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.

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.
Abstract
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:

ABBREVIATIONS 1. Understand the pathogenesis of bronchopulmonary dysplasia.

BOOST Benefits Of Oxygen Saturation
Targeting trial 2. Identify adjunctive therapies used in neonates for the management of
BPD bronchopulmonary dysplasia bronchopulmonary dysplasia
CAP Caffeine for Apnea of
Prematurity trial
3. Understand the mechanism of action of various adjunctive therapies.
iNO inhaled nitric oxide 4. Understand the support or lack thereof for the adjunctive therapies used in
PDA patent ductus arteriosus
RCT randomized, controlled trial
relation to bronchopulmonary dysplasia
ROP retinopathy of prematurity
SOD superoxide dismutase
STOP-ROP Supplemental Therapeutic
Oxygen for Prethreshold INTRODUCTION
Retinopathy Of Prematurity
SUPPORT Surfactant, Positive Pressure,
Bronchopulmonary dysplasia (BPD) or chronic lung disease of prematurity, is the
and Pulse Oximetry most frequent adverse outcome for infants born at less than 30 weeks’ gestational
Randomized Trial 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 sur-
vival 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 prematurity-
induced arrest of alveolar and pulmonary vascular development
seen in BPD. (4)
PATHOGENESIS
BPD results from a dynamic process involving injury, inflam-
mation, repair, and maturation (Fig). “Classic” BPD, charac-
terized by early interstitial and alveolar edema, persistent
inflammation, fibrosis, and small airway disease, (5) was seen
in preterm infants with severe respiratory distress that re-
quired high inspired oxygen concentration and prolonged me-
chanical 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
Figure. Pathogenesis of bronchopulmonary dysplasia. BPD¼bronchopulmonary dysplasia; O2¼oxygen; PDA¼patent ductus arteriosus;
RDS¼respiratory distress syndrome.
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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 cyto-
kines, 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 differen-
tiation. (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
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 post-
treatment 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 med-
ications 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 re-
ceptors 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 signifi-
cant 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 intu-
bation and positive pressure ventilation. However, these short-
term respiratory benefits of caffeine were most significant
if the medication was started within the first 3 days after
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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 pro-
inflammatory 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 mat-
uration reduces neonatal mortality, respiratory distress syn-
drome, 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 inflamma-
tion, increases surfactant production, accelerates lung cell dif-
ferentiation, decreases vascular permeability, and increases
lung fluid resorption. These actions lead to improved ven-
tilator function by increasing lung compliance and tidal
volume, (21) thus leading to the consideration of corticoste-
roids for postnatal use.
Postnatal systemic corticosteroid administration (pre-
dominantly dexamethasone) through the immediate post-
natal, (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 ob-
served 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. Furo-
semide, 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 long-
term 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 sug-
gested, and a Cochrane review found a single dose may
transiently improve lung mechanics, but information to
determine the effect of chronic administration on oxygen-
ation and pulmonary mechanics is not adequate. (28)
Thiazide diuretics are sulfonamide derivatives that are dis-
tinct 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) cotrans-
port. A 2011 Cochrane review of 6 studies in preterm infants
with or developing BPD found that most failed to assess im-
portant 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, there-
fore, 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 chloro-
thiazide and spironolactone versus chlorothiazide alone, no
difference was seen in the need for electrolyte supplemen-
tation. (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 ben-
efits 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 respira-
tory 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 alveolariza-
tion (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 demon-
strated 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 bronchodi-
lators, 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 double-
blind RCT using inhaled salbutamol and beclomethasone
to prevent BPD, evaluated 173 infants of less than 31 weeks’
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 broncho-
constriction 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.
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.
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 short-
age 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
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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
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 mesen-
chymal 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.
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
Vol. 18 No. 3 MARCH 2017 e177
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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-Needs-
Oxygen-At-Home.aspx
• Health Issues of Premature Babies: https://www.healthychildren.org/English/ages-stages/baby/preemie/Pages/Health-Issues-of-
Premature-Babies.aspx
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.

Vol. 18 No. 3 MARCH 2017 e179

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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

Updated Information & including high resolution figures, can be found at:
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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

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/18/3/e173

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