The New BPD Jobe

The New BPD
Alan H. Jobe
NeoReviews 2006;7;e531-e545
DOI: 10.1542/neo.7-10-e531
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Article
respiratory disorders
The New BPD

Alan H. Jobe, MD, PhD*
Author Disclosure
Dr Jobe did not
disclose any financial
Objectives
1.
2.
3.
4.
After completing this article, readers should be able to:
Explain the anatomy of the new bronchopulmonary dysplasia (BPD).

List the factors that contribute to BPD.
Explain the effect of corticosteroids on alveolarization.
Explain the contribution of mechanical ventilation and supplemental oxygen to BPD.
relationships relevant
to this article.
Introduction
BPD was described by Northway and associates in 1967 as a syndrome of severe lung injury
in preterm infants receiving mechanical ventilation and high levels of supplemental
oxygen. (1) The mean birthweight of the infants who survived mechanical ventilation with
BPD was 2.3 kg, and the mean gestational age was 34 weeks. Subsequently, Bonikos and
colleagues demonstrated that oxygen exposure alone could cause many of the anatomic
changes of BPD in newborn mice. (2) The initial description of BPD occurred in the era
when mechanical ventilation was just beginning to be used for preterm infants and few
infants whose birthweights were less than 1 kg survived. This classical BPD was
characterized by prominent airway injury, epithelial metaplasia, smooth muscle hypertrophy, and parenchymal fibrosis alternating with emphysema. The experimental work during
that era demonstrated that the causes of BPD were primarily mechanical ventilation and
oxygen exposure of the preterm lung. (3)
Fortunately, neonatal care practices and outcomes have changed over the last 25 years,
with the use of continuous positive airway pressure, antenatal corticosteroids, surfactant,
improved ventilation equipment and strategies, and improvements in nutrition and other
care practices. Now many infants whose birthweights are less than 1 kg and gestational ages
are less than 28 weeks survive. The infants described by Northway have almost no
long-term lung-related morbidity in 2006. However, the incidence of BPD in survivors of
preterm birth has not decreased because of the survival of large numbers of extremely low
birthweight (ELBW) infants whose gestational ages are less than 28 weeks and birthweights are less than 1 kg. The epidemiology of BPD has changed. With the improvements
in care, factors other than mechanical ventilation and oxygen exposure contribute to the
occurrence of BPD in ELBW infants, including postnatal sepsis, patent ductus arteriosus,
and antenatal chorioamnionitis. (4) Some ELBW infants now develop BPD without
initially having severe respiratory distress syndrome (RDS) or initially requiring much
supplemental oxygen or mechanical ventilation. (5)
In 1999, I reviewed the clinical associations with BPD and relevant experimental studies
and used the term new BPD to describe the arrest in lung development that is prominent
in this new form of the disease in ELBW infants. (6) The term now is being used frequently
to describe a progressive lung injury syndrome in ELBW infants characterized clinically by
hazy lungs, minimal cystic emphysema or hyperinflation that is apparent on chest radiographs, a persistent oxygen requirement that slowly resolves, less airway reactivity, and less
pulmonary hypertension (blue spells) than in the past. Infants who have died of the new
BPD have minimal fibrosis or airway injury but a striking decrease in normal alveolar
septation and microvascular development. (7) These anatomic findings demonstrate that
the new BPD is less of an injury syndrome and more of a syndrome resulting from processes
that interfere with lung development. This review highlights the multiple factors that can
alter lung development to yield the new BPD.
*Professor of Pediatrics, Division of Pulmonary Biology, Cincinnati Childrens Hospital, University of Cincinnati School of
Medicine, Cincinnati, Ohio.
NeoReviews Vol.7 No.10 October 2006 e531
bronchopulmonary dysplasia
whose birthweights were less than

1,250 g surviving to 36 weeks gestation. (9)
The most commonly used diagnosis of BPD as oxygen need at
36 weeks PMA does not require
Treatment with oxygen >21% for at least 28 days plus
antecedent exposures as part of the
Mild BPD: Breathing room air at 36 weeks postmenstrual age (PMA) or
diagnosis (eg, RDS, mechanical
discharge
ventilation), abnormalities on a
Moderate BPD: Need for <30% oxygen at 36 weeks PMA or discharge
chest radiograph, or any laboratory
Severe BPD: Need for >30% oxygen and/or positive pressure (ventilation or
test. Therefore, the diagnosis is
continuous positive airway pressure) at 36 weeks PMA
simply based on the need for oxyPhysiologic Test for Diagnosis of BPD
gen in ELBW infants who have sur Infants at 35 to 37 weeks PMA receiving mechanical ventilation, continuous
vived to 36 weeks gestation. This is
positive airway pressure, or >30% O2 with saturation of <96% have BPD
a soft diagnosis relative to most
Infants receiving <30% O2 or >30% O2 with saturation of >96% tested for
diagnoses in medicine that generO2 need
ally include specific clinical associa O2 progressively decreased gradually to room air
No BPD if saturation is >90% in room air for 30 min
tions and laboratory findings. Certainly part of the problem results
Adapted from Jobe and Bancalari (8) and Walsh, et al (9).
from the progressive nature of and
multiple associations with BPD in
this unique group of infants. Perhaps it is helpful to think about the stages of BPD that are
Diagnosis of BPD
clinically relevant to developing and testing therapies for
The diagnosis of BPD is confounded by a series of
BPD (Fig. 1). Although the diagnosis of BPD presently is
definitions that have been used over the years and by
made at 36 weeks PMA, efforts to prevent BPD need to
changes in the patients at risk. (8) The diagnosis of BPD
begin with antenatal exposures and to focus on the
as characteristic changes on the chest radiograph and
known associations with BPD in the minutes to days after
oxygen need at 28 days after birth initially used for large
preterm birth (Fig. 2). The factors associated with BPD
infants does not apply well to ELBW infants because few
in ELBW infants or in animal models that have a BPD
have normal chest radiograph findings and most are
phenotype are discussed in this article. However, an
receiving some oxygen at this time point. The diagnosis
important caveat is that the clinical diagnosis of BPD
of BPD as oxygen need at 36 weeks postmenstrual age
does not have a direct link to the developmental
(PMA) has been used in most recent reports. A National
abnormalities that cause the lung structural changes
Institutes of Health Workshop in 2000 recommended a
identified as the new BPD. Although we know that
graded diagnosis for BPD to describe better the clinical
infants who die of the new BPD have a severe arrest in
status of affected infants (Table). (8) Because clinicians
lung development, we know virtually nothing about
do not have evidence-based criteria for the use of supplemental oxygen, oxygen use and target saturations vary widely in clinical practice. Walsh and colleagues
(9) developed an oxygen needs test
to make the diagnosis of BPD more
consistent across clinical services.
The physiologic test for oxygen
need also is described in the Table.
Figure 1. Stages of bronchopulmonary dysplasia (BPD). BPD may be initiated with an
When evaluated across 17 clinical
injury phase that may begin prior to preterm birth. The early injury generally occurs
units in the National Institute of following preterm birth at 23 to 28 weeks gestation. The acute progression of BPD
Child Health and Human Develop- probably occurs after the initial injuries over the first several weeks after preterm birth.
ment Neonatal Research Network, An infant is given a diagnosis of BPD at 36 weeks postmenstrual age. The chronic stages
the diagnosis of BPD decreased may last for months, and very little is known about the time frame required for partial or
from 35% to 25% of the infants complete resolution of BPD.
Bronchopulmonary Dysplasia (BPD)

Workshop Definition of BPD for Infants at
Gestational Ages of Less than 32 Weeks
Table.
e532 NeoReviews Vol.7 No.10 October 2006
tion is being studied intensively because of its relevance to BPD in

infants and to emphysema in adults.
Factors known to regulate alveolarization are FGF-18 and plateletderived growth factor-A as well as
pathways for collagen and elastin
metabolism. However, BPD occurs
most frequently between 23 weeks
and 28 weeks gestation in the human, about 1 month after airway
branching has finished and as much
as 3 months before alveolarization
begins.
Burri (11) describes a process of
three generations of saccular septaFigure 2. Flow chart for some of the clinical interventions and occurrences that
contribute to BPD. Extremely low-birthweight infants experience many of these events. tions after 20 weeks gestation to
The progression to BPD should be viewed as a multiple hit sequence resulting in abnormal form 524,000 respiratory bronchioles. These distal saccules further
lung development.
divide into three generations of alveolar ducts. These six branching
generations yield about 4106 saccules that subsethe lungs of the majority of infants who survive with
milder forms of BPD.
quently alveolarize after 32 to 36 weeks gestation. This
64 times increase in saccular structures that occurs between about 20 weeks and about 32 to 36 weeks is a
Developmental Context for
the New BPD

The human lung has completed
about 16 generations of dichotomous airway branching by about
16 to 18 weeks gestation to yield
approximately 65,000 saccules at
the end of terminal bronchioles
(Fig. 3). (10) Considerable mechanistic information is known about
this airway branching, termed primary septation. Genes that are critical for primary septation include
fibroblast growth factor (FGF), epidermal growth factor, and the transcription factor. Secondary septation is the process of alveolarization
of the distal lung saccules. Alveolarization is the anatomic description
of the protrusion of an elastin fiber
and mesenchyme containing a double capillary network into the saccular lumen, resulting in subdivision
of that saccule. (11) In humans,
alveolarization normally begins at
32 to 36 weeks gestation and continues for several years. Alveolariza-
Figure 3. Anatomic development of the human lung. The human lung goes through about
23 generations of dichotomous branching. Airway branching is complete by about
18 weeks gestation to yield about 65,000 distal structures. These saccules divide further
to form respiratory bronchioles and alveolar ducts by 32 to 36 weeks gestation, when
alveolarization begins. Z indicates branching generation number. Figure modified from
Burri. (10)
Figure 4. Comparison of lungs of an infant who has BPD and a normal infant. A. This lung
section is from a 5-month-old infant born at term. B. This lung section is from an infant
who has BPD, was born at 28 weeks gestation, and had a lung biopsy at 8 months of age.
The lungs of the infant who has BPD have enlarged alveolar ducts and few alveoli.
Jacqueline Coalson, University of Texas San Antonio, provided new photomicrographs that
are similar to photomicrographs originally published by Coalson, et al. (7)
complex phase of lung development between airway

branching and alveolarization that does not have a name.
The new BPD may result primarily from interference
with the generation of respiratory bronchioles and alveolar ducts. Concurrently with the expansion of the gas
surface areas of the fetal lung and alveolarization, there is
a large expansion of the pulmonary microvasculature.
The essential development of the pulmonary microstructure occurs during the onset, progression, and healing of
BPD.
Pathology of BPD
The anatomic information available for infants who died
of BPD is biased toward the most severe changes, with
the anatomy demonstrating multiple changes that are
consistent with altered lung development. The lungs
have increased alveolar (saccular) diameters and fewer
alveoli (saccules). (12) The collagen network around the
saccules is disrupted, and elastin is not localized to fibers
in sites for future secondary septation. (13) Acute severe
inflammation is not apparent unless there has been a
secondary infection. The saccules are lined with dysplastic type II cells that express increased amounts of mRNA
for surfactant protein C. Several reports have described
decreased platelet/endothelial cell adhesion molecule-1
(PECAM) staining as a marker for the endothelium of a
decreased pulmonary microvasculature. (14) A recent
report showed increased levels of PECAM protein and
prominent staining of the pulmonary microvasculature in
lungs of infants who died of BPD. (15) Certainly, infants
who die of BPD have pulmonary hypertension and microvascular disease. These contrasting pathologic findings may represent true variability in the pathophysiology
of BPD, perhaps related to the major inciting factors, or
different stages in the progression

of the lung abnormalities. The most
striking abnormality in the lungs of
infants who have BPD is the arrest
of alveolarization, resulting in the
appearance of emphysema (Fig. 4).
However, there is very little anatomic information available for
most infants who survive BPD.
These lungs may have different
findings.
Alveolarization: Lessons
from Animal Models
Mice and other rodents are born at

term with a saccular lung that begins to alveolarize at about 3 days of
age. This postnatal timing of alveolarization, when combined with the transgenic technology available for mice,
is ideal for investigating factors that can interfere with
alveolarization. Mice made to overexpress proinflammatory cytokines such as tumor necrosis factor-alpha, transforming growth factor-alpha, interleukin (IL)-6, IL-1,
and IL-13 during the period of alveolarization experience the development of emphysema because of a
failure of alveolarization. (6) Alveolarization also can be
inhibited by exposure of mice to hyperoxia, and hyperoxia causes inflammation. In preterm ventilated lambs
and baboons, conventional or high-frequency ventilation
disrupts alveolar septation (Fig. 5). (16) These animals
also were exposed to increased oxygen levels, and oxygen
alone can inhibit alveolarization. Supplemental oxygen
and mechanical ventilation probably represent the combination of two hits to the fetal lung: one an oxidant
injury and the other a stretch injury. Both injuries are
transduced to activate inflammatory cascades. In ventilated baboons, the proinflammatory mediators IL-6 and
IL-8 were chronically elevated in airway samples about
10-fold above values measured in term newborn baboons (Fig. 6). (17) Thus, the common theme for the
inhibition of alveolarization is inflammation, suggesting
that inflammation caused by any mechanism will interfere with alveolar septation.
Other factors that can interfere with lung development are corticosteroids and starvation. Newborn rabbits
that are fed less calories have increased sensitivity to
oxidant damage, and adult rodents that are starved develop an emphysematous lung, which returns to normal
with refeeding. (18) There is no information in newborn
humans about the effects of low calorie intake on lung
development. However, nutritional status may be an
lung has decreased numbers of alveoli. In sheep, the corticosteroidinduced changes that occur in the
preterm lung have disappeared by
term. Rodents that alveolarize after
term birth have arrested alveolar
septation when treated with corticosteroids. The corticosteroid effects on alveolarization are independent of inflammation. There is
no information about how corticosteroid effects might interact with
inflammation to influence alveolarization. Nevertheless, infants at risk
of severe BPD are treated with corticosteroids, presumably to decrease inflammation. The risk-tobenefit ratio for a single antenatal
course of betamethasone certainly
favors corticosteroid therapy. (20)
Infants likely to develop severe
BPD also may benefit from postnatal corticosteroid treatments, but
those treatments may adversely affect alveolarization. (21) Clinical
benefit may depend on the importance of inflammation to the process that is being treated in the infant.
Chorioamnionitis:
A Pathway to BPD
Most infants born prior to
30 weeks gestation have been exposed to inflammation because of
an often subclinical ascending inFigure 5. Effect of conventional mechanical ventilation on alveolarization of preterm trauterine infection caused by lowlamb lungs. Preterm lambs delivered at 126 days gestation (term is 150 d) were treated grade pathogens. The most frewith surfactant and ventilated at rates of 20 or 60 breaths/min for 3 weeks. The ventilated quent organisms associated with
lambs were similar to gestation-matched fetal lambs and had not alveolarized over chorioamnionitis, which is defined
3 weeks in comparison to measurements for airspace area and radial alveolar count in as inflammation of the fetal memterm lambs. Redrawn from data of Albertine, et al. (16)
branes, inflammatory cells, or organisms in amniotic fluid, are Ureaimportant and underappreciated variable on the pathway
plasma and Mycoplasma sp. (22) Infants exposed to
to BPD.
chorioamnionitis or delivered after preterm prolonged
Both antenatal and postnatal corticosteroids inhibit
rupture of membranes (a surrogate marker for chorioamalveolarization and pulmonary microvascular complexity
nionitis) have a decreased incidence of RDS but also have
in developing animals. (19) Fetal sheep and monkeys
an increased risk of BPD in some clinical series. In other
exposed to antenatal corticosteroids have a decrease in
series, the increased risk of BPD occurred in infants
the mesenchyme and increased airspace volumes within
exposed to chorioamnionitis who then were ventilated or
24 hours. Subsequently, the alveoli are larger and the
developed postnatal sepsis. (23) Consistent clinical corNeoReviews Vol.7 No.10 October 2006 e535
relates no doubt are confounded by

the imprecision of the diagnosis of
chorioamnionitis where, in most
cases, there is no information on
the duration, intensity, or the organisms responsible for the clinical
or histopathologic diagnosis. Furthermore, the contrasting effects of
clinical lung maturation with less
RDS may tend to protect the infant
from BPD, while the inflammation
already present at birth may contribute to BPD.
The responses of fetal sheep to
inflammatory mediators provide
some insight about how the fetus
copes with inflammation. Intraamniotic injections of Escherichia
coli endotoxin, the proinflammatory cytokine IL-1-alpha, or endotoxin from periodontal organisms
cause chorioamnionitis (inflamed
membranes, inflammatory cells,
and increased IL-8 concentrations
in amniotic fluid). (24) Within
hours, the fetal lung becomes inflamed and the numbers of inflammatory cells increase in the airspaces over several days. The lung
inflammation/injury
response
progresses with cytokine expression
in the fetal lung, cell apoptosis and
proliferation, and microvascular injury. (25)(26) Within 7 days, alve- Figure 6. Interleukin (IL)-6 and IL-8 levels in airway samples from preterm ventilated
olar number decreases and alveolar baboons. The cytokines were increased at all time intervals relative to values for term
size increases (Fig. 7). (27) This newborn or adult baboons. Median values for multiple measurements were adapted from
combination of microvascular in- Coalson, et al. (17)
jury and inhibition of alveolarizaendotoxin for 28 days prior to preterm delivery have
tion is a mild BPD phenotype caused by inflammation of
alveolar simplification but no progression of lung injury.
the fetal lung. (29) Thus, inflammation in the absence of
Prolonged fetal exposure to endotoxin did not cause
supplemental oxygen and ventilation can cause changes
persistent lung abnormalities when the lambs were delivsimilar to BPD in the fetal lung. The clinical outcome of
ered close to term. (31) This surprising result demonthese fetal exposures is lung maturation characterized by
strates that the fetal lung can mount a rapid inflammatory
larger lung gas volumes and large increases in surfactant
response to inflammation/infection but that the inflamlipids and proteins. (28) Fetal sheep lungs colonized by
matory response need not be progressive or severe. The
intra-amniotic injection of live Ureaplasma have minimal
fetus copes with the inflammation with reversible effects
inflammation but striking lung maturation. (30) These
on lung alveolarization and microvascular development,
results replicate the clinical experience that many ELBW
and induced lung maturation is the most clinically apparinfants do not have severe RDS, especially after chorioament outcome after preterm birth. However, antenatal
nionitis or ruptured membranes.
exposure to inflammation has resulted in the recruitment
Fetal sheep exposed continuously to intra-amniotic
chanical ventilation. (33) The clinical implication is that antenatal exposure to inflammation likely will
not cause BPD, but antenatal inflammation may potentiate postnatal inflammatory events. Although
no specific information is available
for infants, most ELBW infants are
exposed to antenatal corticosteroids and many will be exposed simultaneously to chorioamnionitis.
Each exposure can cause BPD-type
structural changes in the developing lung.
Neonatal Resuscitation/
Initiation of Air Breathing
The previous discussion of chorioamnionitis described how antenatal
Figure 7. Effects of intra-amniotic endotoxin on the fetal sheep lung. Intra-amniotic exposure to inflammation or cortiendotoxin increased inflammatory cells and cytokine mRNA expression in the fetal lung. costeroids may promote the initiaMaximal expression of IL-1-beta mRNA occurred with lung injury, as indicated by
tion of injury. The antenatal expoincreased apoptosis. A proliferative response followed the apoptosis. The lung vasculature
sures may occur over days, weeks,
also was injured, as indicated by decreased endothelial nitric oxide xynthase (eNOS)
protein and the mRNA for the vascular endothelial growth factor (VEGF) 188 isoform in or even months. The initiation of
the fetal lung tissue at 2 and 4 days relative to controls. At 7 days, the mcmol/kg of air breathing after preterm birth is a
saturated phosphatidylcholine (Sat PC) in bronchoalveolar lungs (BAL) increased and the rapid transition that must occur
mL/kg lung gas volume measured at 40 cm H2O distending pressure increased, indicating quickly for the infant to survive,
biochemical and functional lung maturation. However, alveolar number decreased by 31% and most ELBW infants receive
relative to the control value. Data redrawn from (25)(27)(28). *P<0.05 versus controls. ventilatory support to facilitate the
transition. The scheme of clinical
variables that may contribute to BPD shown in Figure 2
of monocytes to the airspaces that can mature to macrohas been modified in Figure 8 to emphasize the brief, but
phages that have an increased inflammatory potential.
important, period of delivery room management. The
(32) Fetal sheep exposed to intra-amniotic endotoxin
fetal preterm lung is fluid-filled, often surfactant30 days before preterm delivery had increased numbers
deficient, and very easy to injure because lung structure is
of inflammatory cells in their airspaces after mechanical
immature and the potential gas volume (total lung caventilation, indicating that the antenatal exposure
pacity) is small. For example, the total lung capacity for
changed the postnatal inflammatory response to meinfants who have RDS is only 20 to
30 mL/kg in contrast to volumes
of about 50 mL/kg for term infants
and 80 mL/kg for adults. Lung
injury occurs if the lung is ventilated from lung volumes below the
ideal functional residual capacity
(FRC) (a frequent occurrence with
surfactant deficiency) or to volumes
close to or above the total lung
Figure 8. Delivery room management of ELBW infants within the context of factors capacity (TLC). (34) The ELBW
contributing to BPD. The 15 minutes between delivery and the start of postnatal care is infant has great difficulty establisha complex and often poorly controlled period. Major variables that may injure the lungs ing a reasonable FRC because of
surfactant deficiency, inadequate
during the transition to air breathing are indicated.
with 15 to 20 mL/kg was required

to normalize PCO2 values using a
ventilation rate of 30 breaths/min,
but these tidal volumes also severely
injured the preterm lamb lung. Injury was minimized by use of lower
tidal volumes for initial ventilation
after preterm birth, but the low
tidal volumes resulted in hypercarbia. The use of low tidal volumes,
but no PEEP, increases the injury
that develops after preterm birth
(Fig. 9). (37)
Other potential sources of injury
to the preterm lung are the gases
and the conditioning (temperature,
humidity) of the gases used for resuscitation of the preterm. The new
International Liaison Committee
on Resuscitation (ILCOR) recommendations for neonatal resuscitation suggest that room air or an
Figure 9. Cytokine mRNA expression in lung tissue of preterm lambs 2 hours after oxygen concentration of less than
delivery and ventilation. The animals were ventilated after surfactant treatment at birth 100% are options, but caution is
with either 0 or 4 cm H2O positive end-expiratory pressure (PEEP) with a goal to keep the suggested for using less than 100%
PCO2 greater than 50 mm Hg. The fetal lung expressed very low cytokine mRNA levels. oxygen for the preterm infant. (38)
Ventilation with PEEP resulted in increased IL-1beta and IL-6 mRNA levels, which were However, the preterm infant may
much higher when ventilation was without PEEP. Data redrawn from Naik (37). tP<0.01 be more susceptible to oxidantversus fetal lung and *P<0.05 versus 4 cm H2O PEEP.
mediated injury than the term infant because protective antioxidant
respiratory drive, and a compliant chest wall. The clinisystems are less well developed. The term infant has
cian attempting to ventilate the infant cannot establish
delayed onset of spontaneous breathing and biochemical
and maintain a reasonable FRC without consistent posiindicators of oxidant injury even after a brief exposure to
tive end-expiratory pressure (PEEP) or continuous pos100% oxygen. The possible contribution of 100% oxygen
itive airway pressure (CPAP). Unfortunately, the FRC
to the initiation of lung injury in the preterm infant
cannot be measured in clinical practice. Compliance of
presently is not known. Many delivery rooms use only
the preterm lung is highly variable because of the range
100% oxygen that is neither heated nor humidified.
of surfactant amounts and the TLC, which depend on
There is no information about the potential of unhusurfactant amount and the amount of induced lung matumidified and unheated air or oxygen to injure the airways
ration. Thus, mechanical ventilation is very likely to injure
of term or preterm infants.
the lung of the ELBW infant.
Surfactant treatment before the initiation of breathing
Injury is most likely to occur during neonatal resuscican decrease lung injury strikingly in preterm animals
tation because of the physiologic difficulties of establishthat have surfactant deficiency. (35)(36) The human
ing an FRC while avoiding overdistention of the lung.
situation is more complex because many preterm infants
The anxieties of clinicians to ventilate the infant quickly
have some degree of early lung maturation, and intubapromote excessive ventilation. Bjorklund and associates
tion and ventilation, when not necessary, can increase the
(35) demonstrated that just six large tidal volume breaths
risk of injury to the preterm lung. The relative merits of
could injure the preterm lamb lung severely and that
early surfactant treatment are discussed in another article
surfactant treatment prior to high tidal volume ventilain NeoReviews. (39) The optimal timing of surfactant
tion minimized the injury. Wada and colleagues (36)
treatment for ELBW infants remains unresolved within
demonstrated that 30 minutes of tidal volume ventilation
the context of delivery room management.
The recent ILCOR guidelines

do not address resuscitation of the
preterm infant other than to say
that the lung can be easily injured,
PEEP/CPAP may be helpful, and
maintenance of body temperature
is important. (38) The lack of specific guidelines results from the almost total lack of evidence-based
information concerning resuscitation of the preterm infant. The results from animal models suggest
strongly that PEEP/CPAP are important, as is limiting tidal volumes
to perhaps no more than 5 mL/kg;
100% oxygen seldom is required.
Avoidance of hyperventilation is an
important first step in minimizing
lung injury. The contribution of
lung injury at delivery to the ultimate outcome of BPD may never
be defined clearly because this brief
opportunity to injure the lung soon
is overtaken clinically by prolonged
postnatal management. However,
it is clear that in the extreme, pulmonary interstitial emphysema can
be initiated in the delivery room
and can be a strong indicator of
subsequent poor lung function and
ultimately BPD.
Ventilatory Support as a
Cause of BPD
Figure 10. Meta-analyses of randomized trials comparing high-frequency ventilation

(HFV) and conventional ventilation (CMV) for the outcome of bronchopulmonary
dysplasia. The earlier studies favored HFV, but that benefit has not been maintained in
more recent trials. Explanations for the change in responses include the introduction of
surfactant into clinical care and the use of different ventilation approaches and
equipment. Reprinted with permission from Bollen, et al (41). American Thoracic
Society.
The two primary associations with

the new BPD in ELBW infants are gestational age (birthweight) and exposure to ventilatory support. The association of ventilatory support with BPD has been dominant since the initial description of the disease in 1967.
(3) With each improvement in ventilatory technique, the
new technique initially was believed to be a (partial)
solution to the BPD problem. The introduction of CPAP
and PEEP improved mortality, and negative pressure
ventilation was promoted as the solution to lung injury.
Unfortunately, small infants who have significant lung
disease cannot be supported with negative pressure ventilators, and those are the infants now at significant risk of
developing BPD. High-frequency oscillatory ventilation
(HFOV) had been promoted as the solution to the BPD
problem, initially because of the remarkable demonstrations of decreased injury relative to conventional ventila-
tion of preterm baboons that had RDS. (40) However,

the favorable BPD outcomes initially reported from clinical trials are much less compelling in more recent trials,
and a meta-analysis demonstrates convergence of the
BPD outcome for HFOV and conventional ventilation
(Fig. 10). (41) Because the trials were conducted over
about 15 years, the techniques, equipment, and clinical
goals for all approaches to mechanical ventilation were
improving, and survival of more immature infants was
increasing. The incidence of BPD has not changed, but
the severity of BPD has decreased. (42) Clark made the
point in an editorial that outcomes with ventilatory support depend on both the tool (ventilator) and the
carpenter (clinician). (43)
The physiologic model for ventilator-induced lung
injury in the adult lung is shown in Figure 11. (44) The
sure is required to ventilate the lung

on the deflation limb of the
pressure-volume curve than on the
inflation limb. The preterm lung is
a challenge to ventilate because the
TLC is low, and although FRC also
is less (15 to 20 mL/kg) than in the
adult lung, there is a much smaller
volume range in which injury will
not occur. (45) This model is oversimplified primarily because lung
Figure 11. Hypothetical pressure-volume curves for adult and preterm lungs. Injury inflation is not uniform if the lung is
occurs if the lung is ventilated from below functional residual capacity (FRC) or to diseased or injured. Surfactant defivolumes close to total lung capacity (TLC). When the graphs are scaled such that the ciency increases the pressures
80-mL/kg TLC of the adult lung is shown to be similar to the 30-mL/kg TLC for the needed to achieve the volumes in
preterm lung, the large difference in the lung volume available for ventilation is not the preterm lung and cause nonuniapparent. As indicated, this volume is about 50 mL/kg in the adult and about 15 mL/kg form inflation. The assumptions of
in the preterm infant who has respiratory distress syndrome. Also note that higher this model and the clinical experipressures are required to recruit volume for the preterm than for the adult lung.
ences in older children and adults
are that if mechanical ventilation
occurs in the safe pressure-volume range on the deflation
pressure-volume curve for the normal lung has regions of
limb of the pressure-volume curve, no lung injury occurs.
injury on the inflation and deflation limbs. Lung injury
The goal of HFOV is to keep the lung volume relatively
occurs below a normal FRC of about 30 mL/kg and for
high on the deflation limb of the pressure-volume curve
volumes approaching or above a normal TLC. Less presand use small tidal volumes that do
not approach TLC. Conventional
ventilation of the preterm infant
with sufficient PEEP to hold the
lung at or above FRC and with the
use of small tidal volumes may result in a risk of ventilation-mediated
injury that is similar to that of
HFOV.
CPAP is the ventilatory support
technique now claimed to decrease
BPD when used to avoid intubation and mechanical ventilation.
(46) CPAP should recruit and
maintain the FRC and allow the
infant to breathe, presumably using
tidal volumes that do not approach
TLC. With experience, CPAP can
be used to transition infants successfully from the delivery room to
the neonatal intensive care unit,
Figure 12. Clinical experience with a trial of CPAP in the delivery room. Infants were
and many such infants do not remanaged with CPAP when possible in the delivery room, and their need for intubation by
the second postnatal day was documented. A CPAP success was defined as not needing quire intubation and surfactant
CPAP for the first 7 days after birth. The table gives the percent of overall population in treatment. The clinical experience
each group, mean values for the birthweights, the percent of infants in each outcome of Aly and colleagues (47) is shown
group treated with surfactant, and the occurrence of BPD, defined as oxygen use at in Figure 12. The larger infants
usually required only CPAP. The
36 weeks postmenstrual age. Adapted from Aly, et al. (47)
incidence of BPD was higher in infants who were intubated in the delivery room than in infants managed by
CPAP. However, the occurrence of BPD was still 28% in
infants who were extubated to CPAP soon after delivery.
The infants were not randomized to care strategies, so
this and other clinical experiences do not demonstrate
that CPAP can prevent BPD.
Some experimental observations indicate that a CPAP
strategy preserves lung structure and allows alveolarization to occur. Thomson and associates (48) demonstrated preservation of lung structure for preterm baboons supported with CPAP after an initial period of
surfactant treatment and stabilization with mechanical
ventilation. Preterm lambs have fewer biochemical indicators of lung injury on CPAP than on conventional
ventilation. (49) These experimental results are proof of
principal that CPAP can cause less injury to the preterm
lung than conventional ventilation. However, similar
models were used to show that HFOV was superior to
conventional ventilation, an outcome that has not translated to clinical practice.
My assessment of the controversies about the best
ways to avoid BPD combines concepts of lung injury,
lung development, and reasonable clinical care strategies.
Important advantages of CPAP are the avoidance of
overinflation and inflation without control of PEEP,
especially in the delivery room. The preterm lung is easy
to injure, and the more injury, the more likely that BPD
will develop. However, CPAP, PEEP, and the higher
mean airway pressures used for HFOV stretch the lung,
and stretch can transduce inflammation. The requirements for an FRC and a tidal volume sufficient for gas
exchange, no matter how accomplished, may be sufficient to alter the subsequent development of the saccular
lung. Injury and the other associations with BPD only
make the developmental abnormalities worse.
Oxygen and BPD

In the clinical setting, oxygen has not been disentangled
from ventilation in terms of relative importance for causing BPD. Infants who require ventilatory support also
usually receive supplemental oxygen. The anatomic
changes of delayed alveolar septation and an arrest in
microvascular development occur simply with oxygen
exposure in newborn rodents. (50) There is no information on the importance of oxygen to lung injury immediately after delivery or within the first days after birth in
infants. However, infants who had retinopathy of prematurity and were randomized to a high oxygen saturation
target had more severe BPD that persisted for a longer
period of time than infants randomized to a lower oxy-
gen saturation range in one study. (51) The recent

emphasis on keeping oxygen saturations to a reasonable
range (perhaps 85% to 95%) for oxygen-exposed ELBW
infants should help decrease the severity of BPD, although the optimal oxygen saturation range remains
unknown.
Sepsis and BPD

As reviewed previously, chorioamnionitis is an association with BPD. Infants exposed to chorioamnionitis
range in exposure from mild lung inflammation to a
systemic inflammatory response and sepsis. The lung
inflammation prior to birth is the start of an inflammatory
response that can be amplified by postnatal care that
includes ventilation and oxygen. Infants exposed to chorioamnionitis also have early tracheal colonization with
organisms, which also is an association with BPD. (52)
Postnatal sepsis is a similar insult that occurs after the
lung injury/developmental abnormality sequence has
been initiated. The experimental literature clearly demonstrates that most any cause of inflammation can stop
alveolar septation in newborn rodents. Whenever it occurs, infection with its associated inflammation is likely to
interfere with lung development. Postnatal sepsis is an
important variable that confounds studies of the relative
benefits of different ventilatory support strategies because infection is so common in ELBW infants.
Postnatal Corticosteroids
Corticosteroids have pleotropic effects on the fetus and
newborn, and the lung is a target of corticosteroid action. Corticosteroids mature the fetal lung, primarily by
decreasing the amount of mesenchymal tissue and increasing potential airspace volume. Such anatomic
changes result in an arrest in alveolar (saccular) septation
in fetal monkeys and sheep. (27) Similarly, postnatal
corticosteroids arrest alveolar septation and microvascular development in rodents. (19) Thus, corticosteroids
induce the anatomic equivalent of a mild new BPD. The
fetal exposures are of low dose and short duration relative
to the exposures often provided postnatally. The maturational benefits exceed the risks for fetal exposures.
Postnatal treatments to prevent or treat BPD are primarily used for anti-inflammatory effects. Postnatal corticosteroids are controversial and generally not recommended because of concerns about adverse effects on
neurodevelopment. The recent meta-analysis by Doyle
and colleagues (21) demonstrated that for infants at high
risk of developing BPD, corticosteroid treatments after
approximately 1 week of age may be of benefit (Fig. 13).
Figure 13. Possible benefits of postnatal corticosteroids (CS) depend on risk of chronic lung
disease (CLD). This graph compares the risk difference (RD) for death or cerebral palsy (CP) for
infants randomized to postnatal corticosteroids relative to the percent of control infants who
have CLD. The size of the circle is proportionate to study size. The regression line with 95%
confidence intervals demonstrates that for infants at a high risk of CLD, postnatal corticosteroids may decrease death and CP. Reprinted with permission from Doyle, et al. (21)
have BPD have increased pulmonary problems and poorer neurodevelopment than unaffected ELBW
infants. My interpretation is that all
ELBW infants have some degree of
abnormal lung development, and
BPD is the clinical manifestation of
increased severity of developmental
abnormalities. Preterm infants have
more airway restriction than term
infants at term, and the preterm
infant has more airway reactivity
later in life. Children who survived
the old BPD have some restrictive
airway disease and increased airway
reactivity. (54) There is very little
information about if and how infants who have the new BPD remodel their alveoli and microvasculature with growth. Of concern is the
observation that adolescent monkeys
that were ventilated after preterm
birth continued to have lungs that
had decreased alveolar numbers (Fig.
14). (55) Most infants who have
milder forms of BPD seem to have
minimal residual lung disease, but
normally there is a large respiratory
reserve that decreases after adolescence throughout life. A concern is
how such BPD lungs will age.
ACKNOWLEDGMENTS. This work
was supported in part by grants
HD-12714 and HL-65397 from
the National Institutes of Health.
Figure 14. Decreased alveolar septation in baboon survivors of BPD. Preterm baboons
were delivered and randomized to ventilation with low or high supplemental oxygen for
21 days. The high oxygen plus ventilation-exposed group developed BPD. The BPD animals
survived until 33 weeks of age, and biopsies of the lungs (A) demonstrated larger distal
airspaces than for the comparison preterm ventilated animals exposed to less supplemental oxygen (B). Jacqueline Coalson, University Texas San Antonio, provided micrographs
that are similar to those published by Coalson, et al. (55)
Outcome of Infants Who Have BPD

The long-term lung outcomes for ELBW infants are a
concern. ELBW infants who do not have BPD require
frequent hospitalizations and lung-related medications
in the first 2 postnatal years. (53) ELBW infants who
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NeoReviews Quiz
9. In contrast to classic bronchopulmonary dysplasia (BPD), initially described in 1967, the new BPD in
the more contemporary clinical setting is characterized by different histopathologic findings on
examination of the lung tissue. Of the following, the most striking abnormality in the lungs of infants
who have new BPD is:
A.
B.
C.
D.
E.
Decrease in alveolar septation.

Diffuse leukocytic infiltration.
Epithelial squamous metaplasia.
Hypertrophy of airway smooth muscle.
Lung parenchymal fibrosis.
10. Maternal chorioamnionitis, defined as inflammation of the fetal membranes and the presence of
inflammatory cells or organisms in the amniotic fluid, often is a pathway for the development of BPD in
preterm infants. Of the following, the most frequent organism associated with maternal chorioamnionitis
as a cause of neonatal BPD is:
A.
B.
C.
D.
E.
Escherichia coli.
Group B Streptococcus.
Listeria monocytogenes.
Staphylococcal species.
Ureaplasma urealyticum.
11. The pathogenesis of new BPD in extremely low-birthweight (ELBW) infants involves a complex interplay
of several factors. Of the following, one of the primary associations with the development of new BPD in
ELBW infants is:
A.
B.
C.
D.
E.
Exposure to ventilator support.

Genetic predisposition.
Nutritional deficit.
Postnatal sepsis.
Surfactant deficiency.
12. Corticosteroids have pleiotropic effects on the fetus and newborn, and the lung is a target of
corticosteroid action. Of the following, the most striking anatomic change in the lung in relation to
postnatal corticosteroid treatment is:
A.
B.
C.
D.
E.
Arrested microvascular development.

Decreased airspace volume.
Dysplastic epithelial type 2 cells.
Increased mesenchymal tissue.
Infiltration with inflammatory cells.
The New BPD

Alan H. Jobe
NeoReviews 2006;7;e531-e545
DOI: 10.1542/neo.7-10-e531
Updated Information
& Services
including high-resolution figures, can be found at:

http://neoreviews.aappublications.org/cgi/content/full/neoreview
s;7/10/e531
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The New BPD

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The New BPD

After completing this article, readers should be able to:

Explain the anatomy of the new bronchopulmonary dysplasia (BPD).

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whose birthweights were less than

Bronchopulmonary Dysplasia (BPD)

e532 NeoReviews Vol.7 No.10 October 2006

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tion is being studied intensively because of its relevance to BPD in

the New BPD

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complex phase of lung development between airway

different stages in the progression

Mice and other rodents are born at

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relates no doubt are confounded by

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with 15 to 20 mL/kg was required

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The recent ILCOR guidelines

Figure 10. Meta-analyses of randomized trials comparing high-frequency ventilation

The two primary associations with

tion of preterm baboons that had RDS. (40) However,

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sure is required to ventilate the lung

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Oxygen and BPD

gen saturation range in one study. (51) The recent

Sepsis and BPD

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Outcome of Infants Who Have BPD

DY. Pulmonary disease following respirator therapy of hyaline-membrane disease.

Downloaded from http://neoreviews.aappublications.org. Provided by Health Internetwork on September 14, 2009

chronic lung disease of prematurity. Am J Perinatol. 2001;18:

chronic lung disease in preterm infants. J Pediatr. 2002;140:

Downloaded from http://neoreviews.aappublications.org. Provided by Health Internetwork on September 14, 2009

42. Smith VC, Zupancic JA, McCormick MC, et al. Trends in

e544 NeoReviews Vol.7 No.10 October 2006

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Decrease in alveolar septation.

Exposure to ventilator support.

Arrested microvascular development.

NeoReviews Vol.7 No.10 October 2006 e545

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The New BPD

including high-resolution figures, can be found at:

Permissions & Licensing

Information about reproducing this article in parts (figures,

Information about ordering reprints can be found online:

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