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%20dysplasia
taken from fanaroff 2022 using EKB clinical key

Definition of BPD

the definition of BPD has been modified multiple times to reflect changes in
patient population and to better predict pulmonary outcomes. Initial definitions of
BPD consisted of oxygen use along with radiographic pictures consistent with BPD
at 28 days. 4

4. Bancalari E, et. al.: Bronchopulmonary dysplasia: clinical presentation. J Pediatr

1979; 95: pp. 819-823.

With increasing survival of more immature infants over time, the implication of
oxygen use at 28 days was questioned, and oxygen requirement at 36 weeks was
shown to be more accurate predictor of long-term pulmonary outcomes. 59

59. Shennan AT, et. al.: Abnormal pulmonary outcomes in premature infants:
prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82:
pp. 527-532.

In 2001, a workshop conducted by the National Institutes of Health (NIH)

proposed a severity-based definition of BPD into three categories based on the
 duration and level of oxygen therapy required ( Table 69.1 ). The assessment of
severity of BPD adds richness to the outcome measure and identifies a spectrum of
adverse pulmonary and neurodevelopmental outcomes. As the severity of BPD
increases, the incidence of adverse events also increases. The use of supplemental
oxygen as a criterion to define severity of BPD has some limitations. The use of
supplemental oxygen in these infants is often inconsistent and is not based on a
physiologic assessment, which can greatly affect the reported incidence of BPD. To
overcome this inconsistency, a physiologic test to standardize the need for
supplemental oxygen has been used. 71
71. Walsh MC, et. al.: Safety, reliability, and validity of a physiologic definition of
bronchopulmonary dysplasia. J Perinatol 2003; 23: pp. 451-456.

Some of the other limitations of the current definition of BPD include failure to
classify infants with nonpulmonary causes such as central apnea or airway
complications for need for respiratory support, inability to classify infant dying
secondary to severe respiratory failure prior to 36 weeks, or failure to
appropriately categorize infants on more contemporary modes of respiratory
support like high flow nasal cannula. 53 Definitions of BPD are currently evolving in
an attempt to categorize infants by severity of disease based on level of support. 24a

Higgins RD, Jobe AH, Koso-Thomas M, et. al.: Bronchopulmonary dysplasia:

executive summary of a workshop. J Pediatr 2018; 197: pp. 300-308.

Definition of Bronchopulmonary Dysplasia: Diagnostic Criteria

Adapted from Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care
Med 2001;163:1723.

Gestational Age <32 Weeks ≥32 Weeks

Time point of 36 weeks' PMA or discharge to home, >28 days but <56 days' postnatal age or
assessment whichever comes first discharge to home, whichever comes first
Treatment With >21% Oxygen for at Least 28 Days PLUS
Mild BPD Breathing room air by 36 weeks' PMA or Breathing room air by 56 days' postnatal age
discharge, whichever comes first or discharge, whichever comes first
Moderate BPD Need for <30% oxygen at 36 weeks' PMA or Need for <30% oxygen at 56 days' postnatal
Gestational Age <32 Weeks ≥32 Weeks
discharge, whichever comes first age or discharge, whichever comes first
Severe BPD Need for ≥30% oxygen and/or positive Need for ≥30% oxygen and/or positive
pressure (PPV or NCPAP) at 36 weeks' pressure (PPV or NCPAP) at 56 days'
PMA or discharge, whichever comes first postnatal age or discharge, whichever comes
first
BPD, Bronchopulmonary dysplasia; NCPAP, nasal continuous positive airway pressure; PMA,
postmenstrual age; PPV, positive pressure ventilation.

Pathogenesis of bpd
BPD, as described originally by Northway and colleagues, resulted from
injury to developing lung secondary to prolonged mechanical ventilation
with high airway pressures and inspired oxygen concentration. In contrast,
BPD currently is mostly seen in extremely preterm infants in late
canalicular or early saccular stage of lung development at birth. Multiple
pathogenic factors including pre- and postnatal infections, mechanical
trauma from positive pressure ventilation, oxygen toxicity, and pulmonary
edema secondary to increased pulmonary blood flow from patent ductus
arteriosus (PDA) acts on the immature alveolar and vascular structure of
the immature lung. The complex interplay of lung development, injury by
pathogenic factors, and reparative processes results in the morphologic and
functional lung alterations characteristic of BPD ( Fig. 69.3 ).
Fig. 69.3
Algorithm for pathogenesis of bronchopulmonary dysplasia. IUGR, Intrauterine growth restriction.
(Modified from Abman S, Bancalari E, Jobe A. Am J Respir Crit Care Med. 2017;195(4):421.)

Prenatal Factors

Prematurity is the most important risk factor for development of BPD. The
prevalence of BPD is inversely related to gestational age and birth weight,
strongly suggesting that incomplete development of the lungs plays a
critical role in the pathogenesis of BPD. 30

30. Jobe AJ: The new BPD: an arrest of lung development. Pediatr Res 1999; 46:
pp. 641-643.

Epidemiologic studies have identified male gender, white race, and

maternal smoking and hypertension as risk factors associated with
increased risk for BPD. 34 44 Intrauterine growth restriction is also
associated with increased risk for BPD, likely secondary to impaired
alveolar and vascular growth. 38 57

57. Rozance PJ, et. al.: Intrauterine growth restriction decreases pulmonary
alveolar and vessel growth and causes pulmonary artery endothelial cell
dysfunction in vitro in fetal sheep. Am J Physiol Lung Cell Mol Physiol 2011; 301:
pp. L860-L871.

The role of maternal chorioamnionitis on the risk for BPD has been unclear,
with multiple studies showing increased risk for BPD in infants born to
mothers with evidence for chorioamnionitis; others, however, have failed to
show such association. 2467 The effect of chorioamnionitis on fetal lung
varies from inflammation and lung injury to enhanced lung maturation
depending on fetal inflammatory response, the organism causing the
infection, and the severity or duration of infection.29

29. Jobe AH: Effects of chorioamnionitis on the fetal lung. Clin Perinatol 2012; 39:
pp. 441-457.

Postnatal Factors
Mechanical Trauma
Although high-peak inspiratory pressure is one of the factors implicated as a cause of BPD, it is
difficult to separate the role of the high pressures from the underlying lung disease on the chronic
lung damage. The damaging effect of high airway pressure and tidal volume on the surfactant-
deficient lung was demonstrated in preterm lambs. Lung compliance was decreased after only a
few breaths, with excessive tidal volumes given before surfactant replacement. 8 Experimental
evidence strongly suggests that excessive tidal volumes can damage the lung, initiate an
inflammatory cascade, and interfere with normal lung development. 25 The effect of prolonged
ventilation was shown in newborn mice where ventilation for 24 hours resulted in increased
apoptosis, inhibition of alveolarization, and angiogenesis in the lung. 43

Although injury from the mechanical ventilation continues to be an important factor in the
pathogenesis of BPD, today most premature infants who require prolonged ventilation due to
milder respiratory failure or poor respiratory effort receive lower airway pressures. Therefore,
mechanical trauma appears to play a lesser role among the multiple factors acting concurrently
on a premature lung to result in milder BPD.

Oxygen Toxicity
Clinical and experimental evidence suggested that pulmonary oxygen toxicity was a major factor
in the pathogenesis of the severe original BPD. Although many tissues can be injured by high
oxygen concentrations, the lung is exposed directly to the highest partial pressure of oxygen. The
precise concentration of oxygen that is toxic to the immature lung probably depends on a large
number of variables, including gestational age, nutritional and endocrine status, and duration of
exposure to oxygen and other oxidants. Although a safe level of inspired oxygen has not been
established, any concentration in excess of room air might increase the risk of lung damage when
administered over a long period of time.

The pulmonary changes of oxygen toxicity are nonspecific and consist of atelectasis, edema,
alveolar hemorrhage, inflammation, fibrin deposition, and thickening of alveolar membranes.
There is early damage to capillary endothelium in animals, and plasma leaks into interstitial and
alveolar spaces. Pulmonary surfactant can be inactivated by protein in the airspaces, adding to
the risk of atelectasis. Type 1 alveolar lining cells can be injured early, and bronchiolar and
tracheal ciliated cells can also be damaged by oxygen. Total resolution after oxygen toxicity is
possible if the initial exposure is not overwhelming.

Continued exposure to high inspired oxygen levels is accompanied by influx of

polymorphonuclear leukocytes containing proteolytic enzymes. In addition, the antiprotease
defense system is significantly impaired in infants exposed to prolonged high inspired oxygen
levels, favoring proteolytic damage of structural elements in alveolar walls. This could be an
important pathogenic factor in oxygen toxicity and BPD. High inspired oxygen concentration
can also inhibit the normal process of alveolar and capillary formation in immature animals.

Although the cellular basis for oxygen toxicity has not been completely elucidated, the principal
mechanisms involve the univalent reduction of molecular oxygen and formation of free radical
intermediates. The latter can react with intracellular constituents and membrane lipids, thus
initiating chain reactions that can cause tissue destruction.

To resist the detrimental effects of oxygen, the organism has evolved a number of antioxidant
systems. Antioxidant enzymes such as superoxide dismutase, catalase, and glutathione
peroxidase seem to play an important role in preventing the toxic effects of oxygen. Other
elements, such as vitamin E, glutathione, and selenium, are also part of the endogenous
antioxidant mechanisms. The capacity for synthesizing these enzymes in some animal species
follows a maturational trend similar to the production of surfactant; therefore, animals born
prematurely have lower concentrations of antioxidant enzymes than those born at term.

Loss of mucociliary function may be an additional pathogenic factor in BPD, because exposure
to high oxygen concentrations results in a reduction of ciliary movements.

Postnatal Infection
There is ample evidence supporting the role of infections in the development of BPD, especially
in very small infants in whom nosocomial infections are associated with a marked increase in the
risk of BPD. 56 Evidence suggests that postnatal adenovirus and cytomegalovirus infection might
also increase the risk for BPD. 31 Pulmonary colonization with ureaplasma has been evaluated as
one of the possible risk factors for BPD. Experimental studies in animal models have shown that
colonization of fetal lung with ureaplasma resulted in increased inflammation, fibrosis, and
impaired alveolar development. 1269 Several studies have suggested an association
between Ureaplasma urealyticum tracheal colonization and the development of BPD in
infants with very low birth weight. Surprisingly, trials evaluating treatment with macrolide
antibiotics have so far shown inconsistent effect on BPD. 114768

Patent Ductus Arteriosus and Pulmonary Edema

There is an association between the presence of a PDA and an increased risk for BPD ( Fig.
69.4 ). 2356 This may be secondary to increased pulmonary blood flow producing an increase in
interstitial fluid and a decrease in pulmonary compliance and increased airway resistance. This
can prolong the need for mechanical ventilation with higher ventilatory pressures and oxygen
concentrations, increasing the risk for BPD. Moreover, the increased pulmonary blood flow can
damage the pulmonary capillary endothelium and induce neutrophil margination and activation
in the lung, contributing to the progression of the inflammatory cascade. Data from studies in
preterm baboons also showed decreased alveolarization in animals that remained for a longer
time with an open ductus arteriosus, supporting the role of a persistent ductus arteriosus in the
pathogenesis of BPD. 41 Despite epidemiologic and experimental evidence of association between
PDA and BPD, prospective clinical trials to evaluate early closure of the PDA have failed to
show a decrease in the incidence of BPD. 62

62. Sosenko IR, et. al.: Timing of patent ductus arteriosus treatment and
respiratory outcome in premature infants: a double-blind randomized controlled
trial. J Pediatr 2012; 160: pp. 929-935.e1.

Other Factors
The possibility of a genetic predisposition to BPD has been evaluated in
recent years. Studies evaluating twin pairs have shown that genetic factors
contributed to a significant proportion of the variance in risk for BPD. The
efforts to identify specific candidate genes using genome-wide association
studies have so far not been successful. 35

There is also evidence that vitamin A deficiency could increase the risk for
BPD in preterm infants. Vitamin A levels are lower in infants who develop
BPD when compared to those who recovered without lung sequelae. This
possible association is supported by the similarities between some of the
airway epithelial changes observed in severe BPD and vitamin A deficiency
and by the clinical evidence that vitamin A administration during the weeks
after birth reduces the risk of BPD. 14

Early adrenal insufficiency has also been suggested as a contributing factor

in the development of BPD in the smallest infants. Infants with lower
cortisol levels in the first week of life have an increased incidence of PDA,
more lung inflammation, and increased incidence of BPD. 72

72. Watterberg KL, et. al.: Links between early adrenal function and respiratory
outcome in preterm infants: airway inflammation and patent ductus arteriosus.
Pediatrics 2000; 105: pp. 320-324.

Final Common Pathway

Inflammation plays a crucial role in the development of BPD and can be
triggered by multiple factors such as oxygen, mechanical ventilation, PDA,
and infections. Multiple studies have shown the presence of inflammatory
cells, pro-inflammatory cytokines such as chemokines, interleukin,
leukotrienes, and platelet-activating factor and other mediators in infants
with BPD. Increased desmosine excretion in the urine during the first week
of life has been described in infants who subsequently develop BPD,
indicating increased elastin degradation resulting from lung inflammation
and injury. Increased concentration of inflammatory mediators could
contribute to the bronchoconstriction and vasoconstriction and the
increased vascular permeability characteristic of these infants.

The inflammatory reaction might also be responsible for the decreased

alveolar and capillary formation characteristic of infants with
BPD. 3074 This is a key component in the pathogenesis of BPD and results
in a reduction in alveolar number and gas exchange surface area, as well as
a decrease in lung capillaries. In experimental models of BPD, these
findings have been accompanied by decrease in lung angiogenic growth
factors, such as vascular endothelial growth factor and nitric oxide, and
decreased expression of endothelial markers, such as platelet/endothelial
cell adhesion molecule-1 suggesting impaired angiogenesis. In addition,
reduced expression or impaired function of other growth factors associated
with lung development, including connective tissue growth factor, fibroblast
growth factor, and platelet-derived growth factor have been associated with
BPD. 54

[Link] AP, et. al.: Reduced platelet-derived growth factor receptor expression
is a primary feature of human bronchopulmonary dysplasia. Am J Physiol Lung Cell
Mol Physiol 2014; 307: pp. L231-L239.

Pathology
The pathologic picture of BPD has evolved significantly over the last few
decades. Most of the infants with BPD nowadays are extremely premature
and have milder forms of BPD. These infants have diffuse injury with little
emphysema or fibrosis. The characteristic morphologic changes in lungs
with mild BPD are reduced number and simplified alveoli, decreased and
dysmorphic capillaries, and a reduction in the gas exchange surface area
( Figs. 69.5 and 69.6 ). 10 26

26. Husain AN, Siddiqui NH, Stocker JT: Pathology of arrested acinar development
in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998; 29: pp. 710-717.
Open full size image
Fig. 69.5
Lung tissue section (autopsy) from a term + 5 months child. This specimen shows numerous
secondary crests and alveolar structures within the airspaces and alveolar ducts ( AD ), yielding a
pattern of increased acinar complexity. b, bronchiole.

(From Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol. 2003;
8(1):73-81.)

small number of these infants still go on to require prolonged mechanical

ventilation and high oxygen and end up with severe BPD. Macroscopically,
the lungs of these infants are firm and heavy and have a darker color than
normal. The surface is irregular, often showing emphysematous areas
alternating with areas of collapse. On histologic examination, the lungs are
characterized by areas of emphysema, sometimes coalescing into larger
cystic areas, surrounded by areas of atelectasis, interstitial edema and
increase in fibrous tissue, and widespread bronchial and bronchiolar
mucosal hyperplasia and metaplasia ( Fig. 69.7 ). Often, there are vascular
changes of pulmonary hypertension, such as medial muscle hypertrophy
and elastic degeneration. There also may be evidence of right ventricular
hypertrophy and, in some cases, left ventricular hypertrophy as well.
Open full size image
Fig. 69.7
Low-magnification view showing areas of emphysema alternating with areas of partial collapse.
(From Bancalari E, et al. Barotrauma to the lung. In Milunsky A, et al., eds. Advances in perinatal
medicine. New York: Plenum; 1982:181, with permission of Springer Science and Business
Media.)

Clinical Presentation
In their original description of BPD, also often called old BPD , Northway
and colleagues described the clinical, radiographic, and pathologic course
of a group of infants with severe respiratory distress syndrome (RDS)
requiring mechanical ventilation with high airway pressures and oxygen
concentration. The respiratory course of these infants evolved from the
initial severe RDS to final stage of chronic lung disease with high incidence
of cor pulmonale and mortality. The radiographic picture of these infants
with severe chronic lung disease was characterized by increased densities
secondary to areas of collapse and fibrosis, with adjacent large
emphysematous areas ( Fig. 69.8 ).

Fig. 69.8
Chest radiograph shows areas of hyperinflation and emphysema with adjacent dense areas of
atelectasis. This picture is characteristic of old BPD.

The clinical picture of BPD has evolved significantly in the last few decades due to
increasing survival of extremely premature infants and improvements in the care
of these infants. The majority of these infants initially have mild respiratory disease
requiring continuous positive airway pressure or ventilation with low pressures
and oxygen concentration. During the subsequent days or weeks, a large
proportion of these infants show progressive deterioration in lung function possibly
triggered by pulmonary or systemic infections or increased pulmonary blood flow
secondary to left to right shunting through a large PDA. 23

23. Gonzalez A, et. al.: Influence of infection on patent ductus arteriosus and
chronic lung disease in premature infants weighing 1000 grams or less. J Pediatr
1996; 128: pp. 470-478.

In these cases, the functional and radiographic changes are usually milder,
revealing more diffuse haziness without the marked changes observed in the
severe forms of BPD ( Fig. 69.9 ). This entity has been termed new BPD . 30 Most of
these infants show a slow but steady improvement in their lung function and
radiographic changes and, after variable periods, can be weaned from respiratory
support and supplemental oxygen prior to discharge.

30. Jobe AJ: The new BPD: an arrest of lung development. Pediatr Res 1999; 46:
pp. 641-643.
Fig. 69.9
Chest radiograph from an infant with new BPD showing generalized homogenous opacities with an
interstitial pattern.

A small group of preterm infants have atypical respiratory course with

inadequate response to surfactant and continued severe respiratory failure
requiring mechanical ventilation with high airway pressures and oxygen
concentration. Their respiratory course is often complicated by pulmonary
air leaks, secondary pulmonary infections, and recurrent pulmonary edema
likely due to PDA or inflammation, progressing to severe BPD. The
radiographic picture of these infants commonly resembles that of old BPD.
These infants commonly develop pulmonary hypertension and signs of right
heart failure. In these infants, severe airway damage with bronchomalacia
can lead to severe airway obstruction, especially during episodes of
agitation and increased intrathoracic pressure. 40 Furthermore, anastomoses
between the systemic and pulmonary circulations can aggravate their
pulmonary hypertension.

Because of the respiratory failure, infants with BPD take oral feedings with
difficulty and often require nasogastric or orogastric feeding. Weight gain is
usually less than the expected normal even when they receive an amount of
calories appropriate for their age. This lower weight gain can be a result of
chronic hypoxia and the higher energy expenditure required by the
increased work of breathing.

The diagnosis of BPD is based on the clinical and radiographic course

described earlier, but these signs are not specific for any given etiology. For
this reason, specific etiologies that could lead or contribute to the lung
damage must be considered before concluding that the infant has BPD.
Among these, one must rule out congenital heart disease, congenital
pulmonary anomalies, chemical pneumonitis resulting from recurrent
aspiration, cystic fibrosis, or disorders of surfactant homeostasis.

40. McCoy KS, et. al.: Spirometric and endoscopic evaluation of airway
collapse in infants with bronchopulmonary dysplasia. Pediatr Pulmonol
1992; 14: pp. 23-27.

Prevention of BPD
There is a wide variation in the incidence of BPD among different centers,
suggesting that certain steps in the management of preterm infants can
influence the risk of BPD. 36 Since BPD is a multifactorial disease, effective
prevention requires a combination of strategies to limit lung and vascular
injury and promote normal development ( Table 69.2 ).

TABLE 69.2
Strategies for Prevention of BPD
Strategies From Randomized Clinical Trials/Meta Analyses
Vitamin A 14 RR: 0.87 (CI 0.77-0.99) **
Noninvasive respiratory support 22 OR: 0.83 (CI 0.71-0.96) ** #
Lower oxygen target 2 RR: 0.87 (CI 0.81-0.94) ** τ
High-frequency oscillatory ventilation 13 RR: 0.86 (CI 0.78-0.96) **
Postnatal dexamethasone
Early 16 RR 0.79 (CI 0.71-0.88) **
Late 17 RR 0.76 (CI 0.66-0.88) **
Postnatal hydrocortisone 6 OR: 1⋅48 (1⋅02 to 2⋅16) * ##
Postnatal surfactant + budesonide 76 RR: 0.58 (0.44-0.77) * #
Strategies With Inconclusive Evidence
Antenatal steroids
Exogenous surfactant
Caffeine for apnea or extubation €
Volume-targeted ventilation €
Inhaled nitric oxide
Early PDA closure
Stem cell treatment
View full size
BPD, Bronchopulmonary dysplasia; OR, Odds ratio; PDA, patent ductus arteriosus; RR, risk ratio.
* Randomized controlled trial

** Meta-analysis

# BPD or death

## Survival without BPD

τ BPD: oxygen at 36 weeks

€ Lacking data from trials with BPD as primary outcome

Since BPD is exclusively seen in preterm infants, any strategy that can
prolong pregnancy will reduce the incidence of BPD. Attempts to develop
these strategies have not been very successful, but recent studies to
evaluate use of progesterone prophylaxis in pregnant women at risk of
preterm delivery have shown some effectiveness in reducing the incidence
of preterm birth. Administration of antenatal steroids to promote
maturation of surfactant system has been shown to reduce the incidence
and severity of RDS, but the effect on the incidence of BPD has been less
consistent partly due to improved survival of infants at increased risk for
BPD. 9

There is significant evidence from animal studies suggesting that

injudicious use of respiratory support at birth, even for short duration, may
result in lung injury 25 ; therefore, the effort should be directed to reduce the
infant's exposure to high airway pressures, tidal volumes, and oxygen, as
much as possible. Surfactant replacement therapy after endotracheal
intubation has been shown to decrease mortality, incidence of severe RDS,
and the need for aggressive ventilation but has failed to show reduction in
the incidence of BPD. To decrease the risk of lung injury associated with
positive pressure ventilation during surfactant replacement, multiple less-
invasive methods of surfactant instillation like nebulization or less-invasive
surfactant administration (LISA) are currently being evaluated, showing
some reduction in the incidence of BPD. 27

Although the use of early CPAP to reduce the use of mechanical ventilation
has been shown to have a small effect on reducing the incidence of death or
BPD, 22 a large proportion of the more premature infants fail CPAP and
require invasive ventilation. Nasal positive pressure ventilation (NIPPV) has
been evaluated as an alternative mode of noninvasive ventilation to avoid
endotracheal intubation. The effect of NIPPV on the incidence of BPD has
been inconsistent among trials with recent large RCTs failing to show a
reduction in the incidence of BPD with its use. 3251 High-flow nasal
cannula (HFNC) is another mode of noninvasive respiratory support that
has been evaluated because of its ease of use and less risk of injury to nares
when compared to CPAP. There is increasing evidence that the HFNC is
inferior to CPAP as primary mode of respiratory support after birth with
increased risk of treatment failure and a trend toward increased incidence
of BPD. 5573 These data suggest the type of respiratory support for each
infant should be individualized, with close monitoring of the respiratory
status over time.

Since a large number of preterm infants require invasive mechanical

ventilation, it is crucial to limit the exposure to excessive tidal volume. The
use of volume-targeted ventilation has been shown to reduce the duration of
mechanical ventilation and the combined outcome of death or
BPD. 33 Although there is some data suggesting that high-frequency
ventilation can reduce lung injury, it has not been shown to be consistently
effective in reducing the incidence of BPD. 13

Oxygen is one of the important factors in the pathogenesis of BPD, and

continuous monitoring of arterial oxygen saturation by pulse oximetry
(Sp o 2 ) is a standard practice to titrate oxygen supplementation. To find
the optimum target Sp o 2 range, three large trials in extremely preterm
neonates have compared the effect of lower (85%-89%) and higher (91%-
95%) target Sp o 2 range on mortality and neonatal morbidities. A recent
meta-analysis of these trials showed a significant reduction in the incidence
of BPD in the lower target group. However, the lower target was associated
with a higher incidence of necrotizing enterocolitis (NEC) and mortality,
suggesting a need to strike a critical balance when targeting Sp o 2 . 2
Presently, there is no agreement among clinicians regarding the role of
different PDA management strategies in the development of BPD. Although
some epidemiologic data suggest that the persistence of a hemodynamically
significant PDA is associated with an increased incidence of BPD, 37 the
results of prospective clinical trials to evaluate whether early closure of the
PDA would improve pulmonary outcome have not confirmed this
hypothesis. 62 Postnatal growth failure is common in infants at high risk for
BPD, and undernutrition has been associated with impaired lung growth in
animal models. Despite paucity of clinical evidence, a nutritional strategy
consisting of judicious fluid restriction while providing adequate macro and
micronutrients and preventing growth failure is recommended. There is
some evidence that exclusive breast-milk feeding is associated with lower
incidence of BPD. 63

Administration of postnatal systemic corticosteroids during the early stages

of the respiratory failure to prevent its progression to BPD has been well
studied, with several reports showing rapid improvement in lung function,
facilitating weaning from the ventilator and decreasing the risk of
BPD. 1617 Many potential mechanisms for these beneficial effects include
enhanced production of surfactant and antioxidant enzymes, decreased
bronchospasm, decreased pulmonary and bronchial edema and fibrosis,
improved vitamin A status, and decreased responses of inflammatory cells
and mediators in the injured lung. Potential complications of prolonged
steroid therapy include masking signs of infection, arterial hypertension,
hyperglycemia, increased proteolysis, adrenocortical suppression, somatic
and lung growth suppression, and hypertrophic cardiomyopathy. In
addition, long-term follow-up studies suggest that infants who received
early high-dose postnatal dexamethasone therapy have worse neurologic
outcome than control infants. 75

It appears that treatment with shorter courses and lower doses beyond the
first week of life offers significant advantage and fewer side effects than the
previous more aggressive treatment strategy, confirming the potential role
of low-dose dexamethasone therapy specifically for infants at high risk for
BPD. 19 Furthermore, a meta-regression analysis reported a significant effect
modification by risk for BPD. With a risk for BPD less than 35%,
corticosteroid treatment increased the chance of death or cerebral palsy,
whereas when the risk for BPD exceeded 65%, corticosteroid treatment
reduced this risk. 18 Although the avoidance of steroids may in fact be
detrimental to a class of infants at high risk for BPD, the optimal age of
treatment, dose schedule, and duration of therapy still needs to be
established. 52

In an attempt to avoid the potential neurotoxic effect of dexamethasone,

systemic hydrocortisone treatment has been evaluated as an alternative for
prevention of BPD due to lower neurotoxic effects. 21 Earlier trials evaluating
the use of hydrocortisone soon after birth in extremely preterm infants
showed improvement in respiratory outcomes but with increased risk of
gastrointestinal perforation. There is some recent evidence suggesting that
a lower dose may improve respiratory outcomes without increasing the risk
of gastrointestinal perforation or neurodevelopmental impairment in early
childhood. 67 Most recent available data demonstrate that among
mechanically ventilated very preterm infants, administration of a 22-day
course of systemic hydrocortisone between 7 and 14 days after birth,
compared with placebo, did not improve the composite outcome of death or
BPD at 36 weeks’ postmenstrual age. These findings do not support the use
of hydrocortisone for this indication. 52a To induce the beneficial effects on
the lung but minimize the systemic side effects, steroids have been
administered locally either alone by nebulization or by direct tracheal
instillation with exogenous surfactant. Both of these therapies have been
recently shown to significantly reduce the incidence of BPD, but concerns
for long-term safety and neurodevelopmental effect need to be evaluated in
large trials. 576

The administration of caffeine to wean infants from mechanical ventilation

and to treat apnea of prematurity has been associated with a significant
reduction in the incidence of BPD. 58 Some of the possible mechanisms of
this beneficial effect are shorter duration of mechanical ventilation and the
anti-inflammatory or diuretic effects of caffeine. Vitamin A supplementation
has been shown to result in small reduction in the incidence of BPD, likely
because of its role in lung development and repair of respiratory epithelium
after injury. 14

Since endogenous nitric oxide is required for alveolar and vascular

development, and the low-dose inhaled nitric oxide supplementation in
animal models of BPD inhibits inflammation and reduces lung
injury, 66 clinical trials have evaluated low-dose inhaled nitric oxide
supplementation for the prevention of BPD. These studies have provided
inconsistent results with a systematic review showing no significant effect
of inhaled nitric oxide on BPD. 15

Increasing knowledge of molecular pathways of alveolar and vascular

development has resulted in the development of innovative strategies for
prevention of BPD. Mesenchymal stem cells are among the most promising
of these, with multiple reports of their effectiveness in prevention as well as
treatment of hyperoxia-induced lung injury in animal models. 4265 The
results from a preliminary phase-1 clinical study have been promising, but
additional work is needed to better understand its mechanism of action,
safety and efficacy in preterm infants. Some of the other promising
therapies currently being evaluated for the prevention of BPD include Clara
cell protein (CC10), a protein secreted by nonciliated respiratory epithelial
cells with anti-inflammatory and immunomodulatory properties, and growth
factors involved in alveolar and vascular development such as insulin like
growth factor (IGF-1).

Management of Established BPD

Prevention of further lung damage is the cornerstone of management by avoiding, as much as
possible, all factors that predispose to more injury. There is a lack of good quality evidence base
for managing infants with BPD, resulting in significant variation in treatment practices.

Respiratory Support
During the initial phase of respiratory failure, the goal is to avoid unnecessary intubation and
mechanical ventilation-associated lung injury. When mechanical ventilation is used, the lowest
peak airway pressure necessary to obtain adequate ventilation must be applied. The expiratory
tidal volume (Vt) measured using a flow sensor at the endotracheal tube (proximal flow sensor)
should be closely monitored with avoidance of excessively low (Vt <3 mL/kg) or excessively
high tidal volumes (Vt >7 mL/kg) during acute phase of illness. Short inspiratory times between
0.3-0.5 seconds are used, as shorter inspiratory times exaggerate the maldistribution of the
inspired gas while longer inspiratory times may increase the risk of airspace rupture and
cardiovascular side effects. An end-expiratory pressure between 4 and 8 cm H 2 O is usually
applied to achieve lung recruitment without causing overdistension.

Adequacy of gas exchange should be monitored closely to avoid large fluctuation in ventilation
and oxygenation status. The arterial oxygen tension (Pa o 2 ) and arterial carbon dioxide tension
(Pa co 2 ) measured in arterial blood are considered the reference standards, but the results from
the samples obtained by arterial puncture should be interpreted carefully, because the infant
responds to pain with crying or apnea. Pulse oximeters offer the most reliable estimate of arterial
oxygenation and have the advantage of simplicity of use and the possibility of assessing
oxygenation during feeding and crying. Although there are no conclusive data in the literature on
the optimal level of oxygenation for these infants, in general, it is recommended to maintain the
oxygen saturation in the range of 90%-95% to minimize the risk of oxygen exposure and toxicity
and prevent hypoxemia with associated risk of morbidities. 2 The ideal range of Pa co 2 for infants
with BPD is not established, but avoidance of values higher than 55 and less than 35 mm Hg
during the initial period after birth is warranted to limit changes in cerebral perfusion.

Weaning these patients from the ventilator is often difficult and must be accomplished gradually.
When the patient can maintain an acceptable Sp o 2 and Pa co 2 with low peak pressures (15-
18 cm H 2 O) and Fi o 2 lower than 0.3-0.4, the ventilator rate is gradually reduced to allow the
infant to perform an increasing proportion of the respiratory work. During the process of
weaning, it may be necessary to increase the Fi o 2 . Concurrently, the Pa co 2 can rise, but as long
as the pH is within acceptable limits, some degree of hypercapnia must be tolerated to wean the
patient from the ventilator. In small infants, caffeine is used as a respiratory stimulant during the
weaning phase. 58 The use of nasal continuous positive airway pressure (CPAP) or nasal
ventilation (NIPPV) after extubation can stabilize respiratory function and reduce the need to
reinstitute mechanical ventilation.

Infants with chronic respiratory failure commonly have increased dead space, heterogeneous
areas of different lung compliance, and airway resistance necessitating longer inspiratory times
and higher tidal volumes than those used during early stages of illness. In some of the infants
with severe airway obstruction, especially those with bronchomalacia, the use of high positive
end-expiratory pressure levels of 5-8 cm H 2 O may help reduce expiratory airway resistance and
improve alveolar ventilation.

Although it is necessary to reduce the Fi o 2 as quickly as possible to prevent oxygen toxicity, it

is important to maintain the Sp o 2 above 90% to ensure adequate tissue oxygenation and prevent
the pulmonary hypertension and cor pulmonale that can result from chronic hypoxemia.
Furthermore, infants with BPD might respond to episodes of acute hypoxemia with increased
airway and vascular resistance. Because oxygen consumption increases and Pa o 2 may decrease
during feedings, it might be necessary to provide a higher Fi o 2 to prevent hypoxemia. Oxygen
therapy could be required for several weeks or months. Some of these patients are discharged
with oxygen therapy at home. This practice offers significant advantages, such as a better
environment for the patient and cost savings, but it requires a supportive family and home
environment to be accomplished safely and successfully.

Bronchodilator Therapy
Infants with severe BPD can have airway smooth muscle hypertrophy and airway
hyperreactivity. Because hypoxia can increase airway resistance in these patients, maintenance
of adequate oxygenation is important to avoid bronchoconstriction. Bronchodilators, most of
them β-agonists, administered by inhalation have been shown to reduce airway resistance in
infants with BPD. However, their safety and efficacy have not been evaluated in randomized
clinical trials. Their effect is usually short lived, and many of these drugs have cardiovascular
side effects such as tachycardia, hypertension, and possible arrhythmias. Because of this, it is
preferred to limit their use to the management of acute exacerbations of airway obstruction.

Corticosteroid Therapy
Systemic or inhaled steroids are commonly used in infants with BPD, both as short-term therapy
for acute exacerbation as well as chronic therapy. The potential short-term benefits include
decrease in inflammation, airway edema, capillary leakage, and lung fibrosis. The effects of
steroids in infants with established BPD on long-term respiratory outcomes have not been
evaluated. As described previously, chronic use of steroids is associated with significant side
effects; therefore, their use should be limited with clearly defined goals after due consideration
of risks and benefits of this therapy.

Management of Pulmonary Hypertension in BPD

The clinical course of infants with severe BPD is frequently complicated by pulmonary
hypertension, 46 thereby necessitating the need for close monitoring and early diagnosis by
echocardiogram. Oxygen therapy to prevent hypoxemia is probably the most important first step
to reduce pulmonary hypertension in these infants. Because pulmonary vascular resistance is
extremely sensitive to changes in alveolar P o 2 in infants with BPD, it is important to ensure
normal oxygenation, not only when the infant is quiet or asleep but also when the infant is
performing physical activity such as feeding and crying.

Despite increasing use of pulmonary vasodilators, the evidence for their efficacy in infants with
pulmonary hypertension with BPD is very limited. These therapies include inhaled nitric oxide
(iNO), phosphodiesterase inhibitors (sildenafil), endothelin receptor antagonists, and calcium
channel blockers (nifedipine). Inhaled nitric oxide is commonly used as a pulmonary vasodilator
in acute onset pulmonary hypertension and has been shown to decrease pulmonary vascular
resistance, although its effect on long-term outcomes has not been evaluated. The potential role
of iNO in the prevention of BPD has been evaluated in multiple trials with no clear long-term
benefits so far. Sildenafil, a phosphodiesterase-5 inhibitor, is mostly used as long-term therapy
for pulmonary hypertension in infants with BPD. There are limited data on safety or
effectiveness of this drug in this population, but some clinical reports suggest that the therapy is
safe and may be effective. 45 Nifedipine, a calcium channel blocker, decreases pulmonary
vascular resistance but is also a systemic vasodilator and can produce depression of myocardial
contractility. Other agents like endothelin receptor antagonists and prostacyclin analogs have
been tried in infants who fail to respond to initial treatment, but their efficacy and safety have not
been established.

Fluid Management
Infants with BPD do not tolerate excessive or even normal amounts of fluid intake and have a
marked tendency to accumulate excessive interstitial fluid in the lung. This excess can lead to a
deterioration of pulmonary function, with exaggeration of hypoxemia and hypercapnia and
longer ventilator dependency.

To reduce lung fluid in infants with BPD, water and salt intake should be limited to provide the
calories necessary for metabolic needs and growth. When increased lung water persists despite
fluid restriction, diuretic therapy can be used successfully. The use of diuretics in infants with
BPD can be associated with an acute improvement in lung compliance and decrease in
resistance, but blood gases do not always show improvement. Complications of chronic diuretic
therapy include potential ototoxicity, hypokalemia, hyponatremia, metabolic alkalosis,
hypercalciuria with nephrocalcinosis, and hypochloremia.

Because increased metabolic demands in infants with BPD are associated in severe cases with
low arterial oxygen tension, it is important to maintain a relatively normal blood hemoglobin
concentration. This may be accomplished with blood transfusions or by the administration of
recombinant erythropoietin.

Nutrition
Infants with BPD frequently have impaired growth due to increased metabolic demand partially
caused by increased work of breathing, growth suppression from frequent postnatal steroid and
diuretic use, and frequent interruptions in oral feedings due to exacerbation of respiratory failure.
Malnutrition can delay somatic growth and the development of new alveoli, making successful
weaning from mechanical ventilation less likely. The malnourished patient may also be more
prone to infection and oxygen toxicity. Decreased caloric intake potentiates oxygen-induced lung
damage and can interfere with cell multiplication and lung growth. For these reasons, an
aggressive approach should be taken toward supplying a parenteral or oral caloric intake that is
adequate for growth. High-calorie formulas and supplements of protein, calcium, phosphorus,
and zinc can be used to maximize the intake of calories while restricting fluid intake to prevent
congestive heart failure and pulmonary edema.

Adequacy of nutrition should be closely monitored, and growth charts for weight, head
circumference, and length must be kept. Rib fractures noted on routine chest radiographs,
together with generalized bone demineralization, are often observed in infants with BPD and are
usually a manifestation of rickets. The cause could relate to dietary or parenteral deficiency of
calcium or vitamin D or to the calciuria resulting from long-term diuretic therapy.
Administration of extra calcium and vitamin D is necessary to prevent rickets in these infants.

Infants who receive exclusively parenteral nutrition for prolonged periods are more susceptible
to developing deficiency of specific nutrients, such as vitamins A and E, and trace elements such
as iron, copper, zinc, and selenium, all of which play a role in antioxidant function, protection
against infection, and lung repair.

Gastroesophageal reflux is often observed in infants with BPD, and when severe, may contribute
to the chronic inflammatory process and lung damage. When severe reflux is documented,
antireflux management might be indicated to alleviate respiratory symptoms.

Control of Infection
Any infection can have serious consequences for the child with BPD, and bacterial, viral, or
fungal infection generally results in a profound setback. As a result, the child must be closely
watched for early evidence of infection. Tracheal secretions are collected for culture and Gram
stain, and a change in the quality and quantity of secretions indicates possible infection. A
complete blood count, blood culture, and chest radiograph are obtained if pneumonia is
suspected.

Although it is difficult to distinguish between colonization of the airway and true infection, this
distinction is important because overtreatment with antibiotics can result in the emergence of
resistant and more virulent organisms. Selection of antibiotics is based on the sensitivity of the
implicated organism, and treatment is continued until the infection has been controlled. Measures
to prevent pulmonary nosocomial infection are important. These include careful hand washing
before handling the airway, maintenance of sterility of the respiratory equipment, and isolation
from individuals with respiratory infections.

Infant Stimulation
The infant with severe BPD could be ventilator dependent for many months and thus deprived of
normal parental stimulation. Developmental delays are common and are compounded if any
gross neurologic disability exists. A well-organized program of infant stimulation can help the
infant achieve maximum potential. Such a program instructs the caretakers in helping the infant
with various social, language, cognitive, and motor skills. As a child grows, speech therapy is
useful in teaching communication skills, which are especially important for children with a
tracheostomy. Beanbag chairs, strollers, and other adaptive tools are employed to mobilize the
child and teach gross motor skills. Progress is monitored by periodic developmental evaluations,
and emphasis is placed on areas in which delay is evident.

Parental Support
The parents of an infant with severe BPD lose considerable control of their child to the hospital
staff, particularly in areas related to medical care. Parental participation is critical for the child's
development and for establishment of normal relationships. Therefore, parents are encouraged to
visit as frequently as possible and to participate in the day-to-day care of their child. They are
educated about relevant medical equipment and procedures. In time, many are able to assume
complete responsibility for procedures such as chest physiotherapy and tracheal suctioning, in
addition to holding and playing with their child. During the prolonged hospitalization, every
effort must be made to assign a permanent physician and nursing team to oversee the child's care
and be available for continuing parental support. Parental support groups may also be a valuable
resource for these families.

Outcome
The outcome of infants with BPD has improved in part because of better management but mainly
because of the milder presentation of the disease. The mortality rate for infants with BPD is low.
When death occurs, it is usually a result of respiratory failure, intercurrent infections, or
intractable pulmonary hypertension and cor pulmonale. With adequate nutrition, somatic growth,
and control of infection and heart failure, gradual improvement in pulmonary function may be
accompanied by resolution of cor pulmonale and radiographic evidence of healing.

Lower respiratory tract infections are common during childhood in patients with BPD. Among
survivors of BPD, hospitalizations for episodes of wheezing suggestive of bronchiolitis or
asthma are common during the first 2 years of life, and infection with respiratory syncytial virus
(RSV) can be life threatening. The American Academy of Pediatrics has recommended that all
infants with BPD receive palivizumab during RSV season. Acute radiographic evidence of
hyperinflation can be difficult to appreciate in infants with severe BPD who generally are already
in a state of pulmonary hyperinflation. Such episodes of bronchiolitis are often accompanied by
focal, transient areas of atelectasis.

Pulmonary function studies of children with a history of severe BPD indicate that pulmonary
function may be impaired for many years even though the infants may be
asymptomatic. 2070 Northway and associates have re-evaluated pulmonary function in their
original cohort of infants with severe BPD reported in 1967. 50 At a mean age of 18 years, these
adolescents and young adults still exhibited some evidence of pulmonary dysfunction, including
airway obstruction and hyper-activity as well as hyperinflation. Infants and toddlers with severe
BPD also have decreased pulmonary diffusing capacity consistent with decreased alveolar
capillary surface area. 3 The ultimate clinical consequences of these findings remain to be
determined, but most long-term studies suggest that with growth, pulmonary function tends to
improve. In a study using 3He magnetic resonance, it was found that infants with BPD evaluated
at 10-14 years of age had similar alveolar dimensions as term controls or preterm infants without
BPD. 48 These interesting findings suggest that infants with BPD can have catch-up
alveolarization.
Infants with severe BPD also have more neurodevelopmental sequelae when compared with
similar control groups, and they exhibit transiently impaired growth curves. These
neurodevelopmental and pulmonary impairments persist at 8 years of age, with 54% requiring
special education classes compared with 37% of survivors born at very low birth weight without
BPD. 60 Neurodevelopmental prognosis also depends on the severity of the BPD and on other
associated risk factors that could be present in these infants.

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 76. Yeh TF, et. al.: Intratracheal administration of budesonide/surfactant to prevent

bronchopulmonary dysplasia. Am J Respir Crit Care Med 2016; 193: pp. 86-95.

Treatment of bpd ‫يتم دمجها مع العالج‬

, ‫ فى اخر ال‬treatment

Neonatal pharmacologic therapies are an important tool to reduce the

burden of BPD among very immature infants and different inhaled and
systemic drugs are currently used to prevent or treat BPD. When using
inhaled drugs, the mode of administration is an important factor to
consider. The response to inhaled therapies depends on the amount of
aerosol delivered to the peripheral airways and there is currently
insufficient information available about appropriate aerosol delivery
systems for ventilated infants and neonates on continuous positive airway
pressure. However, it has been convincingly shown in a large randomized,
controlled trial and confirmed by several metaanalyses that early inhaled
budesonide reduces BPD. However, more information about the effects of
inhaled corticosteroids is required to assess overall efficacy and associated
risks. The information currently available to show positive or negative
effects of inhaled bronchodilators for BPD is insufficient, and future and
large well-designed studies are needed. Today, dexamethasone and
hydrocortisone are the most studied systemic corticosteroids for the
prevention or treatment of BPD. Dexamethasone is a synthetic
corticosteroid with potent glucocorticoid effects that is associated with
cerebral palsy if given in the first week of life. Hydrocortisone may have
fewer or no adverse effects on neurosensory development in preterm
infants. As with inhaled corticosteroids, more information about the long-
term effects of hydrocortisone is required to assess overall efficacy and
associated risks. Until such information becomes available, neonatologists
need to carefully balance the risks of neurodevelopmental impairment
owing to systemic corticosteroids against those of BPD itself. Future studies
should, therefore, focus on infants with a very high risk of developing BPD
and include pharmacokinetics and long-term developmental outcomes.

Inhaled Drugs and Systemic Corticosteroids for Bronchopulmonary

Dysplasia RSS Download PDF Dirk Bassler MD, MSc and John van
den Anker MD, PhD Pediatric Clinics of North America, 2017-12-01,
Volume 64, Issue 6, Pages 1355-1367, Copyright © 2017 Elsevier
Inc.

Although various pharmacologic and nonpharmacologic approaches may help prevent or limit BPD, success is
often variable or transient. Research demonstrating the efficacy and safety of PNS use remains
limited.19 Unfortunately, there are no proven safe and effective therapies available for the prevention and
treatment of BPD. The 2002 AAP policy statement specifies that PNS use should be limited to "exceptional
circumstances." Following the policy statement, some experts expressed concerns that by the time the infant is
ventilator dependent, PNS may not be as effective as when given early.58
Studies reporting the long-term outcomes of PNS use yield conflicting results. The studies are difficult to
compare because of heterogeneity in the study populations and differences in timing and dosage of steroid
treatment. In the year since baby T was discharged home, the AAP reviewed current information on PNS use
for the treatment or prevention of BPD and reissued a policy statement in October 2010.59 The
recommendations are as follows: (a) high-dose dexamethasone cannot be recommended because of the
absence of evidence from randomized controlled trials showing improved short- and long-term outcomes; (b)
low-dose dexamethasone cannot be recommended because of insufficient evidence; (c) early administration of
low-dose hydrocortisone may be beneficial for some patients populations but cannot be recommended for all
infants at risk of BPD because of insufficient evidence; and (d) high-dose hydrocortisone cannot be
recommended because of insufficient evidence from RCTs demonstrating improved survival without BPD.
However, the AAP acknowledges that risk of developing BPD is high for patients who remain ventilator
dependent after 1 to 2 weeks of age and the benefits of PNS may outweigh the risks. In such cases, the AAP
suggests that providers use clinical judgment and make decisions in collaboration with the infant's parents on a
case-by-case basis.59 Because more RCTs have evaluated the risks and benefits of dexamethasone for
ventilator-dependent infants than any other corticosteroid, dexamethasone may be the drug of choice at this
time. Short courses with low doses are theoretically safer than higher doses, and on the basis of the clinical
research, appear to be efficacious in facilitating extubation. There is a need for well-designed studies to
examine regimes utilizing lower doses and other PNS such as hydrocortisone. Without additional research,
there will continue to be controversy about how to manage ventilator-dependent infants and BPD.

The Journal of Perinatal & Neonatal Nursing

Issue: Volume 25(3), July/September 2011, p 283-291
Postnatal Steroids for the Treatment of
Copyright: (C) 2011 Lippincott Williams & Wilkins, Inc.

Bronchopulmonary Dysplasia: A Complex Case Presentation

Forest, Sharron DNP, APRN, NNP-BC

Bronchopulmonary dysplasia (BPD) remains a significant contributor to the morbidity and mortality of
premature infants [1], and most therapeutic approaches for BPD are preventive or supportive in nature [2].
Current investigations into the pathogenesis of this disease have highlighted the central role of inflammation as
a key contributor to disease evolution. Mesenchymal stem/stromal cells (MSCs) have anti-inflammatory
properties and have been shown to contribute to tissue regeneration in a variety of clinical settings, leading to
enthusiasm for MSC therapy in BPD.

BPD is a chronic lung disease of premature infants that results in decreased pulmonary function, hyper-reactive
airways, and pulmonary hypertension. The pathogenesis of BPD is multifactorial, with maternal factors,
exposure to inflammation and infection, effects of postnatal ventilation strategies, nutritional status, and
genetic/epigenetic factors all contributing to the evolution of the disease [12]. Ultimately, BPD is thought to
result from disrupted lung and pulmonary vasculature development leading to alveolar simplification. There is
evidence that the lung's endogenous stem and progenitor cells, which regenerate normal lung alveolarization
and pulmonary vascular development, are dysfunctional in BPD [13]. Human infants who develop BPD are 22
times more likely to have MSCs isolated from their tracheal aspirates than controls [14], possibly reflecting
more severe injury and MSC release into the airways.

MSC-based therapies have ushered in great hope for new avenues of treatment for BPD that may be curative.
Despite this enthusiasm, many fundamental questions remain. In addition to further clarification as to the best
source, route, timing, and criteria for patient selection, it is not yet resolved whether MSCs themselves or MSC-
derived exosomes are the most appropriate product, nor is it clear what mechanism(s) of action accounts for
the impact on BPD. MSCs have been shown to have multiple biological effects, as is to be expected from a
population of cells likely heterogenous in phenotype and function.

Stem-cell therapy for bronchopulmonary dysplasia

Collins, Amelie Current Opinion in Pediatrics
Issue: Volume 32(2), April 2020, p 210-215
Copyright: Copyright (C) 2020 Wolters Kluwer Health, Inc. All rights reserved.
Publication Type: [NEONATOLOGY AND PERINATOLOGY: Edited by Tara M. Randis and Thomas A. Hooven]
DOI: 10.1097/MOP.0000000000000862
ISSN: 1040-8703

‫ – الخاتمه‬2 ‫نهاية شابتر‬

Pediatric chronic lung diseases burden their patients and families with heavy
treatment loads, frequent extensive clinic visits to multiple providers, frequent
emergency department visits and hospitalizations, and contribute to significant
psychosocial issues with caregiver’s burnout. The purpose of this chapter is to
outline the psychosocial impact of the major pediatric chronic lung diseases and
the unique role of the psychologist in relieving this burden. These include severe
asthma, cystic fibrosis, bronchopulmonary dysplasia, and dependence on home
mechanical ventilation.
Pediatric chronic lung diseases not only affect the physical aspect of children’s
health but also the emotional health of children and their families. Understanding
the role of physical–emotional or “body–mind” interaction will enable the medical
team to support pediatric patients and their families to thrive during periods of
uncertainty and struggle.

Psychologist’s Unique Role in Improving Quality of Life of Children with

Chronic Lung Diseases and Their Families

Mariam Ischander MBChB and Sheryl Lozowski-Sullivan MPH, PhD

Pediatric Clinics of North America, 2022-10-01, Volume 69, Issue 5, Pages

951-963, Copyright © 2022 Elsevier Inc.

Extreme preterm 10-year-old children with BPD were at increased risk for
decreased cognitive, language and executive function, as well as academic
achievement, and lower health-related quality of life as compared with those
without BPD. 29
BPD is also a risk factor for cerebral palsy. 30

Extreme preterm 10-year-old children with BPD were at increased risk for
decreased cognitive, language and executive function, as well as academic
achievement, and lower health-related quality of life as compared with
those without BPD. 29 BPD is also a risk factor for cerebral palsy. 30

BPD is the abnormal growth and development of the lung due to

prematurity. With advances in the medical field, a reduction in mortality of
extremely premature infants was achieved; however, morbidity increased in
survivors. A database review study published by Jarjour 31 revealed that the
mortality rate of extremely premature infants born at 22 to 25 weeks of
gestation is high and estimated to be ≥ 50%, and severe
neurodevelopmental disabilities on short term follow-up estimated to be
17% to 59%. The rate of survival with minimal or no impairment was 6% to
20% for live-born infants ≤25 weeks of gestation and <5% for infants born
at 22 and 23 weeks of gestation. Long-term follow-up for extremely
premature infants showed that the rate of intellectual disabilities is 5% to
36%, cerebral palsy 9% to 18%, blindness 0.7% to 9%, and deafness at 2%
to 4%. Mild disabilities in learning, behavior, and cognition were also noted
in growing preterm through young adulthood.
Sillers and colleagues 32 reported in a summary of current literature that
very preterm infants with BPD are predisposed to respiratory complications,
increased respiratory medications use, frequent re-hospitalization through
early childhood, and increased susceptibility to early-onset chronic
obstructive lung disease in adulthood

Brady and colleagues concluded in a study that parental perceived health-

related quality of life for their child with severe BPD was lower than
expected for premature and term children. In addition, an increased
number of postnatal morbidities was associated with worse parent-
perceived health-related quality of life. 33

Bray and colleagues reported that having an oxygen-dependent baby

negatively affected maternal well-being for years with ongoing sadness,
hurt, social isolation, decrease self-esteem, and continued worry about
future pregnancies. Stress and anxiety were reported in mothers 1 year
after preterm labor. Children with chronic lung disease felt bullied and
teased by peers in school because of their small size, respiratory symptoms,
and fatigue leading to self-exclusion from social activities, social isolation
and even moving to school. However, children and their parents reported
improvement in competence and confidence over time to deal with the
challenges and live with the long-term condition, yet parents felt frustrated
when their expertise was ignored by health care professionals or schools
and the author suggested that the medical team should integrate the
parents’ expertise in managing their children’s condition. 34

But the journey starts even earlier, at the birth of a premature baby.
Neonatal intensive care unit (NICU) environment despite being a life saver
is stressful for premature infants and their parents, with parents having an
intense feelings of fear, sadness, guilt, worry, or being helpless and
overwhelmed. In addition, sleep disruption in NICU babies is a common
concern. Using music and massage therapy as optional interventions to
improve the neurodevelopmental outcomes of premature babies during
NICU stay has gained a momentum.

Liu and colleagues reported in a literature review article that promoting

better strategies to support the neurodevelopment in infants in the NICU
includes preservation of sleep, positioning, gentle touch, and sound/light
exposure modulation. Sleep preservation can prevent disruption of the
process of normal brain development. 35

Khel and colleagues 36 in a pilot study revealed that creative music therapy
with premature infants and their parents can support the infant–parent
relationship, induce feelings of joy and relaxation in parents, and encourage
profound infant–parent interactions.
Loewy and colleagues 37 concluded in a randomized multicenter clinical trial
of premature infants that music therapy applied by a certified music
therapist can influence cardiorespiratory function, improve feeding/sucking
behavior, and increase awake/quiet time. Parent chosen live lullabies can
promote bonding and consequently decrease stress in parents.

Feeley and colleagues revealed in a study for maternal caregivers of young

children with BPD that maternal caregivers were chronically sleep-deprived
with reported 5.8 h of sleep per night and emphasized the importance of
discussing proper sleep hygiene by providers with maternal caregivers.
Empowering mothers with education, training, and resources like respite
care is essential for relieving stress and promoting a sense of comfort with
the care. 38

Sairankyzy and colleagues 39 concluded in a study that the social

characteristics of a family of a child with BPD showed increased average
age of parents, high incidence of smoking in fathers, poor housing, low
socioeconomic status with the financial situation of the family raising a child
with BPD worsen to a degree that the financial resources available were
only enough for food.

Strategies to work on in the future include prevention of prematurity,

individualizing the care of each infant and the support needed for each
family, minimizing neurodevelopmental impairment in NICU, and for
children with neurodevelopmental delay, and ensuring the availability of
early intervention programs, special education school programs to
maximize their potential.

 27. Eichenwald E.C., Strak A.R., Bronchopulmonary dysplasia:

Definition, pathogenesis, and clinical features, Uptodate. Available
at: [Link]/contents/bronchopulmonary-dysplasia-definition-pathogenesis-and-
clinical-features#! , 2017.

View In Article

 28. Thébaud B., Goss K.N., Laughon M., et. al.: Bronchopulmonary
dysplasia (primer). Nature Reviews: Disease Primers. Available
at: [Link]
bronchopulmonary-dysplasia-primer/docview/2314540163/se-2?accountid=160899 Access
ed November 14, 2019

View In Article

 29. Sriram S., Schreiber M.D., Msall M.E., et. al.: Cognitive
Development and Quality of Life Associated With BPD in 10-Year-Olds
Born Preterm. Pediatrics 2018; 141: pp. e20172719.
 View In Article

 30. Gou X., Yang L., Pan L., et. al.: Association between
bronchopulmonary dysplasia and cerebral palsy in children: a meta-
analysis. BMJ Open 2018; 8: pp. e020735.

View In ArticleCross Ref

 31. Jarjour I.: Neurodevelopmental outcome after extreme

prematurity: a review of the literature. Pediatr Neurol 2014; 52:

View In Article

 32. Sillers L., Alexiou S., Jensen E.A.: A Lifelong pulmonary sequelae
of bronchopulmonary dysplasia. Curr Opin Pediatr 2020; 32: pp. 252-
260.

View In ArticleCross Ref

 33. Brady J.M., Zhang H., Kirpalani H., et. al.: Living with severe
bronchopulmonary dysplasia-parental views of their child's quality of
life. J Pediatr 2019; 207: pp. 117-122.

View In ArticleCross Ref

 34. Bray L., Shaw N.J., Snodin J., et. al.: Living and managing with the
long-term implications of neonatal chronic lung disease: the
experiences and perspectives of children and their parents. Heart &
Lung 2015; 44: pp. 512-516.

View In ArticleCross Ref

 35. Liu W.F., Laudert S., Perkins B., et. al.: The development of
potentially better practices to support the neurodevelopment of
infants in the NICU. J Perinatol 2007; 27: pp. S48-S74. Available
at: [Link]
development-potentially-better-practices-support/docview/220422012/se-2?
accountid=160899

View In ArticleCross Ref

 36. Kehl S.M., La Marca-Ghaemmaghami P., Haller M., et. al.:

Creative music therapy with premature infants and their parents: a
mixed-method pilot study on parents' anxiety, stress and depressive
symptoms and parent-infant attachment. Int J Environ Res Public
Health 2020; 18: pp. 265.

View In ArticleCross Ref

  37. Loewy J., Stewart K., Dassler A., et. al.: The effects of music
therapy on vital signs, feeding, and sleep in premature infants.
Pediatrics 2013; 131: pp. 902-918. Available
at: [Link]
effects-music-therapy-on-vital-signs-feeding/docview/1492672826/se-2

View In ArticleCross Ref

 38. Feeley C.A., Turner-Henson A., Christian B.J., et. al.: Sleep quality,
stress, caregiver burden, and quality of life in maternal caregivers of
young children with bronchopulmonary dysplasia. J Pediatr Nurs
2014; 29: pp. 29-38.

View In ArticleCross Ref

 39. Sairankyzy S., Zhakanovna Seisebayeva R., Nurbakytovna

Nurbakyt A., et. al.: Social portrait of families raising children with
bronchopulmonary dysplasia. Curr Pediatr Res 2021; 25: pp. 987-992.

View In Article

 40. Sterni L.M., Collaco J.M., Baker C.D., et. al.: An official american
thoracic society clinical practice guideline: Pediatric chronic home
invasive ventilation. Am J Respir Crit Care Med 2016; 193: pp. E16-
E35. Available
at: [Link]
official-american-thoracic-society-clinical/docview/1782403669/se-2?accountid=160899

View In Article

The model of the multidisciplinary team in managing BPD as inpatient then

outpatient is the key to success, including a psychologist in the team is
becoming a necessity. BPD children also are in need of other services such
as physical therapy, occupational therapy, speech-language pathologist,
social workers, music therapy, massage therapy, child life, and case
management to optimize the physical and neurodevelopmental outcome.
Outpatient follow-up with multiple specialists is needed and may include
neonatology, pulmonology, nutrition, cardiology, and endocrinology, so
collaboration and communication between providers are essential and the
role of care management is critical.

Providing not only the best medical care but also the psychosocial support
necessary for the infants and their parents during this stressful time is
crucial. Psychologist should screen parents for depression/anxiety and
provide counseling as needed, ensure that family received adequate
training to be able to be comfortable with the care, work with parents on
adherence to therapy melting barriers that interfere with adherence, help
families to advocate for their children and share decision-making with
providers, and provide resources to the family in conjunction with the social
worker to decrease stress due to financial burden. Psychologist should also
help with connecting families with a support group or other parents with
chronic lung disease children.

Psychologist’s Unique Role in Improving Quality of Life of Children with

Chronic Lung Diseases and Their Families

Mariam Ischander MBChB and Sheryl Lozowski-Sullivan MPH, PhD

Pediatric Clinics of North America, 2022-10-01, Volume 69, Issue 5, Pages

951-963, Copyright © 2022 Elsevier Inc.

Discharge of BPD neonates

infants with moderate-severe BPD (ie, those who remain on respiratory support at
36 weeks) and those discharged on oxygen should be targeted for in-person
pulmonary follow-up within 1 month of hospital discharge. Specialized neonatal
follow-up is an alternative for infants with mild BPD. Infants with moderate or
severe BPD should have an echocardiogram performed after 36 weeks to screen
for pulmonary hypertension. Infants with BPD warrant additional evaluations if
they have growth restriction or poor growth, pulmonary hypertension, or
tachypnea and if they are discharged to home on oxygen, diuretics, or nonoral
feeds.

Discharge practices for infants with bronchopulmonary dysplasia: A survey of

national experts
Jonathan C. Levin MD, MBI, Chandler A. Annesi BS, David N. Williams PhD, Steven
H. Abman MD, Sharon A. McGrath-Morrow MD, MBA, Leif D. Nelin MD, Catherine
A. Sheils MD and Lystra P. Hayden MD, MMSc

Journal of Pediatrics, The, Copyright © 2022 Elsevier Inc.

Premature infants with bronchopulmonary dysplasia (BPD) have complex

care needs surrounding discharge from the neonatal intensive care unit
(NICU). BPD affects up to 40% of former preterm infants born at <28 weeks
of gestation, with up to 50 000 new cases of BPD reported each year in the
US. 123 These infants may require ongoing respiratory care, management
of medications and home respiratory support, management of pulmonary
hypertension, monitoring of growth and nutrition, and developmental
follow-up. 456 Discharge from the NICU to home is a high-risk transition of
care, with up to 50% of infants with BPD requiring rehospitalization in the
first year alone. 7 Coordinated follow-up programs may help improve
outcomes and reduce the rate of hospitalization in this population. 8

Diverse follow-up and management strategies are by outpatient BPD clinics

in the US. 9 Although recently published guidelines establish
recommendations for care of children with postprematurity respiratory
disease, they do not address which infants being discharged from the NICU
should be targeted for specialized follow-up for their respiratory disease,
which evaluations should be routinely performed around discharge, and
what family education to provide to optimize successful
discharge. 10 , 11 Additionally, the role of telemedicine in follow-up for this
population is unclear, despite an increased reliance on its use during the
severe acute respiratory syndrome coronavirus 2 pandemic.

Consensus was gained that preterm infants with moderate and severe BPD should have a
pulmonary consultation after NICU discharge if available ( Table II ). This visit is preferred
within 1-2 months of discharge and in person if able. Experts acknowledged that where pediatric
pulmonary resources are scarce, neonatal follow-up may serve the role of respiratory screening
and assessment, but also noted that these infants are at increased risk for early and late
pulmonary complications. 18 Additionally, experts recognized that in certain areas of the country,
BPD-focused clinics are staffed by neonatologists. In-person assessments were preferred to
obtain accurate weights and other growth measurements and to obtain vital signs, including
oxygen saturation. It was suggested that telehealth may be a more acceptable alternative if those
data were available by remote monitoring.

For mild BPD, there were multiple responses in round 2 that individually failed to gain
consensus. Consensus was ultimately gained that these infants should see neonatal follow-up
with a one-time pulmonary consultation if resources allow, particularly if any
symptoms/complications develop. Experts reflected that universal pulmonary follow-up may be
difficult in certain areas owing to limited resources, although at a minimum, a respiratory
assessment by a neonatal follow-up specialist is recommended, because even mild BPD is
associated with early respiratory complications and later abnormalities in pulmonary
function. 192021

For infants with moderate or severe BPD, consensus was gained that an echocardiogram should
be obtained after 36 weeks PMA and prior to discharge. For severe BPD, there was near
consensus about obtaining a routine chest radiograph prior to or soon after discharge, with some
experts commenting that assessments should be symptom-based rather than based on BPD
severity.

Discharge on Home Oxygen

There was agreement that infants with BPD discharged on supplemental oxygen should have
pulmonary follow-up within 1-2 months (some suggested within 2 weeks) and in person if able.
A telehealth visit may be an acceptable alternative if in-person assessment is delayed.
Participants cited the importance of monitoring weight gain and oxygen saturation, ascertaining
comfort with home oxygen, assessing ability to wean, and troubleshooting equipment issues.
Consensus also was gained on obtaining an echocardiogram after 36 weeks PMA and prior to
discharge and obtaining a routine chest radiograph prior to or soon after discharge. There was not
consensus (73%; 22 of 30) on whether blood gases or chemistry (for bicarbonate) should be
obtained; some suggested end-tidal CO 2 as a noninvasive alternative.

 7. Smith V.C., Zupancic J.A., McCormick M.C., Croen L.A., Greene J.,
Escobar G.J., et. al.: Rehospitalization in the first year of life among
infants with bronchopulmonary dysplasia. J Pediatr 2004; 144: pp.
799-803.

View In Article

 8. Rhein L.M., Konnikova L., McGeachey A., Pruchniewski M., Smith

V.C.: The role of pulmonary follow-up in reducing health care
utilization in infants with bronchopulmonary dysplasia. Clin Pediatr
(Phila) 2012; 51: pp. 645-650.

View In ArticleCross Ref

 9. Collaco J.M., Kole A.J., Riekert K.A., Eakin M.N., Okelo S.O.,
McGrath-Morrow S.A.: Respiratory medication adherence in chronic
lung disease of prematurity. Pediatr Pulmonol 2012; 47: pp. 283-291.

View In ArticleCross Ref

 10. Duijts L., van Meel E.R., Moschino L., Baraldi E., Barnhoorn M.,
Bramer W.M., et. al.: European Respiratory Society guideline on long-
term management of children with bronchopulmonary dysplasia. Eur
Respir J 2020; 55:

View In Article
  11. Cristea A.I., Ren C.L., Amin R., Eldredge L.C., Levin J.C.,
Majmudar P.P., et. al.: Outpatient respiratory management of infants,
children, and adolescents with post-prematurity respiratory disease:
an official American Thoracic Society Clinical Practice Guideline. Am J
Respir Crit Care Med 2021; 204: pp. e115-e133.

View In ArticleCross Ref

 12. Das A., Cina L., Mathew A., Aziz H., Aly H.: Telemedicine, a tool
for follow-up of infants discharged from the NICU? Experience from a
pilot project. J Perinatol 2020; 40: pp. 875-880.

View In ArticleCross Ref

‫ جزء اضافى بعد ال عالج‬after the treatment

quality improvement efforts focused on reducing BPD

can be effective. Nearly 70% of the single center and collaborative reports
successfully impacted BPD rates, and many of those that did not see a
change in BPD did impact important respiratory care processes. Several
themes and conclusions can be drawn from this review that warrant
highlighting.

Most QI efforts focused on reducing mechanical ventilation. This is

consistent with our understanding of the pathophysiology of BPD, and the
central role of ventilator-induced lung injury. The benefits of this focus may
extend beyond respiratory outcomes, as even minor reductions in exposure
to mechanical ventilation have been shown to be associated with reductions
in neurodevelopmental impairment in preterm infants [ 81 , 82 ]. Optimizing
non-invasive ventilation and minimizing invasive ventilation are now
standard practice in neonatal intensive care; however, the use of
mechanical ventilation in preterm infants continues to vary substantially
across centers, particularly when examined by race and ethnicity [ 30 ]. This
variation suggests mechanical ventilation may continue to be an
appropriate focus for BPD QI efforts in many NICUs.

Although less common than mechanical ventilation, optimizing surfactant

delivery was another common area of focus. As the preferred mode of
respiratory support for preterm infants with respiratory distress syndrome
has shifted to non-invasive ventilation and avoiding intubation, the
appropriate use of surfactant has become less clear. Alternative, less
invasive modes of surfactant administration that do not require
endotracheal intubation may allow for the benefits of both surfactant
treatment and avoidance of mechanical ventilation [ 83 , 84 ]. While neonatal
practice may be shifting towards the use of alternative methods of
surfactant delivery, numerous methods of surfactant delivery are in use,
and current practice varies widely, particularly between international
regions [ 85 , 86 ]. This likely represents an important area for ongoing
research and QI efforts in the neonatal community.

 81. Vliegenthart R.J.S., Onland W., van Wassenaer-Leemhuis A.G., De

Jaegere A.P.M., Aarnoudse-Moens C.S.H., van Kaam A.H.: Restricted
ventilation associated with reduced neurodevelopmental impairment
in preterm infants. Neonatology 2017; 112: pp. 172-179.

View In ArticleCross Ref

 82. Vliegenthart R.J.S., van Kaam A.H., Aarnoudse-Moens C.S.H., van

Wassenaer A.G., Onland W.: Duration of mechanical ventilation and
neurodevelopment in preterm infants. Arch Dis Child Fetal Neonatal
Ed 2019; 104: pp. F631-F635.

View In ArticleCross Ref

 83. Janssen L.C., Van Der Spil J., van Kaam A.H., Dieleman J.P.,
Andriessen P., Onland W., et. al.: Minimally invasive surfactant
therapy failure: risk factors and outcome. Arch Dis Child Fetal
Neonatal Ed 2019; 104: pp. F636-F642.

View In ArticleCross Ref

 84. Hentschel R., Bohlin K., van Kaam A., Fuchs H., Danhaive O.:
Surfactant replacement therapy: from biological basis to current
clinical practice. Pediatr Res 2020; 88: pp. 176-183.

View In ArticleCross Ref

 85. Herting E., Hartel C., Gopel W.: Less invasive surfactant
administration: best practices and unanswered questions. Curr Opin
Pediatr 2020; 32: pp. 228-234.

View In ArticleCross Ref

 86. Beltempo M., Isayama T., Vento M., Lui K., Kusuda S., Lehtonen
L., et. al.: Respiratory management of extremely preterm infants: an
international survey. Neonatology 2018; 114: pp. 28-36.
View In ArticleCross Ref