Adjunctive Therapies in Bronchopulmonary Dysplasia Echezona Maduekwe, MD,* Joseph D. DeCristofaro, MD* *Department of Pediatrics, Stony Brook Children’s Hospital, Stony Brook, NY

Education Gaps 1. Clinicians should know about the adjunctive therapies used in the management of bronchopulmonary dysplasia. 2. Clinicians need to know the mechanism of actions of these adjunctive therapies used in patients with bronchopulmonary dysplasia.

Abstract

AUTHOR DISCLOSURE Drs Maduekwe and DeCristofaro have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. ABBREVIATIONS BOOST Benefits Of Oxygen Saturation Targeting trial BPD bronchopulmonary dysplasia CAP Caffeine for Apnea of Prematurity trial iNO inhaled nitric oxide PDA patent ductus arteriosus RCT randomized, controlled trial ROP retinopathy of prematurity SOD superoxide dismutase STOP-ROP Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity SUPPORT Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial

Despite the advances in the medical and respiratory support of preterm infants, chronic lung disease in these infants, widely known as bronchopulmonary dysplasia (BPD), remains one of the most challenging complications in preterm infants. The changing definitions of this disease, based on its treatment, have made management both difficult and frustrating to neonatologists. As a result, several therapies, devices, strategies, and adjunctive agents have evolved to either reduce the risk of BPD or alleviate its course. This article focuses on the pathogenesis of BPD, the adjunctive therapies used in relation to BPD, and the mechanisms of action of these adjunctive therapies.

Objectives

After completing this article, readers should be able to:

1. Understand the pathogenesis of bronchopulmonary dysplasia. 2. Identify adjunctive therapies used in neonates for the management of bronchopulmonary dysplasia 3. Understand the mechanism of action of various adjunctive therapies. 4. Understand the support or lack thereof for the adjunctive therapies used in relation to bronchopulmonary dysplasia

INTRODUCTION Bronchopulmonary dysplasia (BPD) or chronic lung disease of prematurity, is the most frequent adverse outcome for infants born at less than 30 weeks’ gestational age. (1) The incidence of BPD in surviving infants of less than or equal to 28 weeks’

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gestational age has been approximately 40% for over 20 years. (2) Although the definition of BPD has evolved with the survival of more immature preterm infants, the disorder is defined based on therapy rather than its pathophysiology. (3) This has given birth to new management approaches, including the use of exogenous surfactant, ventilation strategies, and antenatal corticosteroids. These new strategies, although instrumental in reducing further lung injury, do not help with the prematurityinduced arrest of alveolar and pulmonary vascular development seen in BPD. (4)

PATHOGENESIS BPD results from a dynamic process involving injury, inflammation, repair, and maturation (Fig). “Classic” BPD, characterized by early interstitial and alveolar edema, persistent inflammation, fibrosis, and small airway disease, (5) was seen in preterm infants with severe respiratory distress that required high inspired oxygen concentration and prolonged mechanical ventilation. However, as the surviving preterm infants that develop BPD have become more immature, “classic” BPD has been superseded by the “new” BPD, (6) characterized pathologically by alveolar hypoplasia and abnormal vascular organization. Infections, either prenatal or nosocomial, and the presence of a patent ductus arteriosus (PDA) play major roles in the development of this new BPD. (6) Whereas “classic” BPD is considered to result from an acute insult to the neonatal lung following therapy with high

concentrations of oxygen and mechanical ventilation with high positive pressures, (5) the pathogenesis of the “new” BPD is multifactorial, with inflammation playing a major role. Sepsis in utero, hyperoxia, and ventilator-induced trauma initiate the inflammatory cascade possibly mediated by cytokines, which may act on a genetically predisposed immature lung. The damage can heal with growth, resulting in normal lung architecture. However, in situations in which the lungs heal by fibrosis, normal lung architecture is interspersed with areas of abnormal lung tissue, resulting in typical pathologic features of BPD. These responses of the newborn may, in part, be attributable to genes controlling cell growth and differentiation. (7) In general, if BPD is established as a multisystem disease, the treatment remains mostly supportive, because no single prevention or treatment strategy is likely to be a “one size fits all” therapy.

OXYGEN THERAPY Despite advances in medical and respiratory care of preterm infants, supplemental oxygen remains the mainstay in the treatment of respiratory distress syndrome or BPD. The primary goal of oxygen therapy in the neonatal period is to achieve adequate blood oxygenation to prevent tissue hypoxia and at the same time minimize oxygen toxicity. When exposed to high oxygen levels, the lungs of preterm infants are prone to alveolar simplification and pruning of

Figure. Pathogenesis of bronchopulmonary dysplasia. BPD¼bronchopulmonary dysplasia; O2¼oxygen; PDA¼patent ductus arteriosus; RDS¼respiratory distress syndrome.

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the pulmonary vascular tree, (8) and as a result, oxygen-induced oxidative stress and lung injury. The scientific literature is replete with studies showing associated reduced incidences of retinopathy of prematurity (ROP) and BPD without increased mortality when oxygen is used judiciously to maintain saturations of less than 99%. (9) However, despite multiple recent clinical trials, the optimal dose of oxygen that minimizes harm and maximizes efficacy is still unclear. Whereas the significant progression of ROP was not observed in the Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial, a higher incidence of pneumonia and BPD were noted in infants who received oxygen saturation of more than 95% in the STOP-ROP Trial (10) and in the Australian Benefits of Oxygen Saturation Targeting (BOOST) trial. (11) Collectively, these studies provide evidence in favor of oxygen saturation of less than 95% in the management of preterm infants for reducing the incidence of oxidant-mediated injury like BPD. A similar study by the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) to evaluate posttreatment effects of high (91%–95%) and low (85%–89%) oxygen saturation ranges in preterm infants (12) showed reduced incidence of ROP in the 85% to 89% target group but increased mortality before discharge. A different way of assessing the effects of oxygen exposure is to determine the cumulative oxygen exposure as an area under the curve. (13) In a recent secondary analysis of the trial of late surfactant, using area under the curve, cumulative supplemental oxygen was predictive of BPD or death, with a plateau of predictive accuracy at 14 days. (14)

METHYLXANTHINE THERAPY Methylxanthines are among the most commonly used medications in preterm infants, and caffeine has become the methylxanthine of choice because of its wider therapeutic index, ease of use, and longer half-life. Caffeine antagonizes adenosine selectively at the A2a receptors and nonselectively at the A1 receptor. In addition, it causes production of cyclic adenosine 39 ,59 -monophosphate and cyclic guanosine monophosphate, leading to bronchodilation. One of the major findings of the secondary outcomes of the Caffeine for Apnea of Prematurity (CAP) trial was a significant reduction of BPD in infants who received caffeine (36%) versus those in the placebo group (47%). (15) This decrease in BPD incidence in the caffeine group was associated with a shorter duration (approximately 1 week) of endotracheal intubation and positive pressure ventilation. However, these shortterm respiratory benefits of caffeine were most significant if the medication was started within the first 3 days after

birth. (16) The pulmonary protective effects of caffeine in neonates may be partly attributable to the reduction of the pulmonary inflammation, as evidenced by inhibition of proinflammatory cytokines in both in vitro and in vivo clinical studies. (17) Thus, caffeine has become a standard therapy for the prevention of BPD.

CORTICOSTEROID THERAPY The prevention and/or rescue of infants at risk for BPD has focused on the use of maternal antenatal corticosteroids (18) as well as postnatal corticosteroids, along with various other strategies. The use of antenatal corticosteroids for pulmonary maturation reduces neonatal mortality, respiratory distress syndrome, and intracranial hemorrhage. As a result, antenatal corticosteroids are standard of care for pregnant women in preterm labor. (19) However, despite the widespread use of antenatal corticosteroids, even in combination with postnatal surfactant, there has been no decrease in the overall incidence of BPD. (20)(21) The use of systemic corticosteroids reduces inflammation, increases surfactant production, accelerates lung cell differentiation, decreases vascular permeability, and increases lung fluid resorption. These actions lead to improved ventilator function by increasing lung compliance and tidal volume, (21) thus leading to the consideration of corticosteroids for postnatal use. Postnatal systemic corticosteroid administration (predominantly dexamethasone) through the immediate postnatal, (22) moderately early, (23) and late (24) periods results in improved pulmonary outcomes at the cost of short-term adverse effects. Similarly, beneficial effects were also observed in studies using inhaled budesonide (25) and inhaled fluticasone. (26) However, the use of corticosteroids to treat or prevent BPD remains controversial, largely because of concerns for neurodevelopmental sequelae seen with prolonged courses of dexamethasone.

DIURETICS For either treatment or prevention of BPD, diuretics are frequently used in the NICU. The rationale for using diuretics is to improve lung compliance and oxygenation by reducing pulmonary edema. However, using diuretics requires the knowledge of the mechanisms of action of the various diuretic agents as well as their limitations. Furosemide, thiazide, and spironolactone are commonly used in preterm infants to prevent or alleviate BPD.

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The loop diuretics furosemide and bumetanide act on the ascending loop of Henle, inhibiting active reabsorption of chloride with a resultant active reabsorption of sodium. In addition, they have a direct effect on reabsorption of lung fluid and are characterized by a prompt onset of action and short duration of diuresis. A meta-analysis of treatment effects of loop diuretics concluded that in patients older than 3 weeks, pulmonary mechanics and oxygenation improved after 1 week of furosemide. (27) However, data on relevant longterm clinical outcomes are lacking. As a result, routine use of loop diuretics in this population cannot be recommended. Aerosolized delivery of furosemide has also been suggested, and a Cochrane review found a single dose may transiently improve lung mechanics, but information to determine the effect of chronic administration on oxygenation and pulmonary mechanics is not adequate. (28) Thiazide diuretics are sulfonamide derivatives that are distinct from the loop diuretics. They exert their effects on the distal tubule by binding to the chloride (Cl) site on the transporter, and as a result, inhibiting sodium/chloride (Naþ/Cl) cotransport. A 2011 Cochrane review of 6 studies in preterm infants with or developing BPD found that most failed to assess important clinical outcomes. (29) Because of the limited number of randomized, controlled trials (RCTs) and small number of patients studied, the authors of the systematic review concluded that there is no strong evidence of benefit from the routine use of distal diuretics in preterm infants with BPD. Spironolactone is a synthetic corticosteroid that acts as a competitive aldosterone receptor antagonist. It attenuates sodium reabsorption and spares potassium loss and, therefore, is prescribed primarily for its potassium-sparing effects, typically in conjunction with a thiazide diuretic. In comparing outcomes of infants treated with the combination of chlorothiazide and spironolactone versus chlorothiazide alone, no difference was seen in the need for electrolyte supplementation. (30) It is also unknown whether its antiandrogenic effects occur at doses commonly prescribed to infants. As a result, its long-term use in neonates has raised concerns. Nevertheless, despite deficient data on the long-term benefits of chronic diuretic therapy in infants with BPD, some infants clinically benefit from diuretic therapy. Therefore, if diuretics are to be used, clinicians need to be cognizant of the risk-benefit balance.

INHALED NITRIC OXIDE THERAPY Inhaled nitric oxide (iNO) is routinely used for the treatment of persistent pulmonary hypertension and hypoxic respiratory failure in term and late preterm infants because of its ability to selectively cause vasodilation of the pulmonary

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vasculature. This effect (31) as well as enhanced alveolarization (32) and suppression of inflammation (33) make iNO an excellent candidate for the prevention and treatment of BPD in preterm infants. Hence, many studies have evaluated the effects of iNO in preterm infants at high risk for BPD. A meta-analysis of the therapy encompassed 11 trials that included 96% of published data and 3,298 infants. (34) There was no statistically significant beneficial effect of iNO on death or BPD. As a result, there is no evidence to support the use of iNO in the prevention or treatment of BPD in preterm infants.

PATENT DUCTUS ARTERIOSUS MANAGEMENT One of the associated risk factors for BPD in preterm infants is the presence of a PDA; a causal relationship, however, has not been established. It seems reasonable to assume that the treatment of a PDA should reduce the risk for BPD. Indomethacin, a nonsteroidal anti-inflammatory drug, is one of the medicinal agents used for PDA closure because of its ability to inhibit prostaglandin synthesis by acting on cyclooxygenase enzyme. A systematic review has demonstrated that early prophylaxis with indomethacin will prevent symptomatic PDA but will not prevent BPD. (35) Moreover, there is no evidence that early closure of a symptomatic PDA by medical or surgical means will prevent BPD. Another medication used in the management of PDA is ibuprofen, a nonselective cyclooxygenase inhibitor that reduces prostaglandin-mediated vasodilation. Systematic reviews of multiple studies have demonstrated that ibuprofen is as effective as indomethacin in closing a symptomatic PDA. (36) To date, however, there are no data supporting use of this medication in the prevention of BPD.

BRONCHODILATOR THERAPY Neonates with severe BPD are predisposed to airway smooth muscle hyperreactivity. (37) As a result, inhaled bronchodilators, including b-agonists and muscarinic antagonists, have been administered to reduce airway reactivity and ultimately improve respiratory outcomes. Although short-term benefits like decreased airway resistance and improved gas exchange are noted with the use of bronchodilators, they have not been shown to prevent BPD, effectively treat BPD, or diminish the severity of BPD. (38) b-receptor agonists such as salbutamol and levalbuterol have direct action on b2-receptors to relax smooth muscle and, therefore, cause bronchodilation. Denjean et al, (39) in a doubleblind RCT using inhaled salbutamol and beclomethasone to prevent BPD, evaluated 173 infants of less than 31 weeks’

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gestational age. They concluded that there was no significant effect of treatment on the severity of BPD. Information is also lacking on the long-term sequalae of bronchodilator use on patients with established BPD. It is, therefore, difficult to recommend the routine use of b-receptor agonist therapy in the treatment of infants with BPD. Ipratropium bromide is used in the treatment of infants with BPD based on its ability to reduce cholinergic influence on bronchial musculature, resulting in inhibition of bronchoconstriction and reduction of mucosal secretions. (40) With the exception of case reports, no studies have evaluated the use of ipratropium bromide in the treatment of infants with BPD. (41)(42) In the absence of good evidence from RCTs, the use of ipratropium bromide in the management of BPD cannot be recommended.

important enzymatic antioxidant defenses are vitamin E and superoxide dismutase (SOD). Vitamin E is a lipid-soluble antioxidant that represents a major defense against oxidant-induced membrane injury. Vitamin E has been studied extensively in preterm infants with the expectation that it would prevent oxidative stress– related injury to multiple organs. A systematic review of vitamin E trials to date indicates that this therapy does not reduce the incidence of BPD in the preterm population. (48) SOD is an important endogenous enzymatic antioxidant defense in the lung. However, no benefit was detected in 2 small RCTs that assessed the effect of SOD in preventing BPD. (49) Therefore, the use of SOD in preterm infants for this purpose cannot be recommended.

MESENCHYMAL STEM CELL REPLACEMENT CROMOLYN SODIUM THERAPY Cromolyn sodium is a mast cell stabilizer that inhibits sensitized mast cell degranulation and could play a role in regulating the inflammatory process in the lung. Two RCTs that assessed the early use of cromolyn sodium in preventing BPD did not show any difference in mortality or BPD in either trial. (43) No RCTs have assessed cromolyn therapy for established BPD. As a result, this therapy cannot be recommended in the management of BPD.

Over the last decade, stem cell–based therapies have been investigated as a potential strategy to decrease BPD. In a recent phase 1 clinical trial, administration of umbilical cord– derived mesenchymal stem cells to preterm infants at risk for BPD was shown to be safe and feasible, with some potential beneficial effects. (50) However, data on the use of mesenchymal stem cells in human infants are scarce. Thus, this therapy is not currently recommended, but it is an exciting area of research that may prove to be fruitful in preventing or treating this debilitating disorder.

VITAMIN A THERAPY Vitamin A is an important micronutrient that plays a major role in cell growth and differentiation. In addition, vitamin A has other salutary effects on the respiratory system that make it a prime candidate in the prevention of BPD. For instance, surfactant production (44) and increase in the lung alveoli regeneration in mammals (45) have been shown to be induced by the active metabolite of vitamin A, retinoic acid. A Cochrane systematic review on the prophylactic use of vitamin A for BPD demonstrated a reduction in the incidence at 36 weeks. (46) However, a large cohort study of more than 6,000 infants conducted to evaluate the impact of the shortage of vitamin A on BPD or death found that the incidence of BPD or death was 51% in the vitamin A supplementation group compared with 48% in the group that did not receive vitamin A supplementation (P¼.10). (47) As a result, the benefit of vitamin A supplementation for preventing BPD remains questionable.

ANTIOXIDANT THERAPY Antioxidant defenses in humans do not mature until late in gestation; therefore, infants born prematurely are prone to lung injury attributable to oxidative stress. Included in

CONCLUSIONS Fifty years after the initial descriptions of the disorder, BPD still remains one of the most frustrating complications of prematurity, carrying a significant physical, social, and economic burden for the survivors and their families. We recognize that around the world multiple therapies are used either solely or in combinations for the prevention and management of BPD. Clinicians must recognize, however, that the evidence supporting the routine use of the vast majority of these adjunctive therapies is insufficient. Clearly, further research is needed to find effective treatments.

American Board of Pediatrics Neonatal-Perinatal Content Specifications • Know the pathogenesis, pathophysiology, and pathologic features of bronchopulmonary dysplasia/chronic lung disease • Know the management of bronchopulmonary dysplasia/chronic lung disease

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Parent Resources from the AAP at HealthyChildren.org • When Baby Needs Oxygen at Home: https://www.healthychildren.org/English/ages-stages/baby/preemie/Pages/When-Baby-NeedsOxygen-At-Home.aspx • Health Issues of Premature Babies: https://www.healthychildren.org/English/ages-stages/baby/preemie/Pages/Health-Issues-ofPremature-Babies.aspx For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.

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Adjunctive Therapies in Bronchopulmonary Dysplasia Echezona Maduekwe and Joseph D. DeCristofaro NeoReviews 2017;18;e173 DOI: 10.1542/neo.18-3-e173

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Adjunctive Therapies in Bronchopulmonary Dysplasia Echezona Maduekwe and Joseph D. DeCristofaro NeoReviews 2017;18;e173 DOI: 10.1542/neo.18-3-e173

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