in very low birthweight infants has been shown to lead to pulmonary edema and be predictive of the need for supplemental oxygen and prolonged mechanical ventilation. (60) One might hypothesize that decreased pulmonary edema and the ability to decrease oxygen exposure and ventilator support would lead to less BPD. Therefore, treatment of PDA could theoretically reduce the risk of BPD; however, neither the trials that looked at preventing PDA nor treating PDA with cyclooxygenase inhibitors have led to a reduced risk of BPD. (61) Surgical closure of a symptomatic PDA increases the risk of BPD and is associated with adverse neurodevelopmental outcomes. (62)
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Delivery Room Management

In the delivery room, clinicians are excitably prone to contributing to pulmonary injury secondary to overzealous ventilation of infants in transition. Uncontrolled excessively large or small tidal volumes are injurious to the developing lung. Measuring and controlling tidal volumes in the delivery room, including the use of a T-piece resuscitator, may be desirable but are unproven in terms of prevention of BPD. (69)(70) Using a planned, practiced, and scripted protocol for the resuscitation and rst hour of care of infants at risk (referred to as the Golden Hour) has been proposed to reduce the incidence of BPD. Although these ideas have scientic rationale, they have not been shown to reduce the incidence or severity of BPD.

Role of Quality Improvement

Despite the many interventions that have been attempted and tested, the incidence of BPD has remained relatively constant over the past two decades. (71) The Vermont Oxford Network 2009 Database Summary reveals a 25.2% incidence of BPD at discharge on infants whose birthweight was 1,500 grams. This represents a decrease of almost 3% over the previous 3 years in this large cohort of approximately 50,000 infants from over 700 centers. Despite this modest decrease in the incidence of BPD, many of the proven therapies have not been effectively translated into practice in many medical centers and, perhaps because of this, large variability exists between individual centers. In fact, BPD rates vary by a factor of 10 within the Vermont Oxford Network even after risk adjustment for confounders such as birthweight, gestational age, race, antenatal steroid administration frequency, RDS severity, neonatal intensive care unit volume, and even random effects. Because neither disease severity nor random chance explains the variation that exists between centers, treatment practices must play a signicant role in the observed variation in outcomes. This variation is the justication for a quality improvement approach as a method for BPD reduction; however, studies using these methods have had inconsistent success. Quality improvement methods have, however, been consistently successful when used to improve and change individual processes rather than outcomes, and controversy exists over whether these methods that implement multiple interventions will be effective in limiting pathology of a disease such as BPD with multiple etiologies.

contributing factors that include low birthweight, preterm birth, supplemental oxygen exposure, mechanical ventilation, patent ductus arterious, inammation, genetic predisposition, and postnatal infection. Treatment of existing BPD requires a coordinated approach including optimal nutrition, careful uid management, evidence-based drug therapy administration, and gentle respiratory techniques aimed at minimal lung injury. The best respiratory support strategy remains unclear and requires further investigation but includes avoidance of hyperoxemia and hypocapnea. Optimal oxygen saturation targeting preterm infants is being studied in several ongoing trials. Among the available interventions, antenatal steroids, caffeine, and surfactant have the best riskbenet prole. Systemic postnatal corticosteroids should be used only in ventilated infants unable to be weaned from the ventilator. Quality improvement techniques may have a role towards improvement of hospital systems geared toward reduction of BPD.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications

Know the effects and risks of CPAP. Know the indications for and techniques of positive-pressure ventilation (PPV). Know the effects and risks of PPV. Know the pathogenesis, pathophysiology, and pathologic features of bronchopulmonary dysplasia/ chronic lung disease. Know the prenatal and postnatal risk factors for bronchopulmonary dysplasia/chronic lung disease and be aware of various preventive strategies. Know the management of bronchopulmonary dysplasia/chronic lung disease.

References
1. Northway WH, Jr., Rosan RC, Porter DY. Pulmonary disease
following respirator therapy of hyaline-membrane disease: bronchopulmonary dysplasia. N Engl J Med. 1967;276:357368 2. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163:17231729 3. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics. 1988; 82:527532 4. Walsh MC, Wilson-Costello D, Zadell A, Newman N, Fanaroff A. Safety, reliability, and validity of a physiologic denition of bronchopulmonary dysplasia. J Perinatol. 2003;23:451 456 5. Bancalari E. Changes in the pathogenesis and prevention of chronic lung disease of prematurity. Am J Perinatol. 2001;18:19 6. Jobe AH, Ikegami M. Mechanisms initiating lung injury in the preterm. Early Hum Develop. 1998;53:8194 7. Mourani PM, Ivy DD, Gao D, Abman SH. Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in bronchopulNeoReviews Vol.12 No.11 November 2011 e641

Conclusion
Prevention and management of BPD in infants at risk is challenging due to the complex pathogenesis of multiple

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monary dysplasia. Am J Respir Crit Care Med. 2004;170: 1006 1013 8. Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet. 2006;367:14211431 9. Kraybill EN, Runyan DK, Bose CL, Khan JH. Risk factors for chronic lung disease in infants with birth weights of 751 to 1000 grams. J Pediatr. 1989;115:115120 10. Groneck P, Speer CP. Inammatory mediators and bronchopulmonary dysplasia. Arch Dis Child. 1995;73:F1F3 11. Pierce MR, Bancalari E. The role of inammation in the pathogenesis of bronchopulmonary dysplasia. Pediatr Pulmonol. 1995;19:371378 12. Nickerson BG, Taussig LM. Family history of asthma in infants with bronchopulmonary dysplasia. Pediatrics. 1980;65:1140 1144 13. Clark DA, Pincus LG, Oliphant M, Hubbell C, Oates RP, Davey FR. HLA-A2 and chronic lung disease in neonates. JAMA. 1982;248:1868 1869 14. Berkman ND, Thorp JM, Jr., Lohr KN, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2003;188:1648 1659 15. Raynes-Greenow CH, Roberts CL, Bell JC, Peat B, Gilbert GL. Antibiotics for ureaplasma in the vagina in pregnancy. Cochrane Database of Syst Rev. 2004;(1):CD003767 16. Wright LL, Verter J, Younes N, et al. Antenatal corticosteroid administration and neonatal outcome in very low birth weight infants: the NICHD Neonatal Research Network. Am J Obstet Gynecol. 1995;173:269 274 17. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Syst Rev. 2006;3:CD004454 18. Horbar JD. Antenatal corticosteroid treatment and neonatal outcomes for infants 501 to 1500 gm in the Vermont-Oxford Trials Network. Am J Obstet Gynecol. 1995;173:275281 19. Jobe AH. Antenatal factors and the development of bronchopulmonary dysplasia. Semin Neonatol. 2003;8:9 17 20. Lee BH, Stoll BJ, McDonald SA, Higgins RD. Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone. Pediatrics. 2006;117:15031510 21. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit inuences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117:12531261 22. Howlett A, Ohlsson A. Inositol for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev. 2003;(4): CD000366 23. Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short and long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev. 2007;(4): CD000501 24. Yoder MC, Jr., Chua R, Tepper R. Effect of dexamethasone on pulmonary inammation and pulmonary function of ventilatordependent infants with bronchopulmonary dysplasia. Am Rev Respir Dis. 1991;143:1044 1048 25. Halliday HL. Clinical trials of postnatal corticosteroids: inhaled and systemic. Biol Neonate. 1999;76 Suppl 1:29 40 26. Halliday HL, Ehrenkranz RA, Doyle LW. Early (less than 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2009;(1): CD001146 27. Halliday HL, Ehrenkranz RA, Doyle LW. Late (more than
e642 NeoReviews Vol.12 No.11 November 2011

7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2009;(1):CD001145 28. Watterberg KL. Policy statement: postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics. 2010; 126:800 808 29. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modication by risk for chronic lung disease. Pediatrics. 2005;115:655 661 30. Shah SS, Ohlsson A, Halliday H, Shah VS. Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants. Cochrane Database Syst Rev. 2007;(4):CD002057 31. Shah V, Ohlsson A, Halliday HL, Dunn MS. Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates. Cochrane Database Syst Rev. 2007;(4):CD001969 32. Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2003;(4):CD003665 33. Shah P, Ohlsson A. Alpha-1 proteinase inhibitor (a1PI) for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2001;(3):CD002775 34. Suresh GK, Davis JM, Soll RF. Superoxide dismutase for preventing chronic lung disease in mechanically ventilated preterm infants. Cochrane Database Syst Rev. 2001;(1):CD001968 35. Yeh TF, Lin HC, Chang CH, et al. Early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study. Pediatrics. 2008;121: e1310 e1318 36. Lauterbach R, Szymura-Oleksiak J, Pawlik D, Warchol J, Lisowska-Miszczyk I, Rytlewski K. Nebulized pentoxifylline for prevention of bronchopulmonary dysplasia in very low birth weight infants: a pilot clinical study. J Matern Fetal Neonatal Med. 2006; 19:433 438 37. Jobe AH. Pulmonary surfactant therapy. N Engl J Med. 1993; 328:861 868 38. Soll RF, Morley CJ. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2001(2):CD000510 39. Tin W, Milligan DW, Pennefather P, Hey E. Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation. Arch Dis Child. 2001;84:F106 F110 40. Carlo WA, Finer NN, Walsh MC, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med. 2010;362:1959 1969 41. Greenough A, Dimitriou G, Prendergast M, Milner AD. Synchronized mechanical ventilation for respiratory support in newborn infants. Cochrane Database Syst Rev. 2008;(1):CD000456 42. Clark RH, Gerstmann DR, Jobe AH, Moftt ST, Slutsky AS, Yoder BA. Lung injury in neonates: causes, strategies for prevention, and long-term consequences. J Pediatr. 2001;139:478 486 43. Mariani G, Cifuentes J, Carlo WA. Randomized trial of permissive hypercapnia in preterm infants. Pediatrics. 1999;104: 10821088 44. Carlo WA, Stark AR, Wright LL, et al. Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-low-birthweight infants. J Pediatr. 2002;141:370 374 45. Wheeler K, Klingenberg C, McCallion N, Morley CJ, Davis PG. Volume-targeted versus pressure-limited ventilation in the neonate. Cochrane Database Syst Rev. 2010;(11):CD003666

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on January 27, 2013

pulmonary care

bronchopulmonary dysplasia

46. Avery ME, Tooley WH, Keller JB, et al. Is chronic lung disease
in low birth weight infants preventable? A survey of eight centers. Pediatrics. 1987;79:26 30 47. Finer NN, Carlo WA, Walsh MC, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010;362: 1970 1979 48. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 2008;358:700 708 49. Sandri F, Plavka R, Ancora G, et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics. 2010;125:e1402 e1409 50. Dunn M KJ, de Klerk A, de Klerk R, et al.; Vermont Oxford Network DRM Study Group. The Vermont Oxford Network Delivery Room Management Trial: a randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics. 2011 51. Davis PG, Lemyre B, de Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst Rev. 2001(3):CD003212 52. Ramanathan R. Nasal respiratory support through the nares: its time has come. J Perinatol. 2010;30 Suppl:S67S72 53. Bohlin K, Jonsson B, Gustafsson AS, Blennow M. Continuous positive airway pressure and surfactant. Neonatology. 2008;93: 309 315 54. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006;354:21122121 55. Schmidt B, Roberts RS, Davis P, et al. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007;357: 18931902 56. Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2008(1):CD000503 57. Oh W, Poindexter BB, Perritt R, et al. Association between uid intake and weight loss during the rst ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants. J Pediatr. 2005;147:786 790 58. Kavvadia V, Greenough A, Dimitriou G, Hooper R. Randomized trial of uid restriction in ventilated very low birthweight infants. Arch Dis Child. 2000;83(2):F91F96 59. Kavvadia V, Greenough A, Dimitriou G, Forsling ML. Ran-

domized trial of two levels of uid input in the perinatal period: effect on uid balance, electrolyte and metabolic disturbances in ventilated VLBW infants. Acta Paediatr. 2000;89:237241 60. Cotton RB, Stahlman MT, Kovar I, Catterton WZ. Medical management of small preterm infants with symptomatic patent ductus arteriosus. J Pediatr. 1978;92:467 473 61. Clyman RI. Mechanisms regulating the ductus arteriosus. Biol Neonate. 2006;89:330 335 62. Chorne N, Leonard C, Piecuch R, Clyman RI. Patent ductus arteriosus and its treatment as risk factors for neonatal and neurodevelopmental morbidity. Pediatrics. 2007;119:11651174 63. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110:285291 64. Ng GY, da S, Ohlsson A. Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2001;(3):CD003214 65. Barrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2010;(12): CD000509 66. Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med. 2006;355:343353 67. Krishnan U, Krishnan S, Gewitz M. Treatment of pulmonary hypertension in children with chronic lung disease with newer oral therapies. Pediatr Cardiol. 2008;29:10821086 68. Mourani PM, Sontag MK, Ivy DD, Abman SH. Effects of long-term sildenal treatment for pulmonary hypertension in infants with chronic lung disease. J Pediatr. 2009;154:379 384, e1 e2 69. Bjorklund LJ, Ingimarsson J, Curstedt T, et al. Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs. Pediatric Res. 1997;42:348 355 70. Bennett S, Finer NN, Rich W, Vaucher Y. A comparison of three neonatal resuscitation devices. Resuscitation. 2005;67: 113118 71. Young TE, Kruyer LS, Marshall DD, Bose CL. Populationbased study of chronic lung disease in very low birth weight infants in North Carolina in 1994 with comparisons with 1984. The North Carolina Neonatologists Association. Pediatrics. 1999;104:e17

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NeoReviews Quiz
12. Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease seen in preterm infant survivors. Classic BPD was originally described during an era when mechanical ventilation for neonates was just introduced. Over several decades of improvements in respiratory care, a new BPD has emerged that differs in pathologic features from classic BPD. Of the following, the most characteristic pathologic feature of the lung in new BPD is: A. B. C. D. E. Arrested alveolar septation. Necrotizing tracheobronchitis. Parenchymal lung brosis. Smooth muscle hypertrophy. Squamous metaplasia.

13. BPD is a disease of many causes. Several interventions, both antenatal and postnatal, have been studied in an effort to prevent or ameliorate the development of BPD among preterm infant survivors. Of the following, the postnatal intervention most associated with an improvement in the rate of development of BPD involves: A. B. C. D. E. Alpha-1 protease inhibitor. Inhaled glucocorticosteroid. Superoxide dismutase. Tocopherol. Vitamin A.

14. Mechanical ventilation predisposes the immature lung of a preterm infant to injury and subsequent development of BPD. Several strategies of mechanical ventilation have been studied in an effort to prevent or ameliorate the development of BPD among preterm infant survivors. Of the following, the strategy of mechanical ventilation most associated with an improvement in the rate of development of BPD involves: A. B. C. D. E. Assist control ventilation. High frequency ventilation. Negative pressure ventilation. Pressure limited ventilation. Volume targeted ventilation.

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Pulmonary Care and Adjunctive Therapies for Prevention and Amelioration of Bronchopulmonary Dysplasia Robert H. Pfister and Roger F. Soll Neoreviews 2011;12;e635 DOI: 10.1542/neo.12-11-e635

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including high resolution figures, can be found at: http://neoreviews.aappublications.org/content/12/11/e635 This article cites 51 articles, 15 of which you can access for free at: http://neoreviews.aappublications.org/content/12/11/e635#BIBL This article, along with others on similar topics, appears in the following collection(s): Fetus and Newborn Infant http://neoreviews.aappublications.org/cgi/collection/fetus_newb orn_infant Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml Information about ordering reprints can be found online: /site/misc/reprints.xhtml

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