Pediatric Pulmonology 12.09.20
Julian Allen and Howard Panitch
Bronchopulmonary dysplasia (BPD), or chronic lung disease of infancy,
was first described by Northway et al in 1967 in a now classic article
(1). The authors presented radiographic and pathologic findings in a
series of 32 newborn preterm infants who developed hyaline membrane
disease, required supplemental oxygen and/or mechanical ventilation, and
who subsequently developed abnormal chest radiographs and chronic
supplemental oxygen requirement. Philip reviewed the relative
contributions of oxygen, positive pressure, and lung injury to the
development of BPD (2). However, much of our current understanding of
the pathophysiology of BPD actually antedates the first 1967
description.
Pre- 1960. The first relevant publication to the
pathophysiology of BPD dates back to 1805 when LaPlace (quantitatively)
and Young (qualitatively) described the relationship between radius,
surface tension and pressure in spheres with an air- liquid interface
(3). The simplified version of their equation,
P= 2T/r (or 4T/r if there are inside and outside interfaces)
explains how a smaller radius of curvature (r) generates a higher
pressure (P) given a constant surface tension (T). It also implies that
it will be difficult for connected spheres of different radii to
co-exist if their surface tensions are equal; the smaller spheres,
having higher pressures, will tend to empty into the larger spheres.
These phenomena of surface tension at air-liquid interfaces were
beautifully demonstrated in an elegant series of children’s lectures
delivered by C.V. Boys and published as “Soap-bubbles and the forces
which mould them. Being a course of three lectures delivered in the
theatre of the London Institution on the afternoons of Dec. 30, 1889,
Jan. 1 and 3, 1890, before a juvenile audience (4).” He demonstrated
the requirement of an air-liquid interface for individual hairs of a
paintbrush to stick together by surface tension, whereas a submerged
brush had no such interface and therefore the hairs were not attracted
to one another (Figure 1). He furthermore demonstrated that soap bubbles
with small radii empty into those with large radii (Figure 2).
The inherent instability of a lung composed of alveoli of different
sizes led Avery and Mead to postulate the existence of a surface
tension-lowering agent in the lung, the absence of which in infants with
hyaline membrane disease reduced lung compliance and could lead to the
respiratory distress syndrome (Figure 3) (5). Their work also showed the
reduction of surface tension at smaller surface areas due to the
increasing concentration of surfactant as it was “compressed” as
surface area decreased. This concept, when applied to the surface of
spheres, in turn allows for the coexistence of alveoli of different
radii; if the T/r ratio remains relatively constant as the radius
decreases, this tends to equalize the pressure between alveoli of
different sizes.
There were also therapies that antedated the description of BPD that
played a role in the increased survival of premature infants. In 1958,
Silverman described the importance of the thermal environment in
improving preterm survival (6). In 1963, Usher demonstrated the
importance of nutrition for babies with RDS with the use of glucose and
bicarbonate intravenous infusions to improve survival (7).The 1960s. Prior to the introduction of mechanical ventilation,
the mortality of infants < 28 weeks’ gestation or extremely
low birthweight (ELBW: <1,000g) exceeded 90%. The most famous
example of mortality related to prematurity, and one which raised the
level of public awareness of this problem, was the death of the infant
son of President and Jacqueline Kennedy that occurred in 1963 (Figure
4). The infant was 34 ½ weeks gestation and weighed 2.1 kg (4lb 10oz),
large by today’s standards. At the time, however, survival from hyaline
membrane disease was rare, even at a gestational age of 35 weeks. The
death of baby Patrick Kennedy was a driving force for the development of
research efforts aimed at reducing mortality related to preterm birth.
Before Northway’s report, Wilson and Mikity described a syndrome of
oxygen dependence and chest radiographic abnormalities in preterm
infants (8); however, these infants had not received mechanical
ventilation, and had received little or no supplemental oxygen at birth.
Northway’s series was the first to describe lung disease associated with
mechanical ventilation and supplemental oxygen administration; those
preterm infants had received amounts of supplemental oxygen as high as
80%, but for as little as 150 hours (1). Hawker described a similar
syndrome in infants who had been treated with up to 60% oxygen for as
little as 120 hours (9). Northway’s original paper went on to describe 4
stages of disease progression with associated radiographic changes.
Stage 1 reflected classic hyaline membrane disease with ground glass
pattern and air bronchograms on chest radiographs (Figure 5). Stage 2
was a period of regeneration. Stage 3 described a period of transition
with developing hyperinflation and interstitial thickening indicative of
airway disease and parenchymal fibrosis (Figure 6), and stage 4
described established chronic disease. At about this time in the late
1960s, several investigators described the pathology of oxygen toxicity
in humans and animal models, as well as subsequent mucociliary
dysfunction (10-13), and it was proposed that the changes of BPD were at
least in part due to oxygen toxicity (1, 14).The 1970s. The next decade saw a large increase not only in our
understanding of causal factors in the development of BPD, but also the
introduction of significant new therapies. In 1972, Liggins et al
reported on the use of prenatal maternal betamethasone to reduce the
severity and incidence of neonatal RDS in infants born prematurely (15).
However, the treatment was not adopted as a widespread practice until
the 1990s (16, 17).
At about this time, the understanding of the pathogenesis of BPD was
being refined with the concept of “oxygen plus pressure plus time”
(18). Specific ventilators were being introduced for use in infants. An
NIH consensus conference in 1978 refined the nosology of chronic lung
disease of infancy, distinguishing pathological definitions
(“bronchopulmonary dysplasia”) from clinical definitions (e.g.,
supplemental oxygen requirement at 28 days of postnatal life vs. 36
weeks postconceptional age) (19).
The understanding of the role of pressure in the development of lung
injury led to novel ways to support infants with RDS with the least
amount of barotrauma. The most successful of these was the introduction
of continuous positive airway pressure (“bubble CPAP”) by an
anesthesiologist at Columbia Presbyterian’s Babies Hospital (20, 21).
This ingenious set- up provided CPAP by submerging the distal end of an
oxygen catheter in a container of water to the depth that reflected the
amount of CPAP desired, often 5 cm H20. (Figure 7). The
processes of weaning from mechanical ventilation were also described
during this time. Morray et al reported that infants requiring prolonged
mechanical ventilation reached a “halfway point” at which time a
reduction in their pCO2 heralded an ability to progress
with gradual mechanical ventilation withdrawal, characterized by a
reduction in spontaneous respiratory rates, tolerance of a reduction in
mandatory ventilator rates, and a period of sustained improved weight
gain (22). It was also in the 1970s that clinicians reported the first
experiences sending infants to home while being treated with
supplemental oxygen. Pinney and Cotton described home oxygen delivered
by nasal cannula (23). The early monitoring of oxygen saturation was
accomplished with transcutaneous PO2 monitoring (24). It
was not until the next decade that pulse oximetry was introduced.The 1980s. This decade saw increasing numbers of studies of
oxidative lung damage mechanisms, including the amplifying of hypoxia
and reoxygenation in the lungs (25) and in the brain (26). Those
observations led to several clinical trials of the use of putative
antioxidants, e.g., superoxide dismutase, vitamin A and vitamin D (27,
28). In addition, investigators began to recognize the role of maternal
chorioamnionitis in predisposing towards the development of BPD (29).
Furthermore, controlled clinical trials involving the use of
corticosteroids to enable infants with chronic lung disease to be weaned
from mechanical ventilation (30-32) extended observations that began in
the 1970s (33). Such investigations were based on recognition of the
anti-inflammatory properties of those drugs. Simultaneously, however,
others showed that in animals that undergo postnatal alveolarization,
the systemic exposure of the lung to glucocorticoids hastens maturation
of the capillary membrane, resulting in an inhibition of alveolarization
(34).
Another important advance was the recognition that pulmonary edema
played a role in the pathogenesis of BPD (35), and that its control with
fluid management, diuretics, and correction of a patent ductus
arteriosus to prevent fluid overload could be helpful in improving the
lung mechanics of infants with BPD (36, 37). Other studies that used
lung mechanics measurements as primary outcomes showed that
bronchodilators like theophylline were effective (38). Further advances
during this decade included recognition of the crucial role that
nutrition plays in supporting the overall growth of the infant and the
growth of lung parenchyma and airway size (39). This decade also saw the
first reports of the use of exogenous surfactant in preventing severe
RDS (40). To facilitate hospital discharge, home supplemental oxygen
came into more widespread use (41), made more practical with monitoring
by home pulse oximetry.
Twenty years after BPD was first described, Avery and coworkers
published a report that provided crucial understanding of the how
clinical practices, including the use of positive pressure-sparing
strategies, could reduce the incidence of BPD (20). The authors reported
a significant difference in incidence of BPD among the 8 tertiary care
NICUs studied even when birth weight, race, and sex were taken into
consideration through a multivariate logistic regression analysis. The
Center that had one of the best outcomes for low birth weight infants
and the lowest incidence of chronic lung disease employed the use of
bubble CPAP (Figure 7) (21) as well as the identification of a single
provider from the Anesthesiology Department who took over the infants’
respiratory care. Other factors that improved outcomes in that study
included avoidance of pharmacologic paralysis, more permissive pH
targets, and differences in fluid management. Gradually, the decade also
saw more acceptance of lung protective ventilation strategies that
minimized pressure swings and barotrauma, with avoidance of intubation
when possible, volume targeted ventilation, permissive hypercapnia, and
high frequency ventilation (42). The contribution of central airway
abnormalities like tracheobronchomalacia to chronic or episodic
respiratory distress was first recognized during this decade as well
(43), as was the safety and efficacy of diagnosing central airway
problems with flexible bronchoscopy (44).The 1990s. The decade saw further documentation of the role of
chorioamnionitis in contributing to the development of chronic lung
disease, and the introduction of artificial surfactants (Exosurf © and
Survanta©). These improvements in care fundamentally altered the
pathology of BPD. This new pathology was characterized less by
parenchymal fibrosis and airway damage and more by abnormalities in lung
development, leading primarily to alveolar simplification (45). During
this decade, the outcome for most preterm infants was altered
substantially. Not only did survival improve for each gestational age,
but the severity of residual lung damage also decreased (46).
Another advance that allowed for reduction of the FiO2required to achieve minimal oxygen saturation targets came with the
introduction of inhaled nitric oxide (iNO) into clinical practice (47).
This agent improved ventilation/perfusion mismatch in the lungs,
enhancing perfusion by acting as a vasodilator only to those areas of
the lung that were ventilating well enough to allow entry of the NO.
This was an era where there was also much study of the optimal
oxyhemoglobin targets for end organ oxygenation while minimizing
oxidative damage to the lungs and retinae to prevent retinopathy of
prematurity. Kotecha summarized these studies in 2002 (48), and
recommended a target range of at least 94–96% and avoidance of oxygen
saturations < 92%. He also acknowledged that the saturation
target range for very preterm infants at risk of developing ROP was more
controversial, due to a probably narrower therapeutic range (49, 50).
Finally starting in the 1980s, and continuing into the 2000s, the use of
infant lung function testing, including tidal breathing mechanics,
respiratory inductive plethysmography, the thoracic compression
technique and the raised volume thoracic compression technique, gas
mixing evaluations such as the nitrogen washout technique and
oscillometry to characterize the physiologic derangements in BPD came
into more widespread use (51, 52). Improvements in lung mechanics with
the application of CPAP with or without custom tracheostomy tubes (53,
54) or pharmacologic interventions like cholinergic agents (55) were
described in infants with tracheo-bronchomalacia.
This is also the time that the concept of non-invasive ventilation as a
modality to reduce BPD was introduced, with ongoing studies into the
next decade (56). Although home mechanical ventilation of infants with
severe BPD began in the late 1970s, guidelines for the care of infants
and children with chronic respiratory failure secondary to BPD, and the
equipment needs for those children were not published until the 1990s
when such care became more standardized (57, 58).
The 2000s. An American Thoracic Society Statement on the care
of the child with chronic lung disease was published that emphasized the
appreciation of BPD as a multisystem disease (59). This concept was
summarized in a figure emphasizing the interaction between the various
organ systems affected by BPD (Figure 8).
Investigators had long recognized alterations in the pulmonary
vasculature that accompanied parenchymal lung disease in infants with
BPD, but they began to describe the relationship between severe BPD and
pulmonary hypertension, and how the presence of pulmonary hypertension
increased late mortality of BPD children (60). In addition, small series
reported the successful treatment of infants with BPD and pulmonary
hypertension using sildenafil (61).
In 2006, a clinical trial of caffeine therapy for apnea of prematurity,
given to infants of gestational age as young as 27 weeks who were just
under 1000 gm, demonstrated a reduction in the incidence of BPD (62,
63). The decade also ushered in studies exploring the genetic
underpinnings of BPD, including genetic variants of surfactant proteins
(64, 65) and numerous other genomic and proteomic markers (66, 67).
The 2010s. Additional studies of BPD pathogenesis have taken
place in the past decade, expanding our knowledge of mechanisms of lung
injury in animal models, including the roles of chorioamnionitis,
postnatal inflammation, oxygen toxicity and barotrauma, Ureaplasma
urealyticum infections and genetics (68-71). Further trials of treatment
with postnatal systemic steroids emphasized short term, low dose
protocols balancing the aim of minimizing time on mechanical ventilation
with adverse neurodevelopmental consequences (72-74). Greater
appreciation of the role of the altered pulmonary vasculature and
pulmonary hypertension in severe BPD led to clinical trials of iNO (75)
and other therapies (76). Investigators also proposed novel therapies
with insulin-like growth factor 1 (IGF-1) and mesenchymal stem cells
(71). As the number of infants with severe BPD who required prolonged
mechanical ventilation (Type 2 severe BPD) increased (77), experts
promoted modifications of ventilator strategies, changing from the low
tidal volume lung-protective strategies used to prevent the development
of BPD to strategies that allow for more even distribution of
ventilation in the severely affected BPD lung, including higher tidal
volumes, lower mandatory inspiratory rates and longer inspiratory and
expiratory times (78). Recognition of the presence of dynamic
hyperinflation and the development of intrinsic PEEP in infants with the
most severe lung disease led investigators to use higher levels of PEEP
to improve patient-ventilator synchrony (79). One novel approach now
under investigation comes full circle to the surface tension problem
described by C.V. Boys in the 1890s, as outlined above , with the
investigation of “liquid” ventilation as a way to abolish the
air/liquid interface altogether (80).
Evolving definitions of BPD With the improved outcome for
earlier gestational age infants came a recognition that the pathology of
BPD had changed as well, from parenchymal fibrosis and airway damage to
arrest of alveolar development (71). Part of the problem of interpreting
studies of BPD spanning several decades is that the definitions of BPD
have changed since it was first described by Northway in 1967 (81).
Initial definitions combined the need for supplemental oxygen at 30 days
of life with radiographic changes (82), while subsequent definitions
refined clinical criteria but maintained stereotypical radiographic
findings as a criterion (83). In 1988, a simplified definition of BPD
was proposed, based on the need for supplemental oxygen use at 36 weeks
postmenstrual age in preterm infants born <1500g, a definition
that remains in common use (84). The rationale for this change from a
simple supplemental oxygen requirement at 28 days is that as infants
born at earlier and earlier gestational ages were surviving, a
supplemental oxygen requirement at 28 days in a 36 week gestation infant
likely meant more significant disease than a supplemental oxygen
requirement at 28 days in a 28 week gestation infant. An NIH workshop in
2000 further refined the definitions with differing criteria for infants
greater or less than 32 weeks gestational age, and added categories of
mild, moderate, and severe BPD depending on supplemental O2 and positive
pressure requirements: mild (weaned to room air), moderate
(<30% supplemental oxygen requirement) and severe
(>30% supplemental oxygen requirement or need for positive
pressure). Further refinement of the severe definition into Type 1
(supplemental oxygen dependence) and Type 2 (ventilator dependence) has
led to patient groupings that allow different treatment strategies to be
compared within the various severity groups (85). Newer strategies for
respiratory support, like use of heated, humidified high-flow therapy
challenge current definitions of BPD; this problem will persist as long
as definitions of BPD rely upon therapies used.
The net result of all the improvements in BPD care have led to a
somewhat paradoxical stability in its incidence. A Neonatal Research
Network study showed no change and even a slight increase in incidence
of BPD over last several decades (86), likely resulting from a balance
between increased survival of infants of very low gestational age and
birthweight, and a reduced incidence of BPD at any given gestational
age. However, despite improved neonatal care and survival, BPD
prevalence remains high at 35% -40% among extremely low gestational
age neonates (<28 weeks GA), and thus BPD continues to occur
among 10 to 50% of all premature infants internationally (71).
The future. Respiratory clinicians increasingly appreciate that
the roots of adult chronic obstructive lung disease arise in the
pediatric pulmonary experience (87). Infants with recurrent wheeze are
at increased risk of developing asthma in childhood, and children who
wheeze throughout childhood are at increased risk of developing COPD and
the asthma/COPD overlap syndrome in adulthood (88). BPD is undoubtedly a
risk factor for these adult conditions as well (89). Thus, the history
of BPD is still very much still being written. As the care for infants
and children with BPD continues to improve, so will the respiratory
health of the adults they will become.