Bronchopulmonary Dysplasia: Clinical Perspective
Deepak Jain and Eduardo Bancalari*
Since Northway’s original description of BPD almost 45 years ago, the clinical
presentation of BPD has evolved into a disease process, which mostly
involves extremely premature infants. This new form of BPD is the result of
multiple antenatal and postnatal factors that can cause injury to the
developing lung leading to altered alveolar and vascular development. Over
the years, there has been considerable increase in knowledge of factors that
contribute to the development of BPD. This has led to different strategies for
prevention as well as management of BPD. Some of these strategies have
been successful and have withstood the test of clinical trials, such as vitamin
A supplementation, post-natal steroids, caffeine, and volume targeted
ventilation. The evidence for other interventions has been weak or negative.
Introduction
There have been significant advancements in the field of
neonatal and perinatal medicine since Northway and col-
leagues described “bronchopulmonary dysplasia” in their
original study almost 45 years ago. Although these
advancements have markedly increased survival rates of
extremely premature infants, BPD continues to be one of
the most common complications in these infants with inci-
dence ranging from 25 to 42% in very low birth weight
infants (Walsh et al., 2004; Stoll et al., 2010).
Since its description, the clinical presentation of BPD
has changed significantly with the original severe BPD in
relatively bigger infants being replaced by a milder form
in extremely preterm infants with a very different clinical
and radiographic course. There has also been significant
progress in the understanding of factors contributing to
lung injury and repair, which can lead to development of
preventive and therapeutic strategies in the near future.
Clinical Presentation
When Northway and colleagues first introduced the term
BPD, they described the clinical, radiographic, and patho-
logic course of a group of infants with severe respiratory
distress syndrome (RDS). All of these infants had severe
respiratory failure and were ventilated with high pressures
and high oxygen concentrations. They had a high mortality
rate (59%), and a significant number developed cor
pulmonale.
The respiratory course of these infants was described
in different stages evolving from initial RDS to a final stage
of chronic lung disease at approximately 1 month of age.
University of Miami, Miami, Florida
*Correspondence to: Eduardo Bancalari, University of Miami, PO Box 016960
(R-131), Miami, FL 33101. E-mail: ebancalari@med.miami.edu
Published online 27 February 2014 in Wiley Online Library (wileyonlinelibrary.
com). Doi: 10.1002/bdra.23229
C 2014 Wiley Periodicals, Inc.
V
With better understanding of the complex and multifactorial pathogenesis of
BPD, it is quite clear that any single therapy is very unlikely to eliminate this
problem unless it reduces prematurity. Further development in prevention
and treatment of BPD will likely need a multi-pronged strategy with novel
therapeutic agents acting at various stages of the disease process.
Birth Defects Research (Part A) 100:134–144, 2014.
C 2014 Wiley Periodicals, Inc.
V
Key words: BPD; clinical presentation; prevention; management; premature
This final stage consisted of severe respiratory failure with
a radiographic picture characterized by increased densities
secondary to fibrosis and atelectasis and adjacent large
emphysematous areas (Northway et al., 1967) (Fig. 1).
NEW BPD
Over the years with increasing use of antenatal steroids,
surfactant replacement therapy, and refinement in assisted
ventilation methods, the severe form of BPD has become
less frequent. As more immature preterm infants are sur-
viving and care of preterm infants is improving, BPD now
is seen most commonly in extremely low birth weight
infants with structurally immature lungs and underdevel-
oped pulmonary vasculature. These infants typically have
mild initial respiratory disease, which improves quickly
with noninvasive respiratory support or surfactant treat-
ment. Within a few days, they are with minimal ventilator
settings requiring low FiO2 or are extubated to noninva-
sive respiratory support. A large proportion of these
infants subsequently have progressive respiratory deterio-
ration requiring increasing respiratory support, which may
be due to development of a symptomatic patent ductus
arteriosus (PDA) or pulmonary infections. These infants
may go on to require mechanical ventilation and oxygen
for several weeks or months but a large majority of them
are essentially symptom free at the time of discharge
(Bancalari et al., 2003). This chronic lung disease process
has been termed as “New BPD” to differentiate from the
process described by Northway, “Original BPD.” The radio-
graphic picture in infants with “New BPD” usually pro-
gress from hazy ground glass-opacity, which clears after
surfactant treatment to a hazy opacification by 1 to 2
weeks of age and eventually to a relatively uniform pat-
tern of coarse interstitial opacities (Fig. 2) (Agrons et al.,
2005).
SEVERE BPD
There remains a small group of preterm infants who have
severe initial RDS, lung hypoplasia, or pneumonia who do
BIRTH DEFECTS RESEARCH (PART A) 100:134–144 (2014)
FIGURE 1. Original BPD with areas of hyperinflation and emphysema with
adjacent dense areas of atelectasis.
not respond adequately to surfactant administration. These
infants continue to require mechanical ventilation with
high airway pressure and inspired oxygen concentration.
Many of these infants develop air leak syndrome, second-
ary lung infections, and pulmonary edema secondary to
inflammation or a PDA further aggravating the lung dam-
age. These infants sometimes develop a radiographic pic-
ture characteristic of “Original BPD” and are more likely to
develop pulmonary hypertension and signs of right heart
failure. Except for a minority, most of these infants can
eventually be weaned off from respiratory support but
require supplemental oxygen for prolonged periods of
time and many are discharged home on oxygen.
PULMONARY FUNCTION IN BPD
Infants with established BPD have varying degrees of
altered lung architecture due to disrupted alveolar and
vascular development. The infants with severe BPD com-
monly have increased airway resistance due to mucosal
hyperplasia, tracheomalacia, and bronchomalacia, resulting
in increased time constant and dead space ventilation.
There is heterogeneous damage to distal airways and dis-
tal airspaces, resulting in variable time constant for differ-
ent parts of the lungs. This can lead to areas of over
inflation and atelectasis and ventilation-perfusion mis-
match. These infants also have decreased functional resid-
ual capacity and lung compliance.
One of the major factors leading to pulmonary morbid-
ities associated with BPD is decreased pulmonary vascular
growth and excessive pulmonary vascular remodeling
135
(Abman et al., 2008). These infants have increased pulmo-
nary vascular resistance and abnormal vascular reactivity,
leading to excessive vasoconstrictor response to acute
hypoxia (Abman et al., 1985; Mourani et al., 2004).
Clinically these changes in lung architecture lead to a
varying degree of hypoxemia, which increases during the
periods of physical activity, feeding, or pulmonary infec-
tions and edema. They also commonly have hypercapnia
secondary to alveolar hypoventilation and ventilation-
perfusion mismatch. This leads to compensatory metabolic
alkalosis, which is often exaggerated by the use of loop
diuretics.
Prevention of BPD
Bronchopulmonary dysplasia is the end result of multiple
factors that lead to injury to the developing lung and pul-
monary vasculature. Therefore, effective prevention of BPD
requires a multifactorial approach, which avoids factors
that are injurious to the lung and vasculature and pro-
motes normal growth and development of the lung. Over
the years, multiple strategies have been tried for decreas-
ing the incidence of BPD with variable success (Table 1).
Some of them, which have been more successful, are dis-
cussed here.
ANTENATAL STEROIDS
Corticosteroids are given prenatally to promote maturation
of the surfactant system and reduce the incidence and
severity of RDS (NIH Consensus Development Panel,
1995). Treatment with antenatal corticosteroids has been
associated with overall reduction in RDS (relative risk
[RR], 0.66; 95% confidence interval [CI], 0.59–0.73), and
moderate to severe RDS (RR, 0.55; 95% CI, 0.43–0.71).
However, treatment with antenatal steroids has failed to
show statistically significant reduction in BPD (RR, 0.86;
FIGURE 2. New BPD with generalized homogenous opacities with an interstitial
pattern.
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TABLE 1. Strategies for Prevention of BPD
Proven strategies from randomized clinical trials:
1. Caffeine
2. Vitamin A
3. Volume targeted ventilation
4. Postnatal Steroids
Strategies with equivocal evidence from clinical studies:
1. Antenatal steroids
2. Exogenous surfactant
3. Early PDA closure
4. High frequency ventilation
5. Non invasive respiratory support
6. Inhaled nitric oxide
7. Reduced oxygen exposure
95% CI, 0.61–1.22) (Roberts and Dalziel, 2006). This could
be due to increased number of preterm infants at risk of
BPD being salvaged with use of antenatal steroids.
There has been conflicting evidence regarding the
advantage of multiple courses of antenatal steroids against
single course. There are some animal data suggesting that
repeated glucocorticoid administration may inhibit lung
growth and development (Massaro and Massaro, 1992,
Tschanz et al., 1995). A recent Cochrane review comparing
multiple courses of antenatal steroids with single course
showed reduced RDS but no improvement in BPD with
multiple courses (Crowther et al., 2011).
SURFACTANT TREATMENT
Surfactant treatment has improved survival of extremely
preterm infants reducing the severity of RDS, need for
aggressive ventilation and prolonged oxygen therapy. How-
ever, multiple randomized controlled trials (RCTs) have
failed to show a statistically significant effect of surfactant
on BPD, which may partly be due to increased survival of
the more immature infants resulting from surfactant
treatment.
With the increasing use of nasal continuous positive
airway pressure (NCPAP) and noninvasive ventilation,
there have arisen new questions regarding need and tim-
ing of surfactant use. A recent meta-analysis comparing
prophylactic vs. selective surfactant use concluded that a
prophylactic approach was associated with increased risk
of BPD (RR, 1.13; 95% CI, 1.00–1.28) (Rojas-Reyes et al.,
2012).
One of the areas that have generated interest in recent
years is less invasive methods for administration of surfac-
tant with multiple approaches being currently evaluated
(Finer et al., 2010b; Dargaville et al., 2011). Until there is
robust evidence on effectiveness and safety of these
BRONCHOPULMONARY DYSPLASIA
approaches, early surfactant administration should be con-
sidered in all extremely low birth weight infants with RDS,
who require endotracheal intubation for management of
respiratory failure.
NONINVASIVE VENTILATION
One of the major contributing factors for development of
BPD is injury to the premature lung due to respiratory
support required to sustain life. Therefore, use of noninva-
sive ventilation, if it can provide adequate gas exchange,
may decrease the incidence of BPD. This was first shown
by Avery et al. who described a lower incidence of BPD in
centers with highest use of continuous positive airway
pressure (CPAP) and avoidance of mechanical ventilation
(Avery et al., 1987). Since then, numerous clinical trials
have examined use of early CPAP instead of mechanical
ventilation on incidence of BPD with no significant reduc-
tion in incidence of BPD with use of early CPAP (Verder
et al., 1994; Morley et al., 2008). Recently, a meta-analysis
of studies evaluating strategies to avoid endotracheal
mechanical ventilation did show a small but statistically
significant reduction in incidence of BPD or death (odds
ratio, 0.83; 95% CI, 0.71–0.96) by avoiding endotracheal
mechanical ventilation (Fischer and Buhrer, 2013).
Most clinical trials performed to evaluate use of early
CPAP have shown that 50 to 80% of these infants develop
respiratory failure that requires endotracheal intubation
(Morley et al., 2008; Finer et al., 2010a). High failure rate
of NCPAP has led to studies evaluating use of nasal inter-
mittent positive pressure ventilation (NIPPV) as the initial
mode of respiratory support and its effect on BPD. These
studies have provided conflicting results with one study of
43 infants showing reduction in BPD (5% vs. 33%,
p < 0.05, for infants with birth weight <1500 gm) (Kugel-
man et al., 2007) and others showing no change in inci-
dence of BPD (Sai Sunil Kishore et al., 2009; Meneses
et al., 2011). A recently published large RCT of 1009
infants with birth weight less than 1000 gm comparing
NIPPV with NCPAP failed to show reduction in incidence
of death or BPD with nasal ventilation (38.4% vs. 36.7%,
adjusted odds ratio, 1.09; CI, 0.83–1.43; p 5 0.56) (Kirpa-
lani et al., 2013).
MECHANICAL VENTILATION STRATEGIES FOR PREVENTION OF BPD
A significant number of ELBW infants require mechanical
ventilation which, although required for gas exchange and
sustaining life, predisposes them to lung injury and
increased risk of BPD.
One of the strategies that has been proposed to limit
ventilator-associated injury is permissive hypercapnia. The
evidence for effect of this strategy on BPD has been incon-
sistent with no clear reduction in BPD (Mariani et al.,
1999; Carlo et al., 2002). A small trial has shown a possi-
ble increase in mortality and neurologic impairment in the
minimal ventilation group (Thome et al., 2006). Another
BIRTH DEFECTS RESEARCH (PART A) 100:134–144 (2014)
strategy that has been studied extensively by large RCTs is
high frequency ventilation to decrease volutrauma. A
recent Cochrane review failed to show that high frequency
oscillatory ventilation consistently decreases the incidence
of BPD (Soll, 2013).
Volume targeted ventilation is one of the strategies to
limit volutrauma and achieve automatic weaning of PIP,
which can potentially limit ventilator-associated lung
injury. A recent Cochrane review analyzed 12 RCTs com-
paring pressure-limited ventilation with volume targeted
ventilation and reported reduction in combined outcome
of death or BPD with the latter (Wheeler et al., 2010).
Other strategies for mechanical ventilation that are
being evaluated are proportional assist ventilation
(Schulze et al., 1999), addition of pressure support to
synchronized intermittent mandatory ventilation (Reyes
et al., 2006), and neurally adjusted ventilator assist venti-
lation (Beck et al., 2009). These still require well-designed
large RCTs to evaluate their effect on incidence of BPD.
OXYGEN THERAPY AND BPD PREVENTION
Oxygen is the most commonly used therapy in the neona-
tal ICU with large variation in target oxygen saturations.
There is extensive evidence in experimental models docu-
menting oxygen induced lung injury, but until recently
actual evidence showing reduction in oxygen exposure
leads to decreased incidence of BPD had been lacking. In
the past few years, three large multicentric RCTs have
been published comparing the effects of two different oxy-
gen saturation targets on neonatal mortality and morbid-
ities (Carlo et al., 2010; Stenson et al., 2013; Schmidt
et al., 2013). Two of these trials, SUPPORT and BOOST-II,
have shown significant reduction in incidence of BPD
defined as oxygen requirement at 36 weeks, and severe
retinopathy of prematurity with use of oxygen saturation
targets between 85 and 89% against 91 and 95%. More
importantly, the SUPPORT trial showed a significant
increase in mortality in the low saturation group (19.9%
vs. 16.2%; odds ratio, 1.27; 95% CI, 1.01–1.6), which was
confirmed by a recent meta-analysis of the three trials
(Saugstad and Dagfinn, 2014). Considering these results, it
seems prudent to avoid targeting extremes by trying to
keep oxygen saturations between 90 and 95%.
In all of the above-mentioned studies, it was difficult
to maintain oxygen saturation targets within a tightly pre-
scribed range. Therefore, it is likely that tools such as
automated regulation of inspired oxygen using “closed
loop” systems will be used in the future to improve oxy-
gen targeting (Claure et al., 2009).
PREVENTION OF INFECTION
The association between antenatal infection and BPD has
been extensively studied in the past two decades with
variable results. Watterberg et al. were first to report that
histologic chorioamnionitis is associated with decreased
137
risk of RDS but increased risk of BPD (Watterberg et al.,
1996). Since then, antenatal and neonatal care for the
infants exposed to chorioamnionitis has changed dramati-
cally, which might explain why some recent studies have
failed to show association of chorioamnionitis with
increased risk of BPD (Richardson et al., 2006; Andrews
et al., 2006).
Colonization of the respiratory tract with Ureaplasma
urealyticum has been associated with increased incidence
of BPD (Schelonka et al., 2005). However, the effect of
treatment of this colonization with macrolide antibiotics
on the incidence of BPD has been inconsistent. A Cochrane
review of two small RCTs evaluating the use of erythromy-
cin did not find a decrease in incidence of BPD with this
therapy (Mabanta et al., 2003). Since then, some studies
have evaluated the role of newer macrolides, such as azi-
thromycin and clarithromycin, on prevention of BPD.
These studies have had variable results with one study by
Ballard et al. showing decreased incidence of BPD with
azithromycin in Ureaplasma positive infants. However, this
study reported a very high incidence of BPD in both
groups, and clearance of Ureaplasma was unaffected by
treatment with azithromycin (Ballard et al., 2011; Ozdemir
et al., 2011). There is a need for large RCTs evaluating the
safety and efficacy of this treatment before it can be
recommended.
Other postnatal infections have also been associated
with increased risk of BPD. Coagulase negative staphylo-
coccal sepsis has been associated with significantly higher
risk of BPD (64% vs. 24%; RR, 2.6; 95% CI, 1.5–4.6;
p 5 0.001) (Liljedahl et al., 2004). Sawyer et al. (1987)
evaluated the role of postnatal CMV infection in develop-
ment of BPD. They showed roentgenographic evidence of
BPD in 24 of 32 postnatally CMV-infected premature
infants compared with 12 of 32 of the age-matched nonin-
fected control group.
INHALED NITRIC OXIDE
Inhaled nitric oxide (iNO) has been used extensively in the
treatment of pulmonary hypertension due to its selective
pulmonary vasodilatation and absence of short-term side
effects. There is considerable evidence in animal models of
BPD that endogenous nitric oxide plays a vital role in alve-
olar and vascular development. Impaired endogenous NO
production contributes in the pathogenesis of BPD (Afshar
et al., 2003; Balasubramaniam et al., 2003) and adminis-
tration of low dose NO attenuates the effects of factors
causing BPD in animal models (Horst et al., 2007; Lin
et al., 2005).
Clinically, there have been multiple RCTs evaluating the
effect of iNO therapy on BPD, but results have been incon-
sistent. A recent systematic review of 14 RCTs, 7 follow-up
studies, and 1 observational study by Donohue et al.
(2011) failed to show a statistically significant difference
in incidence of BPD at 36 weeks (RR, 0.93; 95% CI,
138
0.86–1.003), or mortality rate (RR, 0.97; 95% CI, 0.82–
1.15) but did show a small difference in favor of iNO in
composite outcome of death or BPD (RR, 0.93; 95% CI,
0.87–0.99).
There are currently at least four large multicentric
RCTs in progress evaluating the effect of iNO therapy on
BPD. Results of these trials are eagerly awaited, but until
then, iNO to prevent BPD should only be used under trial
protocols.
VITAMIN A
Vitamin A and its metabolites are important mediators in
lung development and maturation (Mollard et al., 2000).
They also play an important role in repair of respiratory
epithelium after lung injury (McGowan, 2002). Preterm
infants have low levels of vitamin A at birth. Darlow and
Graham, in a recent systematic review, analyzed data from
eight vitamin A supplementation RCTs and showed statisti-
cally significant reduction in combined outcome of death
or oxygen use at 36 weeks (RR, 0.91; 95% CI, 0.82–1.00;
number needed to treat, 17), but no effect on death, reti-
nopathy of prematurity, or sepsis in infants who received
supplemental vitamin A (Darlow and Graham, 2007).
Despite vitamin A supplementation being one of the
only few strategies that have been proven to have some
effect on decreasing incidence of BPD, it is not universally
used (Ambalavanan et al., 2004). Some of the limiting fac-
tors are limited availability of vitamin A, need for frequent
intramuscular injections, or perceived small benefit. There
is a need for further research to better understand vitamin
A action at various stages of lung injury and explore alter-
native routes of administration.
CAFFEINE
Caffeine is a competitive adenosine receptor antagonist
resulting in stimulation of medullary respiratory center,
increased sensitivity to carbon dioxide, and increased dia-
phragmatic contractility. Its use in treatment of apnea of
prematurity is well documented.
Schmidt et al. (2006) showed a significant reduction in
BPD at 36 weeks (36.3% vs. 46.9%, p < 0.01), a secondary
outcome, in a large multicentric RCT in infants treated
with caffeine for treatment of apnea of prematurity or to
support extubation within the first 10 days of life. Some of
the possible mechanisms to explain this beneficial effect
may be the decreased duration of mechanical ventilation
in caffeine group, or the anti-inflammatory and diuretic
effects of this drug.
Bancalari raised a word of caution against generaliza-
tion of the results of this trial as these infants were com-
paratively more mature and healthier and the effect on
BPD was one of the secondary outcomes for the trial (Ban-
calari, 2006). There is an urgent need for more RCTs to
evaluate whether caffeine supplementation since birth
decreases the duration of ventilation and incidence of
BRONCHOPULMONARY DYSPLASIA
BPD, before caffeine use becomes a standard practice in
all preterm infants without more robust evidence.
MANAGEMENT OF PDA
PDA is present in up to 70% of infants born at less than
28 weeks gestational age. There is significant evidence
from animal models that left to right shunting through the
PDA has both short- and long-term adverse effects on pul-
monary vasculature and alveolar architecture, which could
lead to development of BPD (McCurnin et al., 2008). How-
ever, the evidence linking persistent PDA with BPD in
humans is not very robust, although there is some indirect
evidence suggesting that hemodynamically significant PDA
over a prolonged period of time is associated with
increased incidence of BPD (Rojas et al., 1995; Farstad
et al., 2011).
There is a wide variation in treatment practices for
PDA closure among different neonatal centers as well as
within centers (Kulkarni et al., 2013). This is due to multi-
ple reasons, including spontaneous closure of majority of
PDAs, no clear markers of hemodynamic significance of
PDA, inconsistent success rate of medical treatment in clo-
sure of PDA, side effects of drugs used for PDA closure,
and a paucity of good quality RCTs documenting improved
outcomes with early PDA closure.
There is some evidence that delayed closure of PDA
when compared with early closure does not result in
adverse respiratory outcomes and leads to less need for
PDA treatment (Sosenko et al., 2012). There are increasing
data that PDA ligation may be associated with increased
morbidities, with several studies showing acute hemody-
namic side effects and long-term respiratory and neuro-
logic morbidities in infants who had PDA ligation (Kabra
et al., 2007; Jhaveri et al., 2010; McNamara et al., 2010).
There is a pressing need for a safer and more effective
treatment of PDA as well as large RCTs documenting if in
fact early closure of PDA improves morbidity and mortal-
ity. Until then, treatment of PDA is very likely to continue
to be individualized based on each patient and the physi-
cian taking care of that infant.
Management of Established BPD
As with the prevention of BPD, management of BPD is
also multifactorial. Depending on severity of the BPD, it
could be a very challenging and frustrating task for the
physicians taking care of these babies. There are a limited
number of strategies with variable success rates available
to avoid further injury and promote development of
alveoli and pulmonary vasculature. Some of the most com-
mon strategies are discussed below.
NUTRITION AND FLUID MANAGEMENT
Infants at risk of developing BPD often are unable to get
adequate nutrition in early postnatal life due to multiple
reasons, including being acutely ill, glucose intolerance,
BIRTH DEFECTS RESEARCH (PART A) 100:134–144 (2014)
attempts at fluid restriction for PDA, delay in initiation of
feeds, or feeding intolerance. Infants with established BPD
also have increased demand due to increased work of
breathing, inflammation, and need for catch up growth
(Denne, 2001).
There is some evidence from animal studies that
under-nutrition, specifically protein and lipid, is associated
with increased risk of lung injury (Deneke et al., 1983;
Sosenko et al., 1988) and impaired lung growth (Bhatia
and Parish, 2009). A recent study showed that infants who
developed BPD had significantly less weight gain, and
received less calories and fat during the first postnatal
month (Akram Khan et al., 2006).
There is some evidence that high fluid intake during
the first days of life may lead to persistence of PDA (Ste-
phens et al., 2008) and increase risk for development of
BPD (Oh et al., 2005). This could be secondary to
increased fluid content in pulmonary interstitium leading
to decreased compliance. This may increase the need for
respiratory support leading to lung injury and BPD. A
recent Cochrane review comparing varying water intake in
preterm infants found that restricted water intake signifi-
cantly reduces the risk of PDA and NEC as well as trend
toward decreased risk of BPD (Bell and Acarregui, 2008).
Therefore, it is prudent to carefully restrict fluid intake
during the first few days of life while ensuring adequate
nutrition and avoiding significant dehydration.
Even though there is no clear evidence from large
RCTs (Lai et al., 2006), aggressive approach toward nutri-
tion by early enteral nutrition, ensuring adequate caloric
and protein intake, while avoiding fluid overload to pre-
vent pulmonary edema has sound physiological rationale.
RESPIRATORY SUPPORT
Infants with severe BPD commonly have heterogeneous
lung disease with areas of atelectasis and overdistension
leading to different time constants for different regions of
lungs. Due to prolonged mechanical ventilation, these
infants commonly have airway injury leading to mucosal
edema, tracheomalacia, or bronchomalacia.
During mechanical ventilation, these infants may bene-
fit from low mechanical rates with longer inspiratory time
and adequate expiratory time to ensure emptying of lung
units with long time constants. This decreases the risk of
inadvertent positive end-expiratory pressure and overdis-
tension, which may worsen ventilation-perfusion mismatch
and pulmonary hypertension. These infants also require
higher tidal volumes to account for increased anatomical
and physiological dead space and achieve adequate alveo-
lar ventilation and CO2 elimination. Although physiologi-
cally sound, there have been no RCTs comparing a low
rate, high tidal volume strategy to a high rate, low tidal
volume strategy in infants with established BPD.
Infants with BPD continue to require respiratory sup-
port for prolonged periods of time after extubation. Some
139
of the methods currently used are CPAP, NIPPV, neurally
adjusted ventilator assist, and high flow nasal cannula oxy-
gen with no clear advantage of one versus another. Fre-
quently, choice of the method is decided by the individual
physician’s familiarity with the method or the individual
patient’s response. The role of these different respiratory
support methods needs to be further explored in large
RCTs.
POSTNATAL CORTICOSTEROIDS
Postnatal corticosteroids for prevention or management of
BPD has been one of the most controversial topics in neo-
natology. Corticosteroids may act by decreasing inflamma-
tion, reducing vascular permeability and lung edema,
improving compliance, and decreasing lung fibrosis (Ban-
calari, 1998; Rhen and Cidlowski, 2005).
The role of dexamethasone in prevention of BPD was
first described almost 30 years ago, which showed sub-
stantial improvement in lung function with faster weaning
from mechanical ventilation and earlier extubation (Avery
et al., 1985). Subsequently multiple trials followed with
similar results in improved short-term respiratory out-
comes, but as data for long-term neurological outcomes
were reported, they showed increased risk of cerebral
palsy in infants who received steroids.
Studies evaluating use of dexamethasone for BPD have
used either an early or late strategy. A recent meta-
analysis by Halliday et al. showed that early use of dexa-
methasone within the first 7 days of birth leads to less
incidence of BPD, but has increased short-term adverse
effects such as gastrointestinal hemorrhage, bowel perfora-
tion, as well as increased risk of cerebral palsy at follow
up (Halliday et al., 2010). In a similar analysis, late dexa-
methasone use after the first 7 days was associated with
decreased risk of BPD, with no definite increase in long-
term adverse neurological outcomes (Halliday et al.,
2009).
One of the problems with combining different studies
for meta-analysis is the inclusion of patient populations
with different baseline risk for BPD. Because BPD itself is
associated with poor neurological outcomes, a selective
group of patients with high risk of BPD may benefit from
low dose dexamethasone. Doyle et al., who performed a
risk-weighted meta-analysis, addressed this issue and
showed that, in studies enrolling infants with high risk of
BPD, use of dexamethasone was associated with decreased
risk of cerebral palsy or death (Doyle et al., 2005). Thus,
in infants with high risk of BPD, such as those remaining
on mechanical ventilation after 2 to 3 weeks of life, the
beneficial effect of low dose dexamethasone may outweigh
its neurological adverse effects (Watterberg, 2012). In
keeping with these evidences, recent position statements
from both American Academy of Pediatrics and Canadian
Pediatric Society states that clinicians might consider a
short course of low dose dexamethasone in individual
140
infants at very high risk of BPD after 1 to 2 weeks of age
(Jefferies, 2012; Watterberg et al., 2010).
Hydrocortisone is another corticosteroid, which has
been studied as a replacement therapy in preterm infants
with decreased inherent adrenal activity. These trials have
used hydrocortisone within the first week of life with
mixed results and some increased risk of gastrointestinal
perforation, especially when used in combination with
indomethacin (Watterberg et al., 2004; Doyle et al., 2010).
There are two RCTs currently ongoing to evaluate the
effect of early hydrocortisone on BPD (PREMILOC trial,
Onland et al., 2011). Until the results of these trials are
available, its use should be limited to protocol conditions.
Inhaled steroids have been used in the management of
BPD with the possible advantages of direct topical affect
and avoiding systemic side effects. So far, the RCTs have
failed to show any significant effect on BPD or an advant-
age over systemic corticosteroids (Onland et al., 2012).
Some of the possible reasons could be low effective drug
delivery due to particle size, or the type of inhaled steroid
used. Currently, there are two large RCTs under way to
establish their efficacy and safety (Bassler et al., 2010;
QVAR trial).
PULMONARY VASODILATORS
Pulmonary hypertension is present in a large proportion
of infants with severe BPD and is associated with signifi-
cantly increased morbidity and mortality (Mourani and
Abman, 2013). Many agents, including sildenafil and iNO,
are commonly used clinically with no clear evidence of
their effect on pulmonary hypertension secondary to BPD.
Sildenafil and iNO are currently used for pulmonary
vasodilatation, and both drugs have also been shown to
improve alveolar growth and angiogenesis in animal mod-
els (Lin et al., 2005; Horst et al., 2007; Nyp et al., 2012).
Currently, there is limited evidence except case reports for
their role in pulmonary hypertension associated with BPD
(discussed in more detail in the article on Pulmonary Vas-
cular Disease in BPD in the current issue of this journal).
DIURETICS
Infants with BPD are predisposed to development of pul-
monary edema secondary to multiple reasons, such as vol-
ume overload secondary to left to right shunt through
PDA, capillary leak due to inflammation or ventilator asso-
ciated injury, or excessive fluid administration. Diuretics
have been used in BPD with the expectation of improving
pulmonary edema, hence improving lung compliance
resulting in improved ventilation and oxygenation.
There is some evidence that chronic administration of
furosemide improves lung compliance and oxygenation in
infants with BPD or a single dose of furosemide hastens
weaning from mechanical ventilation (McCann et al.,
1985). However, there is little evidence of reduction in
duration of ventilator support, days on oxygen, or other
BRONCHOPULMONARY DYSPLASIA
important long-term outcomes. As a result, a recent meta-
analysis concluded that routine or sustained use of sys-
temic loop diuretics could not be recommended in infants
with (or developing) BPD (Stewart and Brion, 2011). Furo-
semide has also been tried in aerosolized form to avoid
systemic side effects, with no significant improvement in
long-term pulmonary outcomes (Brion et al., 2010).
Thiazide diuretics are commonly used along with
potassium sparing diuretics in infants with BPD as they
have decreased risk of electrolyte abnormalities when
compared with loop diuretics. A double-blinded placebo
RCT in BPD patients showed decreased oxygen require-
ment and improved lung function but no improvement in
survival rate, duration of oxygen requirement, or length of
hospital stay (Kao et al., 1994). There is a need for large
RCTs before their routine use can be recommended.
BRONCHODILATORS
Infants with BPD have increased airway resistance due to
smooth muscle hypertrophy and hyper reactivity, which
makes use of bronchodilators a promising prospect. How-
ever, there are no RCTs performed to evaluate the effect
on important long-term pulmonary outcomes (Ng et al.,
2012). Because bronchodilator use has side effects such as
tachycardia and hypokalemia and there is no evidence that
long-term outcome is improved, their use in BPD cannot
be recommended at present.
EMERGING THERAPIES
As our knowledge of mechanisms of alveolar and vascular
development, injury, and repair is increasing, new possibil-
ities for prevention and treatment of BPD at the molecular
level are opening.
Stem cells are one of the most promising therapeutic
approaches in various diseases, including BPD. In animal
models of BPD, use of mesenchymal stem cells has been
shown to be effective in prevention as well as reversal of
neonatal lung injury (Zhang et al., 2012, Sutsko et al.,
2013). There is still a significant amount of work that
needs to be done to understand the mechanisms of action,
safety, and efficacy of this therapy before it can be used in
routine clinical practice.
Other promising therapies include modulation of selec-
tive inflammatory pathways, targeted gene therapy, and
use of molecules blocking signaling pathways leading to
lung injury at the cellular level (Hummler et al., 2013).
CONCLUSIONS
Since Northway’s description almost 45 years ago, the
clinical picture of BPD has evolved with New BPD being
secondary to interplay of multiple factors causing lung
injury and altered lung and pulmonary vascular develop-
ment. Even though there has been considerable increase
in knowledge of these factors, BPD continues to be one of
the major challenges faced by neonatologists. Because BPD
is a multifactorial disease, it is unlikely that any single
BIRTH DEFECTS RESEARCH (PART A) 100:134–144 (2014)
therapy will be able to eliminate this problem. Further
development in prevention and treatment of BPD will
likely need a multi-pronged strategy with novel therapeu-
tic agents acting at various stages of the disease process.
Disclosure
E. Bancalari has a patent on an algorithm for automated
adjustment of inspired oxygen and a licensing agreement
with Carefusion.
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