This document discusses bronchopulmonary dysplasia (BPD), a chronic lung disease that occurs in premature infants requiring respiratory support. It covers the definition, risk factors, pathogenesis, clinical features, prevention, and treatment of BPD. The definition has evolved over time from relying solely on oxygen need at 28 days to incorporating factors like oxygen need, pressure support, and gestational age. BPD results from lung injury and disrupted lung development due to prematurity and respiratory support. Management aims to protect the lung from injury through gentle ventilation, optimal oxygen levels, and other strategies.

1. Bronchopulmonary Dysplasia

2. BPD
 Introduction
 Etiological factors
 Pathogenesis
 Clinical Features
 Management
 Preventive measures
 Treatment
 Newer / experimental modalities
 Long term outcome

3. Introduction
 Chronic lung disease (CLD) or bronchopulmonary
dysplasia (BPD) usually occurs in preterm infants who
require mechanical ventilation and/or oxygen therapy for a
primary lung disorder in early neonatal period.
 Incidence of CLD has largely remained unchanged over
the years, although better treatment modalities are
available now but the improved survival of more
immature infants has led to increased numbers of BPD.
 The definition, pathophysiology, and management of
bronchopulmonary dysplasia (BPD) has evolved
significantly since first described by Northway almost 50
years ago.
 Northway, W.H., Jr.; Rosan, R.C.; Porter, D.Y. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. New
Engl. J. Med. 1967, 276, 357–368.

4. Definition
 The earliest clinical definition of BPD was limited to
oxygen requirement at 28 days with consistent
radiologic changes.(Northway et al in 1967 )
 These were originally modified to include continuing
need for oxygen therapy at 36 weeks corrected
gestational age(CGA).
 To address the inconsistencies in the diagnostic
criteria, the United States National Institute of
Health (NIH) organized a consensus conference in
2000 which suggested a new definition by
incorporating many elements of previous definitions of
BPD.

5. Definition
 The definition now takes into account total duration
of oxygen supplementation, positive pressure
requirements and gestational age, in addition to
oxygen dependency at 36 weeks post menstrual age
(PMA).
 As per oxygen need / ventilatory support severity of
BPD was decided.
American Thoracic Society. Copyright © 2016 American Thoracic Society. Jobe, A.H.; Bancalari, E.Bronchopulmonary Dysplasia. Am.
J. Respir. Crit. Care Med. 2001, 163, 1723–1729. The American Journal of Respiratory and Critical Care Medicine is an official journal
of the American Thoracic Society.

6. <32 weeks GA >32 weeks GA
Treatment with
oxygen
>21% for at least 28 days >21% for at least 28 days
Time point of
assessment
36 weeks PMA or discharge* >28 days but <56 days
postnatal age or discharge*
Grade :
Mild Breathing room air at 36 weeks
PMA or discharge*
Breathing room air at 56
days Postnatal age or
discharge*
Moderate Need for <30% oxygen at 36
weeks PMA or discharge*
Need for <30% oxygen at
56 days Postnatal age or
discharge*
Severe Need for ≥30% oxygen and/or
positive pressure (IMV/CPAP) at
36 weeks PMA or discharge*
Need for ≥30% oxygen
and/or positive pressure
(IMV/CPAP) at 56 days
Postnatal age or discharge*
Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9 Definition of Bronchopulmonary Dysplasia: Diagnostic Criteria. Reprinted
with permission of
the American Thoracic Society. Copyright © 2016 American Thoracic Society. Jobe, A.H.; Bancalari, E.Bronchopulmonary Dysplasia. Am. J. Respir. Crit. Care Med. 2001, 163,

7. limitations –
 Fails to classify infants with respect to airway issues
(including tracheal or bronchomalacia and/or
reactive airway disease) and pulmonary vascular
disease.
 Infants who had intervals of off oxygen period in the
first few weeks.
 Use of high-flow nasal cannula, is not addressed
and can result in misclassification.
 Does not include morbidities in early infancy
associated with BPD.
 Poindexter, B.B.; Feng, R.; Schmidt, B.; Aschner, J.L.; Ballard, R.A.; Hamvas, A.; Reynolds, A.M.; Shaw, P.A.;Jobe, A.H.
Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes
program. Ann. Am. Thorac. Soc. 2015, 12, 1822–1830.

8. Incidence
 Few reports are available from the centers in India; one
study from Chandigarh found the incidence of CLD
(defined as need for oxygen at or beyond 28 days of life) to
be 50% and 9% in ELBW and VLBW infants respectively.
 Narang A, Kumar P, Kumar R. Chronic Lung Disease in Neonates: Emerging problem in India. Indian Pediatr 2002; 39: 158-62
 Recently, Ehrenkranz et al validated the consensus
definition in a cohort of preterm (<32 weeks) extremely low
birth weight (ELBW) infants and reported an incidence of
77% by the new criteria.
 Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA,Wrage LA, Poole K; National Institutes of Child Health and Human
Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.
Pediatrics 2005;116:1353-60

9. Incidence
 In the NICHD Neonatal Network, the incidence of BPD at
36 weeks postmenstrual age in all infants weighing 501 to
1500 g (<32 weeks) at birth increased from 19% in 1990 to
22% in 2000, with another increase to 27% in 2003.
Increased survival has been associated with these trends.
 The highest rates of BPD were in the smallest infants, 66%
for those 501 to 750 g and 40% for those 751 to 1000 g
birthweight, (Fanaroff et al, 2007).

10. Risk factors
 Prematurity- The lung is most susceptible before alveolar
septation begins (Near Term). Injury at this stage may lead to an
arrest of alveolarization.
 Mechanical ventilation- pressure and volume trauma to
growing lung
 Oxygen toxicity – high levels of free oxygen radicles
damage lung tissues
 Patent ductus arteriosus (PDA)- fluid overload
 Pre- and postnatal infection & Inflammation -
damage lung tissues
 Growth restriction or nutritional deficits- poor lung
growth
 Genetic predisposition- history of hyperreactive lung
disease in families
 Excessive early intravenous fluid administration-
contributes to pulmonary edema

11. Stages of lung development:
 Embryonic stage (week:8)
 Pseudoglandular (weeks:8-16)
 Canalicular (weeks: 16-24)
 Saccular (weeks:24-near term)
 Alveolar (weeks: 34 weeks to postnatal
period)
 The specific timing and duration of exposures
influences the pattern of pulmonary damage.

13. Pathogenesis
 The etiology of BPD is clearly multifactorial and
involves:-
 derangements in multiple aspects of lung function
 Surfactant production,
 Repair from injury (e.g., elastin deposition) and
 Growth and development (e.g., alveologenesis).

14. Pathogenesis
 The phenotype seen with BPD is the end
result of a complex multifactorial process in
which various pre- and postnatal factors
compromise normal development in the
immature lung.
 Susceptible host with immature lung structure,
 Developmental deficiencies of factors crucial to lung
development and function such as
• surfactant,
• nitric oxide,
• innate immune defense, and
• antioxidant capability
 Inadequate nutrition,resulting in postnatal growth failure,

16. Clinical and Radiological features
 Respiratory signs in infants with CLD include fast
breathing, retractions, and paradoxical breathing. Rales
and coarse rhonchi are usually heard on auscultation.
 Radiographic features of ‘old’ and ‘new’ BPD are quite
different.
 New BPD shows haziness reflecting diffuse loss of lung
volume. Occasionally they have dense areas of segmental
or lobar atelectasis or pneumonic infiltrates, but they do
not show severe overinflation.
 ‘Old’ BPD, as originally described by Northway, had four
distinct stages.

17. Stages of ‘old’BPD
Stages of BPD
(old BPD)
features
Stage- 1 consistent with hyaline membrane disease
Stage-2 opaque lung fields with air bronchograms due to areas of
atelectasis alternating with emphysema; / normal-low lung
volume
Stage-3 small radiolucent fields, streaky densities with early
hyperinfl ation
Stage-4 hyperinflated lungs with generalized cystic areas and
dense fibrotic strands.

18. Old v/s New BPD
Old BPD New BPD
Etiology High O2 & mechanical
ventilation
Disorder of lung
development
Babies Originally reported by
Northway in 1967,
infants with a mean
gestational age of 33 weeks
and a birth weight of 2,000
g.
mean gestational age
under 28 weeks and birth
weight under 1,000 g.
Pathology emphysema, atelectasis
and fibrosis, and marked
epithelial metaplasia and
smooth muscle hypertrophy
in the airways and in the
pulmonary vasculature.
The major abnormalities are
a decrease in alveolar
number (referred to as
alveolar hypoplasia) and
dysregulated
microvascular growth
(Bhatt et al, 2001; Burri, 1997; Coalson et al, 1999; De Paepe et al, 2006, 2008; Husain et al, 1998; Maniscalcoet al, 2002).

19. Preventive measures
Antenatal steroids Probable benefits (indirect)
Surfactant replacement therapy Probable benefits (indirect)
Gentle ventilation and CPAP Needs more studies
Fluid restriction Needs more studies
Vitamin A Proven benefits
Postnatal corticosteroids Proven benefits
Antioxidant Therapy Needs more studies
Inhaled nitric oxide Needs more studies
Caffeine Probable benefits
Azithromycin - Only in proven infection
Early Entral /parentral nutrition

20. Prevention of BPD
 Management strategies are aimed at protecting against
lung injury and the development of BPD.
 As the pathogenesis of disease is multifactorial, diverse
approaches have been adopted including both ventilation
and medical strategies.

21. Antenatal Steroids
 The effect of antenatal glucocorticoids on the incidence of
BPD among survivors has been inconsistent.
 Some studies have demonstrated a benefit (Gagliardi et
al,2007; Van Marter et al, 1990).
 The inconsistent effect of antenatal steroids on BPD may
be due to increased survival of less mature preterm
infants.
 Antenatal steroids less RDS/HMDless BPD
 ( but more survival of less mature preterms increased
BPD)

22. Ventilation
 In spite of the development of numerous sophisticated
ventilators for the newborn, there is still no clear advantage to
any one approach to ventilating the preterm infant.
 Early initiation of nasal CPAP (other non invasive modes) has been
shown to reduce the need for intubation and mechanical ventilation.
Mechanical ventilation is major risk factors for, so use of early CPAP
should logically reduce its incidence.
 If invasive ventilation is done, babies can be extubated more
successfully if post extubation put on to nasal CPAP.(Gupta et al
2009; Ho et al, 2002).
 The general approach should be one of preventing atelectasis,
sustaining FRC, using a minimal tidal volume (usually 4 to 6
mL/kg), and allowing the infant to trigger his or her own
ventilation as much as possible (Carlo et al, 2002).

23. Saturation targets
 Specific to the outcome of BPD, the Surfactant, Positive
Pressure and Oxygenation Randomization Trial
(SUPPORT) conducted in the US found slightly lower rates
of BPD (38% vs. 41.7%) in the low-saturation group
without statistical significance. (with low 85%–89% and
high 91%–95%)
 The Canadian Oxygen Trial (COT) similarly identified a
similar trend with BPD rates of 31.8% and 33.1% in the
low- and high-saturation groups respectively.
 Despite the theoretical concerns for increased risk of
oxidative lung injury and pulmonary vascular remodeling,
many units now use higher saturation limits of 91%–95%
based upon the collective finding of improved survival in
multiple trials.
 Saugstad, O.D.; Aune, D. Optimal oxygenation of extremely low birth weight infants: A meta-analysis and systematic review of the
oxygen saturation target studies. Neonatology 2014, 105, 55–63.

24. Surfactant Replacement Therapy
 Surfactant replacement therapy is clearly associated with
decreased severity of RDS and its associated mortality.
 Although there is not substantial evidence that survivors
have a decreased incidence of BPD. (Engle and the
Committee on Fetus and Newborn, 2008).
 In addition, it is possible that later replacement
surfactant, during a period of secondary surfactant
dysfunction (Merrill et al, 2004), could be an effective way
to prevent BPD in those infants who continue to require
mechanical ventilation after the 1st week of life.

25. Exogenous surfactant:
 Prophylactic surfactant therapy in infants born before
30 weeks of gestation has not been shown to reduce
the incidence of BPD.
 However, surfactant treatment for established RDS
(‘rescue therapy’) in infants born at or after 30 weeks
gestation is associated with significant reduction in
the incidence of BPD.
 Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn.Surfactant-replacement therapy for respiratory distress in the preterm
and term neonate.Pediatrics 2008;121:419-32
 The apparent lack of effect in the first group could
probably be due to the increased survival of more
immature infants (similar to antenatal steroids).
 Interestingly, both antenatal steroids and
surfactant reduce rates of RDS and improve
survival; however, neither has been shown to
reduce incidence of BPD.

26. Exogenous surfactant
 Meta-analysis of randomized clinical trials
comparing prophylactic or early use of surfactant
to initial support by continuous airway pressure
(CPAP) have identified reduction in the combined
outcome of death or BPD with avoidance of
intubation.
 Still more evidence is needed in this regard
before coming to any meaningful conclusion.
 Fischer, H.S.; Buhrer, C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: A meta-
analysis. Pediatrics 2013, 132, e1351–e1360. [CrossRef] [PubMed]
 Schmolzer, G.M.; Kumar, M.; Pichler, G.; Aziz, K.; O’Reilly, M.; Cheung, P.Y. Non-invasive versus invasive
respiratory support in preterm infants at birth: Systematic review and meta-analysis. BMJ 2013, 347, f5980.
[CrossRef] [PubMed]
 Subramaniam, P.; Ho, J.J.; Davis, P.G. Prophylactic nasal continuous positive airway pressure for preventing
morbidity and mortality in very preterm infants. Cochrane Database Syst. Rev. 2016. [CrossRef]

27. Postnatal Corticosteroids
 Treatment with glucocorticoids does not appear
to have a substantial impact on long-term
pulmonary outcomes, such as duration of
supplemental O2 requirement, length of hospital
stay, or mortality.
 Currently, recommendations of the American
Academy of Pediatrics and the Canadian
Pediatric Society 2002 are that the use of
postnatal steroids be restricted to randomized,
controlled trials and, when these agents are given
outside such trials, they be used only under
exceptional circumstances of severity and after
fully informing the parents of the potential
problems with neurodevelopmental outcome.

28. Steroids:
 The DART study randomized 70 ventilator dependent
infants with average birth weights less than 700g to a
10 day tapered dose of dexamethasone or placebo at
a mean postnatal age of 23d.
 Treatment schedules of 0.2 mg/kg of dexamethasone
or less tapered over 7 to 10d seem to avoid the
hyperglycemia and hypertension frequently
encountered with the higher doses and longer
treatment schedules.
 Doyle LW, Davis PG, Morley CJ, et al. Low-dose dexamethasone facilitates extubation among chronically ventilator-
dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics. 2006;117:75.
 Prednisolone also has been used, but not evaluated
in randomized trials
 Bhandari A, Schramm CM, Kimble C, et al. Effect of a short course of prednisolone in infants with oxygen-dependent bronchopulmonary
dysplasia. Pediatrics. 2008;121:e344. [

29. Fluids
 Fluid restriction: old studies indicate that relative fluid restriction
reduces incidence of BPD in preterm infants.
 However, the systematic review of studies on fluid restriction has
not found any significant reduction.
 Barrington KJ, Al-Hazzani FN. Fluid restriction for treatment of preterm babies with chronic lung disease. (Protocol) Cochrane
Database of Systematic Reviews 2005; (3):CD005389.
 Multiple studies suggest that fluid overload contributes to
an increased risk of BPD (Oh et al, 2005) However,
extremely restrictive fluid administration contributes to the
problem of undernutrition, thereby contributing to failure of
alveologenesis.
 Moreover what represents fluid restriction in VLBW infants is not
definitely known. Hence, no definite recommendation can be
made regarding fluid restriction as a strategy for reducing the
incidence of BPD.

30. Nutrition:
 Nutrition plays an important role in lung development and
maturation. Aggressive parenteral nutrition and early
enteral feeding may help decrease the incidence of BPD in
VLBW infants.
 Biniwale MA, Ehrenkranz RA. The role of nutrition in the prevention and management of bronchopulmonary
dysplasia. Semin Perinatol 2006;30:200-8
 Ideally, nutritional management should begin as soon as
posible after birth to minimize the respiratory morbidities.
The initial management should meet the estimated fluid,
protein, lipids and energy needs.
 Infants developing BPD require 20 to 40% more
calories than their age-matched healthy controls.
Their caloric requirement varies from 120 to 150
Kcal/kg/day.

31. Nutrition:
 This can be achieved by fortifying breast milk with
human milk fortifier (HMF) or infant formula.
 For infants who require more calories, fat
supplementation (e.g. MCT oil) is preferred.
 The role of specific nutrients (e.g. inositol,
vitamin E, selenium, glutamine etc. except for
vitamin A) however, remains speculative till
now.

32. Vitamin A
 Vitamin A deficiency may predispose to chronic
lung disease as it is a key regulator of normal
lung growth . It plays a critical role in maintaining
the integrity of respiratory tract epithelium and
stored in the septal cells of the alveoli involved in
alveolar septation (Albertine et al, 1999)
 Vitamin A is accumulated predominantly in the
third trimester, preterm infants have deficient liver
stores of this vitamin (Zachman, 1989).
 A number of clinical trials have investigated
whether supplementation with vitamin A, typically
by intramuscular injections, would result in a
decrease in BPD.

33. Route of vitamin A administration
 I.V.-Vitamin A added to parenteral nutrition
solutions is degraded by light and can adhere to
the intravenous tubing, making it largely
inaccessible.
 I.M.-Administration requires intramuscular
injections which is associated with significant
discomfort and potentially an increased risk of
infection.
 Oral-A large trial is currently in progress
evaluating the efficacy of oral vitamin A
supplementation with hopes that a simpler route
of administration may also be effective.
 Meyer, S.; Gortner, L.; NeoVitaA Trial investigators. Up-date on the NeoVitaA Trial: Obstacles, challenges,perspectives, and local
experiences. Wien. Med. Wochenschr. 2016.

34. Vitamin A
 A large RCT of 807 infants with a birth weight of less
than 1000 g has shown that a large dose of
intramuscular vitamin A (5000 units three times a
week for 4 weeks from birth) decreases the risk of
CLD.A meta-analysis of seven RCTs has also
confirmed this finding.
 Darlow BA, Graham PJ. Vitamin A supplementation for preventing morbidity and mortality in very low birth weight
infants. Cochrane Database Syst Rev 2002; 4:CD000501.
 The largest study to date, by the NICHD Neonatal
Network, also used one of the higher doses that has
been studied and demonstrated a significant
decrease in BPD or death at 36 weeks following
treatment with vitamin A (55% vs. 62%) (Tyson et al,
1999).

35. Antioxidant Therapy
 Superoxide dismutase is a naturally occurring
enzyme that protects against oxygen free radical
injury.
 Human studies have suggested that
administration of intratracheal recombinant
human superoxide dismutase (rhSOD) is well
tolerated and might have beneficial effects on the
lung (Davis, 2002; Davis et al, 2003).
 Further trials of this intervention are needed
before it can be recommended as useful in
preventing BPD.

36. Nitric Oxide
 Most clinical studies in preterm infants with severe
respiratory failure have not demonstrated any
reduction in the risk of death or CLD with iNO.
 Recently, two large RCTs conducted in this regard
indicate that iNO therapy might be beneficial in a
select group of preterm infants.
 Expert review of the topic resulted in consensus
opinions from both the NIH and the American
Academy of Pediatrics do not recommend the
routine use of iNO in premature infants.
 Despite these statements, off-label use of iNO in extremely
premature infants remains on the rise .
 Ellsworth, M.A.; Harris, M.N.; Carey,W.A.; Spitzer, A.R.; Clark, R.H. Off-label use of inhaled nitric oxide after release of nih consensus statement. Pediatrics 2015,
135, 643–648.
 Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med
2006;355:354-64

37. Nitric Oxide
 the appropriate dose, timing, duration, and more
importantly, the subgroup of infants who are likely to
benefit with this mode of therapy have not yet been
clearly defined.
 Subsequent meta-analysis suggested no specific
benefit with prematurity and stated routine use could
not be recommended.
 Moreover, the prohibitive cost of iNO therapy
precludes its use on a routine basis
 Barrington, K.J.; Finer, N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane DatabaseSyst. Rev. 2010. [CrossRef]
 119. Askie, L.M.; Ballard, R.A.; Cutter, G.R.; Dani, C.; Elbourne, D.; Field, D.; Hascoet, J.M.; Hibbs, A.M.;Kinsella, J.P.; Mercier, J.C.; et al.
Inhaled nitric oxide in preterm infants: An individual-patient data meta-analysis of randomized trials. Pediatrics 2011, 128, 729–739.
 Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PJ, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J
Med 2006;355:343-53

38. Others
 Indomethacin / Ibuprofen therapy for PDA:
treatment of symptomatic PDA could possibly
reduce the incidence of BPD. Patent ductus
arteriosus is one of the major risk factors for BPD.
 No role of prophylactic indomethacin/ibuprofen for
BPD.
 Caffine citrate- decrease incidence of apnea of
prematurity and intubation/ventilation.
 Azithromycin- decrease the risk of developing
BPD in infants with documented Ureaplasma
colonization or infection. Cloherty

39. Treatment
Ventilation
Caffeine
Inhaled Nitric oxide
Diuretics
Bronchodilator therapy
Postnatal corticosteroids
Nutrition

40. Ventilatory strategies
 Given that no ‘ideal’ pharmacological agents are
available for prevention of BPD, attention has
now shifted to ‘optimal’ ventilatory strategies that
would prevent/reduce lung injury and permit
adequate lung development.

41. Ventilatory- Strategies:
 Minimizing ventilatory support
 Prefer non invasive ventilation, whenever it is
possible
 CPAP/HHHFNC
 If invasive ventilation used:
 Volume targeted ventilation
 Patient triggered ventilation (SIMV)
 Low tidal volume (3-6 ml/kg)
 Moderate PEEP (4-5 cm H2o)
 Slightly high Ti (0.4-0.45)
 Permissive hypercapnea (PaCO2 (45-55 mm Hg provided pH >7.25)
 Ambalavanan N, Carlo WA. Ventilatory strategies in the prevention and management of bronchopulmonary dysplasia. Semin
Perinatol 2006;30:192-9
 AIIMS protocol

42. Continuous positive airway
pressure (CPAP):
 Non invasive ventilation is always better than
invasive modalities.
 Numerous studies, mostly non-randomized, have
reported the benefits of early CPAP in minimizing
the need for mechanical ventilation and the
incidence of chronic lung disease.
 Lemyre, B.; Davis, P.G.; De Paoli, A.G.; Kirpalani, H. Nasal intermittent positive pressure ventilation(NIPPV)
versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.Cochrane
Database Syst. Rev. 2014.

43. Patient-triggered ventilation
(PTV):
 Patient triggered modes (SIMV, assist-control,
and pressure support ventilation) improve the
infant-ventilator asynchrony and reduce the risk
of Ventilator induced lung injury.
 The Cochrane review concluded that though PTV
is associated with shorter duration of ventilation, it
does not reduce the incidence of BPD.
 Greenough A, Dimitriou G, Prendergast M, Milner AD. Synchronized mechanical ventilation for respiratory support in newborn infants. Cochrane
Database of Systematic Reviews 2008;3: CD000456.

44. High-frequency ventilation
(HFV):
 Animal studies indicate that HFV could lead to
less lung injury when compared to conventional
ventilation.
 However, randomized controlled trials comparing
elective use of HFV with conventional ventilation
in preterm infants have yielded conflicting results.
 A recent meta-analysis that included 17 RCTs of
conventional versus high frequency ventilation
found no significant difference in the incidence of
BPD. Therefore, elective use of HFV cannot be
recommended for preterm infants with RDS at
present.
 Thome UH, Carlo WA, Pohlandt F. Ventilation strategies and outcome in Randomised Trials of High Frequency Ventilation. Arch
Dis Child. 2005;90:F466-73

45. Volume targeted ventilation:
 The observation that volutrauma and not barotrauma
is the primary determinant of Ventilator Iinduced
Lung Iinjury has enthused neonatologists to use
volume controlled/targeted modes of ventilation in
place of conventional pressure controlled modes.
 Only a few randomized trials are available in this
regard till date.
 The Cochrane review that included four RCTs found
significant reduction in the duration of ventilation and
pneumothorax rates but only a borderline reduction in
the incidence of BPD.
 McCallionN, Davis PG, MorleyCJ. Volume-targeted versus pressure-limited ventilation in the neonate. Cochrane
Database of Systematic Reviews 2005;3: CD003666.
 More studies are needed to address the question of
whether volume controlled ventilation would result in
better long term respiratory outcomes.

46. Permissive hypercapnia
 Retrospective studies have suggested that
hypocapnia that occurs during assisted ventilation is
an independent risk factor for BPD.
 Subsequently, ‘minimal ventilation’ using smaller tidal
volumes / less peak inflation pressures while
accepting mild hypercapnia (PaCO2 45-55 mm Hg)
was studied in preterm infants.
 One such study in preterm ELBW infants (target
PaCO2 >52 mm Hg in study group) reported less
need for mechanical ventilation but no reduction in the
need for supplemental oxygen at 36 weeks PMA.
 Clearly, more studies are needed to prove the
intended benefits of this promising strategy.
 Carlo WA, Stark AR, Wright LL, Tyson JE, Papile LA, Shankaran S, et al. Minimal ventilation to prevent bronchopulmonary
dysplasia in extremely-low-birth-weight infants. J Pediatr 2002;141:370-4

47. Permissive hypoxemia:
 Exposure to high oxygen concentration has long been
recognized as an important factor in the pathogenesis
of BPD. Preterm infants are more vulnerable to the
harmful effects of free oxygen radicals.
 Surprisingly, there are few data to suggest either the
optimal oxygen level required or the optimum target
range for oxygen saturations (SpO2) in these infants.
 Observational studies suggest that in comparison with
the more liberal oxygen therapy, the restrictive
approach of accepting lower oxygen saturation values
is associated with decreased incidences of CLD
and ROP.
 Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. Oxygen-saturation targets and outcomes in
extremely preterm infants. N Engl J Med 2003; 4;349:959-67

48. Permissive hypoxemia:
 Two RCTs have been conducted to see whether it is
better to aim for high oxygen saturation in infants who
are more than a few weeks old: BOOST-trial and
STOP-ROP trial.
 Both these studies indicate that maintaining higher
oxygen saturation (>95%) is associated with
increased need for oxygen at 36 weeks PMA and
greater use of postnatal steroids and diuretics in
premature infants (when compared to maintaining
lower oxygen saturation of 89-94%).
 Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOPROP),a
randomized, controlled trial. I: primary outcomes. Pediatrics.2000;105:295-310
 Still, the uncertainty about ‘optimal’ oxygenation has
led to wide variation of policies on oxygen-monitoring
and therapy in neonatal nurseries.

49. Diuretic therapy:
 In infants with well-developed BPD, pulmonary
edema is a major component of the illness.
Diuretics help by increasing the reabsorption of
fluid from the lungs.
 There is clear evidence that either daily or
alternate-day therapy with furosemide improves
lung mechanics and gas exchange in infants with
established BPD. (Hazinski, 2000)
 Thiazide type diuretics alone or in combination
with spironolactone also have improved lung
function in some studies. (Rush et al, 2001).

50. Diuretics
 In view of the lack of data from randomized trials
concerning effects on important clinical outcomes,
routine or sustained use of systemic loop diuretics in
infants with (or developing) CLD cannot be
recommended based on current evidence. Cochrane Central Register of
Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2003), MEDLINE (1966 to April 2003), EMBASE (1974 to 1998)
 However, diuretics can be used sparingly if there are
clinical/radiographic features of pulmonary edema in
an infant with evolving or established BPD.(Baveja R, Christou H.
Pharmacological strategies in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006;30:209-18)
 An acute clinical response may be seen within 1 hour,
although maximal effect may not be achieved until 1
week of therapy.

51. Diuretics
 Diuretics have not been shown to improve
clinical outcomes such as duration of ventilator
dependence, hospital length of stay, or long-term
outcome.
 Still most centers use diuretics at some point in
the management of infants with BPD.
 Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2003), MEDLINE (1966 to April
2003), EMBASE (1974 to 1998)
 Drugs- furosemide / chlorothiazide
/spironolactone

52. Bronchodilator Therapy
 With established BPD, there is a significant
increase in airway resistance, and there may also
be persistent or intermittent wheezing may be
related to increased airway tone or
bronchospasm.
 Inhaled albuterol has been the most widely used
agent. Systemic use of bronchodilators has been
more restricted because of a high incidence of
side effects and a very narrow therapeutic index
(DeBoeck et al, 1998).

53. Bronchodilator Therapy
 Infants with developing CLD may benefit as early
as the second week of age.
 a. Albuterol nebulization every 6 to 8 hours
 S/E- tachycardia
 b. Ipratropium bromide- more potent
bronchodilator .
 Combination therapy is more effactive compared
to single agent.(Nelson, textbook of pediatrics -20th edition)
 Diuretics and bronchodilators can be used if the
clinical condition warrants but should be stopped
if no response occurs within 24-48 hours of
initiation of therapy.

54. Mast cell stabilizers:
 Cromolyn sodium has been shown to decrease
neutrophil migration and activation thus
minimizing inflammation in the lungs. Two trials
that have studied the possible role of cromolyn for
prevention and treatment of BPD have not shown
any benefit.
 Ng GY, Ohlsson A. Cromolyn sodium for the prevention of chronic lung disease in preterm infants. Cochrane Database Syst Rev.
2001;(2):CD003059

55. Postnatal steroids:
 Inflammation plays a central role in the pathogenesis of BPD,
steroids were thought to be a choice of management as anti-
inflammatory agent.
 Conventionally, steroid therapy is categorized into 3 broad
groups based on the timing of initiation: (I.V. Dexamethasone –
DART study; Doyle 2000a)
 early (during the first 96 hrs after birth),
 moderately early (between postnatal days 7 and 14), and
 delayed (after 3 weeks of age).
 Meta-analyses of RCTs of the first two regimes have shown a
significant reduction in the incidence of BPD at 36 weeks PMA.
 Halliday HL, Ehrenkranz RA. Moderately early (7–14 days) postnatal corticosteroids forpreventing chronic lung disease in preterm infants.
Cochrane Database Syst Rev 2003;(1): CD001144.

56. Postnatal steroids:
 However, there are important concerns regarding both
short-term (hypertension, gastrointestinal perforation,
poor somatic growth) as well as long-term adverse
effects (neurodevelopmental outcomes including
cerebral palsy).
 Rates of use of systemic steroids for prevention of
BPD have markedly decreased following American
Academy of Pediatrics (AAP) and Canadian Pediatric
Society (CPS) recommendations in 2002 against
routine use.
 Specifically, rates of postnatal corticosteroids use
declined from 20% in 1997–2000 to only 12% in
2001–2002 and then again to 8% in 2004 with no
significant change thereafter. Fanaroff, A.A Korones, S.B.; Laptook, A.R.; et al.
Trends in neonatal morbidity and mortality for very low birthweight infants. Am. J. Obstet. Gynecol. 2007, 196, 147.e1–
147.e8.

57. Inhaled corticosteroids
 Based on this updated review, there is increasing
evidence from the trials reviewed that early
administration of inhaled steroids to VLBW neonates
is effective in reducing the incidence of death or CLD
at 36 weeks' PMA among either all randomised
infants or among survivors. (Cochrane review 2017)
 Further studies are needed to identify the risk/benefit
ratio of different delivery techniques and dosing
schedules for the administration of these medications.
Studies need to address both the short- and long-term
benefits and adverse effects of inhaled steroids with
particular attention to neurodevelopmental outcome.
 Clouse, B.J.; Jadcherla, S.R.; Slaughter, J.L. Systematic review of inhaled bronchodilator and corticosteroid therapies
in infants with bronchopulmonary dysplasia: Implications and future directions. PLoS ONE 2016,11, e0148188.
[CrossRef] [PubMed]
 105. Onland, W.; Offringa, M.; van Kaam, A. Late (7 days) inhalation corticosteroids to reduce bronchopulmonary
dysplasia in preterm infants. Cochrane Database Syst. Rev. 2012.

58. Caffeine
 Methylxanthines- increase respiratory drive/ decrease
apnoea / improve diaphragmatic contractility/has diuretic
effect/ decrease PVR & increase lung compliance probably
through direct smooth muscle relaxation.
 In the recent randomized, multicenter Caffeine for Apnea
of Prematurity (CAP) trial, early initiation of caffeine was
found to result in lower incidence of BPD as well as a
shorter course of respiratory support as compared to
controls. Schmidt, B.; Roberts, R.S.; Davis, P.; Doyle, L.W.; Barrington, K.J.; Ohlsson, A.; Solimano, A.; Tin, W. Caffeinetherapy for
apnea of prematurity. New Engl. J. Med. 2006, 354, 2112–2121
 The specific mechanism by which caffeine protects against
lung injury remains unclear, and improved outcomes may
have been due to decreased incidence of apnea of
prematurity.(Schmidt et al,2006b).

59. Strategies Proven
benefits
Promising
(need more
studies)
Probable
benefits
(effects +/-)
No benefit
Ventilatory - NIPPV
Volume
targeted
ventilation
Permissive
hypercapnea/
hypoxemia
Early CPAP
Patient
triggered mode
HFO
Fluid & nutrition - Aggressive
early entral &
parentral
nutrition
Fluid restriction -
Pharmacologica
l
Vitamin A
Postnatal
steroids ( S/E +)
Superoxide
dysmutase
Antenatal
steroids
Methylxanthine
s
Surfactant
Diuretics
iNO
Prophylactic
indomethacin/ib
upprofen
Mastcell
stabilizer

60. Long-Term Outcomes
 Long-term outcomes of BPD remain difficult to
characterize as adult populations currently
available to study represent survivors of outdated
care.
 Mortality. Mortality is estimated at 10% to 20%
during the fi rst year of life. The risk increases
with duration of O2 exposure and level of
ventilatory support. Death is frequently caused by
infection.
 Jobe AH. The new bronchopulmonary dysplasia. Curr Opin Pediatr 2011;23(2):167–172.Kinsella JP, Greenough A, Abman SH.
Bronchopulmonary dysplasia. Lancet 2006;367(9520):1421–1431.

61. Long term outcome
 Pulmonary functions- Numerous studies have
evaluated long-term pulmonary function after
premature birth alone.
 A meta-analysis including 59 articles identified
that percent of predicted forced expiratory volume
in 1 second (FEV1) is decreased in preterm-born
survivors, even in patients who did not have a
history of BPD.
 Evaluation of teenaged or young adult survivors
of BPD specifically confirmed lower FEV1, as well
as decreased forced vital capacity (FVC) and
forced expiratory flow rate at 50% of FVC as
compared to controls.

62. Long term outcome
 Pulmonary defence –
 Premature infants have increased susceptibility to
infection which persists into childhood.
 Common respiratory infections can result in severe
morbidity and potential mortality in BPD survivors.
 Exposure to environmental insults including respiratory
infections, tobacco and pollution may complicate
resolution of BPD and prolong risks of pulmonary
morbidity
 Beyond environmental insults, pulmonary morbidity in
ex-preterm infants can be complicated by chronic reflux
and microaspiration with risk of aspiration pneumonia
and/or chronic inflammation.
 Collaco, J.M.; Aherrera, A.D.; Ryan, T.; McGrath-Morrow, S.A. Secondhand smoke exposure in preterm infants with
bronchopulmonary dysplasia. Pediatr. Pulmonol. 2014, 49, 173–178.

63. Long term outcome
 Asthma like symptoms-
 Long-term follow-up of infants born <26 weeks
gestation identified that 25% had an asthma
diagnosis at 11 years of age and around 56% had
evidence of abnormal spirometry.
 Many survivors of BPD demonstrate a component of
reactive airway disease. While children with BPD
have asthma-like symptoms, they are less likely to
demonstrate airway hyper-responsiveness or
response to bronchodilators as they may suffer a
fixed peripheral airway narrowing.
 Fawke, J.; Lum, S.; Kirkby, J.; Hennessy, E.; Marlow, N.; Rowell, V.; Thomas, S.; Stocks, J. Lung function and respiratory
symptoms at 11 years in children born extremely preterm: The epicure study. Am. J. Respir. Crit.Care Med. 2010, 182, 237–245.

64. Long term outcome
 Exercise intolerance -Significant risk of
exercise-induced bronchoconstriction has been
demonstrated in children with BPD consistent
with concerns for reactive airway disease. Joshi, S.;
Powell, T.; Watkins, W.J.; Drayton, M.; Williams, E.M.; Kotecha, S. Exercise-induced bronchoconstriction in
school-aged children who had chronic lung disease in infancy. J. Pediatr. 2013,162, 813–818.

65. Long term outcome
 Pulmonary artery hypertension
 Dysmorphic pulmonary vasculature and
compromised angiogenesis with BPD results in
risk of elevated pulmonary pressures or BPD-
associated pulmonary hypertension (PH).
 Retrospective studies of infants with BPD
suggested that 25%–37% of infants with BPD
develop associated PH, but these data are limited
by inconsistent definition and screening protocols.
 An, H.S.; Bae, E.J.; Kim, G.B.; Kwon, B.S.; Beak, J.S.; Kim, E.K.; Kim, H.S.; Choi, J.H.; Noh, C.I.; Yun, Y.S.Pulmonary hypertension in preterm
infants with bronchopulmonary dysplasia. Korean Circ. J. 2010, 40,131–136.

66. Conditions may be associated with
BPD
System Morbidities
Respiratory Oxygen dependency for hypoxia
Airway obstructive disease
Laryngo-tracheo-bronchomalacia
Subglottic stenosis
Respiratory viral infections
Aspiration pneumonitis
Cardio vascular Pulmonary hypertension
Cor pulmonale
G.I. system & growth GER
Poor growth
CNS Developmental abnormalities
Behavioural problems
Ophthalmology ROP
Forfer & Arneil’s -7th edition

67. Conclusion
 Advances in neonatal care have resulted in
increased rates of survival of extremely
premature infants leading to both a new set of
management challenges as well as an emerging
population of long-term survivors of BPD.
 Non invasive ventilation is preferred over
invasive ventilation.
 During invasive ventilation - Volume controlled,
patient triggered ventilation with moderate PEEP,
low tidal volume and slightly high Ti is used to
minimize ventilator induced lung injury.

68. Conclusion
 Interdisciplinary care to manage the complex
pulmonary, nutritional and developmental needs
of these patients is critical and may itself
influence outcomes of severe BPD.
 Subclinical right ventricular dysfunction,
obstructive lung disease, exercise intolerance,
and asthma-like symptoms in survivors are
frequent and should be evaluated and managed
accordingly.

69. THANK YOU

73.  The definition, pathophysiology, and management
of bronchopulmonary dysplasia (BPD) has
evolved significantly since first described by
Northway almost 50 years ago.

74. Nasal intermittent positive
pressure ventilation (NIPPV):
 In contrast, a Cochrane review including eight trials
comparing NIPPV with CPAP identified less extubation
failure with NIPPV, but no specific benefit with respect to
risk of BPD . NIPPV is a method of augmenting NCPAP by
delivering ventilator breaths via the nasal prongs.
 It is thought to improve the tidal and minute volumes and
decrease the inspiratory effort required by neonates as
compared to nCPAP.
 This should reduce the need for reintubation thus avoiding
ventilator induced lung injury (VILI).
 The Cochrane review that included three RCTs found a
trend towards reduction in rates of chronic lung disease
(typical RR 0.73; 95% CI: 0.49, 1.07).16
 However, more trials are required to document the safety
and effectiveness of this relatively new modality.
 Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB; COIN Trial Investigators. Nasal CPAP or intubation
at birth for very preterm infants. N Engl J Med 2008;14;358:700-8
 Davis PG, Lemyre B, De Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous
positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database of Systematic Reviews
2001;3:CD003212

75. Ventilatory - Strategies
Evolving BPD
(2-4 weeks)
Established BPD
(>4 weeks)
Minimizing ventilatory support
(e.g. using nCPAP whenever possible)
Tolerating slightly higher PaCO2 (45-
55 mm Hg provided pH >7.25)
Target SpO2 : 88-93%
If on IMV:
Use PTVif possible
Slow rates (25-40/min)
Moderate PEEP (4-5 cm H2O)
Moderate Ti (0.35-0.45 sec)
Low tidal volume (3-6 mL/kg)
 Early extubation to CPAP
Minimizing ventilatory support
Tolerating higher PaCO2 (55-60 mm
Hg provided pH >7.25)
Target SpO2 : 89-94%
If on IMV:
Use PTVif possible
Slow rates (20-40/min)
Moderate PEEP (4-8 cm H2O)
Longer Ti (0.4-0.7 sec)
Larger tidal volume (5-8 mL/kg)

76. Continuous positive airway
pressure (CPAP):
 Recently, a multi-centric study on CPAP versus
intubation and ventilation in infants born at 25-28
weeks’ gestation found significant reduction in the
need for oxygen at 28 days of life but not at 36
weeks PMA.
 Fischer, H.S.; Buhrer, C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia:
A meta-analysis. Pediatrics 2013, 132, e1351–e1360.
 Schmolzer, G.M.; Kumar, M.; Pichler, G.; Aziz, K.; O’Reilly, M.; Cheung, P.Y. Non-invasive versus
invasive respiratory support in preterm infants at birth: Systematic review and meta-analysis. BMJ
2013, 347, f5980.
 Subramaniam, P.; Ho, J.J.; Davis, P.G. Prophylactic nasal continuous positive airway pressure for
preventing morbidity and mortality in very preterm infants. Cochrane Database Syst. Rev. 2016.