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bronchopulmonary
dysplasia

Dr. Sultana Jahan

Year 4 resident, Neonatology
Dr. Asaduzzaman
Year 1 resident, Neonatology
Case scenerio
• Fatema Rahman, 79 days old baby , 4 th issue of non-
consanguineous parents was admitted in NICU, BSMMU at
postnatal age D35 with prematurity (30 weeks), very low birth
weight(1420g), delayed cry after birth and respiratory distress
soon after birth. Initially respiratory support was given in the
form of O2 inhalation 5 L/min. At D5 baby was put on MV due
to repeated apnea & upto D35 baby was on MV. After that baby
was put on CPAP. At D44 baby was again put MV. At D61 baby
was weaned from MV & put on CPAP again. At D77 weaned
from CPAP & D79 O2 was omited.
Chronic lung disease
Outline of presentation
• Introduction
• Definition
• Epidemiology
• Risk factors
• Pathophysiology
• Clinical Presentation
• Management
• Outcome
Introduction

• The World Health Organization estimates the prevalence of

preterm birth to be 5–18% and the rate has been increasing
since the early 1980s.
• Preterm births account for 70% of neonatal deaths and up to
75% of neonatal morbidity, and contribute to long-term
neurocognitive deficits, pulmonary dysfunction and
ophthalmologic disorders
• All forms of respiratory morbidity, including transient
tachypnea of the newborn, respiratory distress syndrome,
pneumonia, and pulmonary hypertension, affect preterm
infants at a higher rate than term infants. 50% of babies less
than 30 weeks develop RDS.
• The most frequently used clinical predictor of long-term
respiratory risk is the presence of bronchopulmonary dysplasia
(BPD).
• 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.
• Better treatment modalities causing improved survival of more
immature infants leads to increased number of BPD.
• The definition, pathophysiology, and management of
bronchopulmonary dysplasia (BPD) has evolved significantly
since Northway et al. described in 1967.
Definition
• The earliest clinical definition of BPD was limited to
oxygen requirement at 28 days with consistent
radiologic changes (Northway et al. 1967 )

• Described as disorder which resulted from effects of

high concentration of oxygen and mechanical
ventilation in premature infants with severe RDS.

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 .
 New BPD

 National Institutes of Health Consensus (2001)

recommended that babies be considered to have BPD

:
• If they had been Oxygen dependent for at least 28 days

• Classified according to their respiratory support requirement.

NICHHD Criteria
<32 weeks >32 weeks

Time point of at 36 weeks postmenstrual at 56 days postnatal age or

assessment age (PMA) or at discharge at discharge whichever
home, whichever comes comes first.
first
Mild BPD Breathing air (FiO2 21%) Breathing air (FiO2 21%)

Moderate BPD requiring <30% requiring <30%

supplemental O2. supplemental O2.

Severe BPD > 30% O2 or CPAP or > 30% O2 or CPAP or

positive pressure positive pressure
ventilation. ventilation.
New BPD Old BPD

Surfactant treated ELBW infants Seen prior to availability of

surfactant

Disruption of lung development Due to mechanical

ventilation/oxygen toxicity

Decreased septation Airway injury

Alveolar hypoplasia Inflammation
(Fewer & larger alveoli with Parenchymal fibrosis
reduced surface area)
Dysregulated development of Abnormal arterial vascularization
pulmonary vasculature resulting obliteration of vessels may occur.
in increased pulmonary
resistence
Old BPD New BPD
Epidemiology
• Approximately 15,000 new cases of BPD occur in
the United States.
• Incidence of BPD increases with decreasing
gestational age & birth weight.
• Infants <1250g birth weight are more susceptible.
• Icidence of BPD in VLBW babies vary from 15 to
50%.
Incidence of BPD
Birthweight (g) Incidence (%)

501-750 46

751-1000 33

1001-1250 14

1251-1500 6
Lung development & risk factors for
BPD

Baraldi E & Fillippone M. N Engl J Med 2007;357:1946-5

Risk factors

Monte LF, Silva Filho LV, Miyoshi MH, Rozov T. Displasia

broncopulmonar (bronchopulmonary dysplasia). J Pediatr (Rio J).
2005;81(2):99–110.
Bronchopulmonary Dysplasia in Preterm Neonates in a Level III
Neonatal Unit in India
Authors: Savita Bhunwal, Kanya Mukhopadhyay, Shalmoli
Bhattacharya, Pranab Dey and Lakhbir Kaur Dhaliwal
Source: Indian Pediatrics 2018;55:211-215
Results: Out of 250 neonates enrolled, 170 (68%) survived till day 28
and BPD developed in 19 (11.2%) infants. The mean gestation and
birth weight were significantly lower in infants who developed BPD.
Chorioamnionitis (clinical 5.3% vs 1.9%, P=0.375; and histological
37.5% vs 16.7%, P<0.001), patent ductus arteriosus (PDA)
(52.6% vs 8.9%, P<0.001), median (IQR) sepsis episodes [2 (2,3) vs 1
(1,2), P<0.001], invasive ventilation (84.2% vs 11.3%, P<0.001), and
duration of ventilation [56 (4) d vs 4 (5) d, P=0.001] were significantly
higher in infants with BPD. Serum MDA, SOD and Catalase levels
were comparable between the two groups.
Conclusion: Chorioamnionitis, PDA and sepsis were significantly
associated with BPD.
Source: American Journal of Respiratory and Critical Care Medicine
Volume 196 Number 3, August 1 2017

Measurements and Main Results: After adjusting for covariates, they

found that maternal smoking prior to preterm birth increased the odds of
having an infant with BPD by twofold (P = 0.02). Maternal smoking was
associated with prolonged mechanical ventilation and respiratory support
during the neonatal intensive care unit admission. Preexisting hypertension
was associated with a twofold (P = 0.04) increase in odds for BPD. Lower
gestational age and birth weight z-scores were associated with BPD.
Preterm infants who were exposed to maternal smoking had higher rates of
late respiratory disease during childhood. Twenty-two percent of infants
diagnosed with BPD and 34% of preterm infants without BPD had no
clinical signs of late respiratory disease during early childhood.
Risk factors for bronchopulmonary dysplasia in very low birth
weight newborns treated with mechanical ventilation in the first
week of life.
Cunha GS, Mezzacappa-Filho F, Ribeiro JD.
Journal of Tropical Pediatrics. 2005 Dec;51(6):334-40. Epub 2005
May 31.
Among the 86 very low BW newborns, 45 developed BPD. The univariate analysis showed
that besides BW and gestational age (GA), other factors such as FiO(2) > or = 0.60 (RR :
2.03; 95% CI: 1.4-2.94), PIP > or = 21 cm H(2)O (RR : 1.73; 95% CI: 1.12-2.65),
surfactant therapy (RR : 1.68; 95% CI: 1.14-2.48), fluid volume on day 7 >131 ml/kg/day
(RR : 1.81; 95% CI: 1.18-2.78), presence of PDA (RR : 1.95; 95% CI: 1.36-2.8) and
pneumothorax (RR : 1.71; 95% CI: 1.18-2.45) were associated to an increase in the risk of
BPD. When the variables were analysed concomitantly, using the multivariate logistic
regression model, the most important risk factors for the development of BPD were GA <
or = 30 weeks (RR : 2.76; 95% CI: 1.23-6.19), PIP > or = 21 cm H(2)O (RR : 1.92; 95%
CI: 1.04-3.54), fluid volume on day 7 >131 ml/kg/day (RR : 2.09; 95% CI: 1.14-3.85) and
presence of PDA (RR : 1.94; 95% CI : 1.03-3.65). The risk for BPD due to the association
of these four factors was 96.4%. Finally, it was observed that the most important risk
factors for BPD were prematurity, PDA and elevated levels of PIP as well as fluid volume.
 Pathogenesis
• Acute lung injury
Combination of O2 toxicity, barotrauma and volutrauma from
mechanical ventilation
Cellular & interstitual injury

Release of proinflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α)

Secondary changes in alveolar permeability and recruit inflammatory

cells into interstitial and alveolar spaces; Further injury from
proteases, oxidants, additional chemokines and chemoattractants
Pathogenesis

Alveolar development inturrupted and parenchyma is destroyed

leading to emphysematous change.

Sloughed cells & secretions not cleared adequately by damaged

mucocilliary transport system

Inhomogenous peripheral airway obstruction leading to

alternating areas of collapse & hyperinflation
Pathogenesis
• Chronic phase of lung injury
- Fibrosis and cellular hyperplasia from excessive release
of growth facor and cytokines.
- Pulmonary fluid retention (due to disruption of
interstitial fluid clearence)
- Airway muscularinization and hyperreactivity
- Decreased lung compliance, increased airway resistance,
air trapping and ventilation-perfusion mismatch
Clinical features
• Tachypnea
• Chest wall retractions and diffuse fine rales.
• Wheeze or prolongation of expiration
• Continued need for oxygen or ventilatory support
• Peripheral cyanosis
• Poor growth
• Use of excessory muscles of respiration
Contd.

• CVS: right ventricular heave, single S2 or prominent P2 ( cor

pulmonale)
• Abdomen: Palpable liver ( secondary to right sided heart failre
or lung hyperinflation)
Investigations
• ABG:
Hypoxemia (low O2)
Hypercarbia (high PCO2)
pH low (initially) and later normal with metabolic
compensation.
 CXR:

• In early description of BPD (Northway et al. 19670:

Stage I: Indistinguishable from severe RDS (1-3 days)
Stage II: Marked radioopacity of the lungs (4-10 days)
Stage III: Clearing of the radioopacity into a cystic, bubbly pattern ( 10-20 days).
Stage IV: Hyperexpansion, streaks of abnormal density and areas of emphysema
with variable cardiomegaly.
• New BPD:
stage II changes that may evolve if the condition progress.
• Electrocardiogram(ECG):
Right ventricular hypertrophy (Cor pulmonale).
Left ventricular hypertrophy ( Systemic hypertension).
• Echocardiogram: To exclude left to right shunt and
pulmonary hypertension
• Renal USG: Nephrocalcinosis.
 Infant pulmonary function test (iPFT):Infant pulmonary
function test (iPFT): increased respiratory system resistance
and decreased dynamic pulmonary compliance are hall marks
of BPD
• Decreased forced expiratory flow rate
• Increased functional residual capacity (FRC)
• Increased residual volume (RV)
• Increased RV/ total lung capacity
• S. Electrolytes:
↑ HCO3 (from CO2 retention)
Hyponatremia, hypokalemia or hypochloremia (Diuretic
therapy)
↑ BUN & creatinine ( Fluid restriction)
• CBC: Neutropenia or elevated WBC count in sepsis.
• Urinalysis: microscopic hematuria ( nephrocalcinosis from
prolonged diuretic treatment)
Management

 Goal:

• Minimize further lung injury (barotrauma and volutrauma, O2

toxicity, inflammation).
• Maximize nutrition
• Diminish O2 consumption.
Prevention of BPD
Antenatal:
• Prevention of prematurity and RDS: Improving prenatal care
& Antenatal corticosteroid
Natal:
• Delivery room care to avoid over-aggressive ventilation
during resuscitation.
Postnatal:
• Early surfactant replacement therapy
• Avoidence of mechanical ventilation and intubation with the
initiation of CPAP shortly after birth.
• Minimize exposure to O2 (SPO2 90-95%)
• Fluid restriction & Management of PDA
• Prevention and treatment of infection
Medications:
• Vitamin A: 5,000 IU IM three times weekly for the first 28
days reduced the incidence of CLD in ELBW infants by
10%. The impact on long term outcome is uncertain.
• Vitamin E: act as scavanger of free redicals although vit E
does not prevent BPD and high dose IV Vit E increase the
rate of sepsis.
• Caffeine citrate: in premature infants resulted in a significant
reduction in BPD with few side effects.
• Azithromycin: decrease the risk of developing BPD in infants
with documented Ureaplasma colonization or infection.
• Inhaled nitric oxide: controversial. Reduce pulmonary
vascular tone and diminish lung inflammation.
Results: Six studies involving 469 preterm infants were eligible for
the analysis. Macrolides when used prophylactically (4 studies) did
not show significant reduction in BPD (risk ratio, RR, 0.88, 95%
confidence interval, CI, 0.75–1.03), death (RR 0.89, 95% CI 0.79–
1.01) or in the composite outcome of BPD/death. Similarly, there was
no significant reduction in BPD (RR 0.64, 95% CI 0.31–1.31) or the
composite outcome of BPD/death (RR 0.41, 95% CI 0.05– 3.13), when
macrolides were used in Ureaplasma -positive infants. However,
prophylactic azithromycin therapy (3 studies) was associated with
significant reduction in BPD (RR 0.83, 95% CI 0.71–0.97; number
needed to treat, NNT, 10) and composite outcome of BPD/death (RR
0.86, 95% CI 0.77– 0.97; NNT 10).
Conclusion: This meta-analysis demonstrates prophylactic
azithromycin therapy was associated with statistically significant
reduction in BPD and the composite outcome of BPD/death in
preterm infants. However, given the limited information on
pharmacokinetics and potential harmful effects, further studies
should be done before routine use of azithromycin in the neonatal
Treatment of BPD
• Supplemental O2:
SPO2 90-95%,
<32 weeks 85% to 93%, >32 weeks 87% to 97%
PaO2>55mmHg
• Positive pressure ventilation:
Only when clearly indicated.
Low PIP at the expense of tolerating PCO2 50-60 mmHg
(permissive hypercapnea).
Nasal CPAP can be useful as an adjunctive therapy after
extubation
Treatment
• Fluid restriction: to 120 ml/kg is often required.
• Diuretics: to treat pulmonary fluid retention.
 Frusemide (1-2 mg/kg every 12 hours)
 Bumetanide (0.015-0.1 mg/kg daily or every other day)
 Chlorothiazide (20-40 mg/kg/day) and spironolactone (2
mg/kg/day)
• Bronchodilator:
 Β2 agonists- Salbutamol, albuterol.
 Anticholinergic agents- Ipratropium bromide
 Methylxanthine
Treatment
• Corticosteroids:
 Dexamethasone: Initiate at >7 days at 0.25 mg/kg twice daily for 3
days and then gradually taper by 10% every days for a total course of
42 days.
 Methylprednisolone
 Hydrocortisone: 5 mg/kg/day every 6 hours for 1 week and then
gradually tapered for the following 2-5 weeks.
 Prednisolone: 2 mg/kg/day orally twice per day for 5 days, then 1
mg/kg/day for 3 days and then 1 mg/kg/dose every other day for 3
doses ( To wean from O2 before discharge home)
• The purpose of this revised statement is to review current
information on the use of postnatal glucocorticoids to prevent
or treat bronchopulmonary dysplasia in the preterm infant and
to make updated recommendations regarding their use. High-
dose dexamethasone (0.5 mg/kg per day) does not seem to
confer additional therapeutic benefit over lower doses and is
not recommended. Evidence is insufficient to make a
recommendation regarding other glucocorticoid doses and
preparations. The clinician must use clinical judgment when
attempting to balance the potential adverse effects of
glucocorticoid treatment with those of bronchopulmonary
dysplasia. Pediatrics 2010;126:800–808.
There was no evidence that inhaling steroids compared to systemic
steroids prevented the primary outcome of death
or bronchopulmonary dysplasia. The number of days the baby needed
mechanical ventilation support or additional oxygen were increased in
infants who received inhaled steroids versus infants who received
systemic steroids. These outcomes were reported in both the trials.
The rate of patent ductus arteriosus (failure for the ductus arteriosus,
an arterial shunt in fetal life, to close after birth) was increased in the
group receiving inhaled steroids. There was a lower incidence of high
blood sugars in the inhaled steroid group compared with the systemic
steroid group. These secondary outcomes were reported in only one
trial (the larger trial). In a sub‐sample of 52 children at age 7 years
there were no differences in long‐term follow‐up outcomes between
the inhaled and the systemic steroid groups. in an even smaller
sample of 48 infants the outcome of 'ever diagnosed as asthmatic by
seven years of age' was significantly lower in the inhaled steroid
THE NEW ENGLAND JOURNAL OF MEDICINE; January 11, 2018
Volume: 378: issue 2, 148-157
Methylprednisolone, an alternative to dexamethasone in very
premature infants at risk of chronic lung disease.
André P, Thébaud B, Odièvre MH, Razafimahefa H, Zupan V, Dehan M,
Lacaze-Masmonteil T.
Intensive Care Medicine. 2000 Oct;26(10):1496-500.

RESULTS:
There were no differences between groups in the rate of survivors
without chronic lung disease. Infants treated with methylprednisolone
had a higher rate of body weight gain during the treatment period
(median 120 g, range 0 to 190, vs. 70 g, range -110 to 210, P = 0.01)
and between birth and the age of 40 weeks (median 1660 g, range
1170-2520, vs. 1580 g, range 1,040 to 2,120, P = 0.02). The incidence
of both glucose intolerance requiring insulin (0 % vs. 18 %, P = 0.006)
and cystic periventricular leukomalacia (2 % vs. 18%, P = 0.03) was
lower among methylprednisolone-treated infants.
CONCLUSION:
Our observations confirm methylprednisolone to be as effective as
dexamethasone and to have fewer side effects. A randomized control
trial is needed to further study the efficacy and safety of
methylprednisolone in very premature infants at risk of chronic lung
disease.
Ventilator strategy
• Volume targeted(3-5 ml/Kg)
• Permissive hypercapnea (55-65)
• Permissive hypoxia.(50 -80 mmHg)
• Minimum PIP,Ti & FiO2.
• High rate(40-60)
• Early weaning.
Newer options
• Recombinant superoxide dismutase.
• Dietary interventions: Omega-3 long chain polyunsaturated
fatty acid, L-citruline.
• Estradiol and Progesterone
• Erythropoietin
• Mesenchymal stem cell therapy
Outpatient Management

• Use of a multidisciplinary group or consultation

• Home oxygen to maintain saturations >90%
• Nutritional support
• Routine immunizations, including against influenza
• Respiratory syncytial virus prophylaxis
• Developmental follow up and intervention
Outcome
• Mortality: with severe CLD is ~25%. Main causes of death are
cor pulmonale, lower respiratory tract infection and sudden death.

 Long term complications:

• Respiratory: Recurrent infections, central apnea, bronchial

hyper-reactivity

• Cardiovascular: Pulmonary hypertension, Cor pulmonale,

bronchopulmonary shunts.

• Growth delay

• GI: Feeding difficulties, Gastroesophageal reflux, aspiration

• Associated conditions (but unlikely due to CLD):

Hearing loss

Developmental delay

Cerebral palsy

Intraventricular hemorrhage and white matter CNS damage.

Lex W. Doyle , Peter J. Anderson

Conclusions: Compared with children without BPD, those with BPD have
higher rates of adverse neurological outcomes, including motor,visual and
auditory problems. They exhibit low average IQ, more academic difficulties,
delayed speech and language development, more visual–motor integration
impairments and behaviour problems, and they have more attention
problems, memory and learning deficits, and executive dysfunction.
Subjects with BPD have worse respiratory function and more respiratory ill-
health than those of similar size and gestational age who did not have BPD.
As survival rates of ELBW and very preterm babies are increasing rapidly,
with no decrease in the rate of BPD in survivors, the increasing number of
children with BPD is going to add to the burden of neurological and
respiratory disease into later life. Reducing the rate of BPD remains one of
the biggest challenges in neonatal care.
Key message
• Bronchopulmonary dysplasia (BPD) is a condition that affects
preterm infants mostly born at <30 weeks, and its definition continues
to evolve.
• It results from damage to the lung caused by mechanical ventilation
and long term use of oxygen.
• Glucocorticoid , diuretics, and bronchodilator are used for respiratory
symptoms in BPD, although evidenced based strategies are lacking.
• BPD is a chronic respiratory condition that can lead to cardiovascular
disease and neurodevelopmental impairment.
Prevention:

• Prevention of premature delivery

• Minimize exposure to O2
• Early initiation of nasal CPAP reduce the need for intubation and
mechanical ventilation hence BPD.
• Fluid restriction & management of PDA
Thank you