Evolution and management strategies in BPD

1. Dr. Saima F. Khan
BRONCHOPULMONARY DYSPLASIA

2. DEFINITION
• First described by Northway (1967)- disorder which
resulted from effects of oxygen and mechanical
ventilation in premature infants with severe RDS. Need
for oxygen at 28 days was added.
• Subsequently redefined using oxygen requirement at
36 weeks PMA, ventilator requirements and radiologic
features.

3. DEFINITION
Earlier definitions do not account for –
• Changes in population at risk – increased survival at
earlier GA ( <30 weeks or b.w. <1000g)
• Increased incidence of milder forms of BPD due to
advances in neonatal management – surfactant, AN
steroids, gentler ventilation.

4. NICHHD Criteria - 2003

5. PHYSIOLOGIC TEST FOR DIAGNOSIS OF BPD
• Infants at 35 to 37 weeks PMA receiving mechanical ventilation,
continuous positive airway pressure, or >30% O2 with saturation
of <96% have BPD
• Infants receiving <30% O2 or >30% O2 with saturation of >96%
tested for O2 need
• — O2 progressively decreased gradually to room air
• — No BPD if saturation is >90% in room air for 30 min
Walsh MC et al. Impact of a physiologic definition of bronchopulmonary
dysplasia rates. Pediatrics. 2004
Evaluated across 17 NICHHD centres – incidence of BPD reduced from 35% to 25% -
importance of standardized definition of BPD

6. INCIDENCE
• Study of 18,000 VLBW infants 1997- 2002
• According to birth weight
• 1251g – 1500g: 6%
• 1001g – 1250g: 14%
• 751g – 1000g: 33%
• 501g – 750g: 46%

7. INCIDENCE
• No Indian database
• Study from PGI -2002
< 1000 grams---50%
1000-1249 g---8.1%
1250-1499 g---2.3%

8. PATHOLOGY

9. ETIOLOGY - MULTIFACTORIAL
• Prematurity –
• Most important factor
• Lung most susceptible to damage during saccular stage of
development – 23 – 32 weeks gestation
• Poorly developed airway supporting structures, surfactant
deficiency, decreased compliance, underdeveloped antioxidant
mechanism, inadequate fluid clearance

10. PATHOGENESIS

11. NEW VS OLD BPD
“New” BPD Classic / “Old” BPD
Surfactant treated ELBW infants
Disruption of lung development
Decreased septation
Alveolar hypoplasia
( fewer and larger alveoli with reduced
surface area)
Dysregulated development of pulmonary
vasculature resulting in increased pulmonary
resistance
Airway injury and inflammation less
prominant
Seen prior to availability of SRT
Due to mechanical ventillation/ oxygen
toxicity
Airway injury
Inflammation
Parenchymal fibrosis
Abnormal arterial vascularization and
obliteration of vessels may occur
May be seen in surfactant treated infants
with severe BPD. Changes of “old” BPD
superimposed on characteristic features of
“new” BPD

12. MECHANICAL VENTILATION
• Major role of aggressive mechanical ventilation in pathogenesis
of BPD
• Primarily due to large tidal volumes that over distend the airway
and airspaces (volutrauma) rather than increased airway
pressures.
• Acute lung injury results from inflations that are close to the
maximum lung volume of small immature lungs
• Increasing risk of BPD with decreasing PCO2 – measure of
aggressive ventilation
• Increased use of non-invasive support / avoidance of high tidal
volumes on mechanical ventilation – evolution of milder forms of
BPD ( new BPD)
• Even a small no. of large inflations soon after birth can adversely affect surfactant
deficient lungs. Animal studies show that at 4 hours of life bagged lungs had lower
inspiratory capacity, lesser no. of well expanded alveoli, were more difficult to
ventilate, and more widespread histopathologic damage as compared with controls.
Björklund LJ et al. Manual ventilation with a few large breaths at birth compromises the therapeutic effect of
subsequent surfactant replacement in immature lambs. Pediatr Res 1997.

13. OXYGEN TOXICITY
• Cellular damage caused by overproduction of cytotoxic reactive oxygen
metabolites
• Immature antioxidant system in pretetm neonate due to –
• Nutrient deficiencies ( Vit. A & E, Fe, Cu, Zn, Se )
• Immature antioxidant enzyme systems ( superoxide
dismutase, catalase, glutathione peroxidase, glutathione-S-
transferase )
• Manar MH et al.Association of glutathione-S-transferase-P1 (GST-P1)
polymorphisms with bronchopulmonary dysplasia. J Perinatol 2004
• Upregulation of this system seen in preterm infants with BPD
• Exact level or duration of unsafe exposure not known.

14. INFECTION
• Postnatal
• Sepsis associated with increased risk of BPD
• Candidemia has highest risk.
• Lahra Mm et al. Intrauterine inflammation, neonatal sepsis, and chronic
lung disease: a 13-year hospital cohort study. Pediatrics 2009.
• Rate of BPD increased when sepsis present in conjunction with a symptomatic PDA
(OR 48.3) as compared with PDA alone (OR 6.2) or sepsis alone (OR 4.4)
• Rojas MA et al. Changing trends in the epidemiology and pathogenesis of
neonatal chronic lung disease. J Pediatr 1995

15. PRENATAL- CHORIOAMNIONITIS
• Unclear
• Antenatal infection has been suggested as a risk factor in development of BPD
• Based on Inc. Conc. Of proinflammatory cytokines (IL-6, IL-1β and IL-8) in amniotic fluid
that cause lung injury and arrest of lung growth
• U. urealyticum causes sustained dysregulated inflammatory response – impairs lung
development - increased BPD
• Lowe J et al. Association between pulmonary ureaplasma colonization and
bronchopulmonary dysplasia in preterm infants: updated systematic review and
meta-analysis. Pediatr Infect Dis J 2014
• Conversely, a retrospective study of preterm infants (<29 w) admitted to a neonatal unit
from 2000-2006, reported decreased risk of BPD, risk of combined outcome of BPD and
death, and evidence of fetal inflammatory response in infants with histologic
chorioamnionitis than infants without HC.
• Plakkal N et al. Histological chorioamnionitis and bronchopulmonary dysplasia: a
retrospective cohort study. J Perinatol 2013

16. INFLAMMATION
• Presence of proinflammatory and chemotactic factors
• Complement activation
• Increased vascular permeability
• Protein leakage
• Neutrophil mobilisation into interstitial and alveolar space
• Release of reactive oxygen radicals, elastase, collagenase by activated
macrophages causing lung injury
• Development of BPD may begin before birth in some infants through intrauterine
exposure to proinflammatory cytokines / chorioamnionitis – controversial

17. GENETICS
• Nickerson found a positive family history of asthma in 77% of infants with
RDS who subsequently developed BPD, compared with only 33% who did
not .
• Clark and associates found that only infants with HLA-A2 developed BPD.
• Correlation of developing BPD more in monozygotic than dizygotic twins
• Lavoie PM et al. Heritability of bronchopulmonary dysplasia, defined according to
the consensus statement of the national institutes of health. Pediatrics 2008.
• Conflicting results from other studies.

18. OTHER POTENTIAL FACTORS
• Late surfactant deficiency – studies suggest that premature infants who require
continued ventilatory support have transient surfactant dysfunction. More trials for
high dose surfactant vs low dose surfactant or surfactant with iNO vs iNO alone and
late surfactant with iNO prevents BPD.
• Impaired angiogenesis – growth of lung blood vessels promotes alveolar growth
• Elevated endostatin (antiangiogenic growth factor) levels in cord plasma associated
with BPD in VLBW infants
• Preeclampsia – two times risk of BPD, suggest that factors that trigger maternal
endothelial dysfunction are transferred to infants
• Eriksson L et al. Prenatal inflammatory risk factors for development of
bronchopulmonary dysplasia. Pediatr Pulmonol 2014.
• Bombesin- like Peptides from pulmonary neuroendocrine cells important in lung
growth and maturation – elevated urine BLP in first 4 days ass with increased risk of
BPD

19. CLINICAL FEATURES
• Variable
• Tachypnea, retractions, crepts and ronchi
• Patients with severe BPD are hypoxemic and hypercapnic d/t
• Decreased tidal volume
• Increased airway resistance
• Decreased compliance
• Uneven airway obstruction leading to hyperinflation
• Increased vascular resistance

20. CHEST RADIOGRAPH
A: 25w at birth – normal to low lung
volume
B: two weeks later, which
shows a coarsened interstitial
pattern and diffuse haziness-
atelectasis / inflammation /
pulmonary edema
C: 5 weeks –further
coarsening, hyperinflation.
Streaky densities or cystic
areas may be seen due to
fibrotic changes.

22. OLD BPD – 4 DISTINCT STAGES DESCRIBED BY
NORTHWAY
Stage 1
Hyaline membrane.
Alveolar and interstitial
oedema.
Necrosis of bronchial
mucosa.
Stage 2
Areas of emphysema
Atelectasis
Areas of necrosis and repair
of bronchial mucosa.
Stage3
Cystic areas with
hyperinflation.
Bronchial metaplasia and
hyperplasia.
Interstitial oedema.
Stage 4
Hyperinflation,
Interstitial streak densities
Flatter chest

23. • Infants with new BPD show only haziness reflecting diffuse loss
of lung volume or increased lung fluid.
• Occasionally they have dense areas of segmental or lobar
atelectasis or pneumonic infiltrates, but they do not show severe
over inflation.

24. CLINICAL COURSE
• ELGAN study – multicenter prospective study 2002-2004 – 1340
infants < 28w
• First 2 weeks of postnatal life – 3 clinical pulmonary courses with
different rates of BPD
1. Persistent lung dysfunction (40%) – consistent requirement of FiO2
>0.25 – 2/3rd developed BPD
2. Deterioration of lung function (40%) – increase of FiO2 requirement
>0.25 at 14 days of age – ½ developed BPD
3. No / minimum lung dysfunction (20%) – no consistent need of FiO2
>0.25 – 17% developed BPD
• Laughon M et al. Patterns of respiratory disease during the first 2
postnatal weeks in extremely premature infants. Pediatrics 2009

25. CLINICAL COURSE
• Most infants improve over 2 – 4 months – weaned to nCPAP – HFNC –
Supplemental oxygen – room air
• Some develop severe BPD – marked instability during forst few weeks after
birth with swings in O2 saturation, intermittant episodes od acute
deterioration requiring increased ventilator support. – improves slowly after
4- 6 weeks, rarely beyond 6 m
• Pulmonary hypertension – important complication, a/w increased mortality.
• 18% of 145 ELBW babies had PH at 4 weeks on ECHO. 96% had associated
BPD (as defined by o2 req at 36w PMA)

26. PREVENTION OF BPD
• BEFORE BIRTH
• Prenatal antibiotics and infection prevention
• Prompt treatment of chorioamnionitis with antibiotics.
• ANTENATAL STEROIDS
• Use of antenatal steroids in mothers at risk for delivering a premature infant
reduces the incidence of neonatal deaths and RDS but does not reduce the
incidence of CLD
• Cochrane Database Syst Rev 2006

27. PRACTICES IN DELIVERY ROOM
• The goal in babies being resuscitated at birth,whether born at term or
preterm, should be an oxygen saturation value in the interquartile range of
preductal saturations
• These targets may be achieved by initiating resuscitation with air or a
blended oxygen and titrating the oxygen concentration to achieve an SpO2 in
the target range using pulse oximetry
• If blended oxygen is not available, resuscitation should be initiated with air
• If the baby is bradycardic (HR 60 per minute) after 90 seconds of
resuscitation------ increase to 100 % o2.
• Use lower target inflation pressure range between 20- 25 cm h2o

29. VENTILATORY STRATEGIES
• Continuous positive airway pressure (CPAP):
• Early initiation of nasal CPAP has been shown to reduce the need for
intubation and mechanical ventilation

30. NIPPV
• Nasal intermittent positive pressure ventilation (NIPPV) is a method of augmenting
NCPAP by delivering ventilator breaths via nasal prongs
• NIPPV reduces the incidence of symptoms of extubation failure and need for
reintubation within 48 hours to one week more effectively than NCPAP; however, it
has no effect on chronic lung disease or mortality.
• Synchronisation may be important in delivering effective NIPPV. The device used to
deliver NIPPV may also be important.
• Nasal intermittent positive pressure ventilation (NIPPV ) versus
nasal continuous positive airway pressure (NCPAP) for preterm
neonates after extubation. Cochrane Database of Systematic
Reviews September 2014

31. MECHANICAL VENTILATION
• Small tidal volumes preferable
• Maintaining PEEP of 5-7 cm H2O minimize atelectasis ,pulmonary edema in
BPD
• Slightly prolonged inspiratory duration sometimes required for uniform lung
inflation – 0.4 – 0.5 s
• Ongoing pulseox, intermittent blood gas PCO2
• Prolonged ventilation may require tracheostomy

32. SYNCHRONIZED MECHANICAL VENTILATION &HIGH FREQUENCY
POSITIVE PRESSURE VENTILATION (HFPPV)
• During synchronized mechanical ventilation, positive airway pressure and
spontaneous inspiration coincide. If synchronous ventilation is provided,
adequate gas exchange should be achieved at lower peak airway pressures,
potentially reducing baro/volutrauma, air leak and bronchopulmonary
dysplasia.
• Synchronous ventilation can potentially be achieved by manipulation of rate
and inspiratory time during conventional ventilation and employment of
patient triggered ventilation.
• Compared to conventional ventilation, benefit is demonstrated for both
HFPPV and triggered ventilation with regard to a reduction in air leak and a
shorter duration of ventilation but no difference in incidence of BPD
• Synchronized mechanical ventilation for respiratory support in
newborn infants,Cochrane Neonatal Group2008

33. OXYGEN
• Required to ensure adequate tissue oxygenation and avoid alveolar hypoxia
– may lead to pulmonary vascular resiatance and cor pulmonate in infants
with BPD
• Even small changes may cause ROP / pulmonary inflammation- pulmonary
edema.
• In preterm infants, targeted oxygen saturation goal between 90 and 95
percent (Grade 2B)

34. • Permissive hypoxemia - Accepting lower oxygen saturation values is
associated with decreased incidences of CLD and ROP
• In the BOOST II & SUPPORT trials infants in the lower SpO2 group
had higher mortality were less likely to develop ROP but there was no
difference between the two groups regarding the risk of BPD.
• COT no difference in mortality / no difference in BPD
• Spo2 b/w 85-93% ---- < 32 wks
• 87-94%---->32 wks

35. PERMISSIVE HYPERCAPNEA
:
• Hypocapnia that occurs during assisted ventilation is a risk factor for BPD.
• Co2 targets of 45-55 mm hg are now recommended in order to reduce the
days of ventilation. (upto 65 acceptable )

36. NUTRITION
• Metabolic rate and energy expenditure are elevated in BPD
• Infants developing BPD require 20 to 40% more calories than their
age-matched healthy controls.
• caloric requirement varies from 120 to 150 Kcal/kg/day
• Protein intake of 3.5 – 4 g/kg/day is needed
• Enteral feeding is often delayed in these infants due to gastrointestinal
immaturity, parenteral nutrition with proteins and lipids should be
initiated as soon as possible after birth and fortified human milk when
possible.
• In fluid restricted infants fortified EBM alternate with preterm formula
to increase calories
.

37. FLUID RESTRICTION
• Restricted fluid intake to avoid pulmonary edema and improve pulmonary
function – reducing risk of mortality and BPD
• Restricted versus liberal water intake for preventing morbidity and
mortality in preterm infants. Cochrane Database Syst Rev 2008
• Adequate nutrition must be provided
• modest – 140- 150 ml/kg/day
• Severe – 110 – 120 ml/kg/day- milk should be supplemented to ~ 30 cal/oz,
iron and vitamins- pediatric nutritionist.

38. PHARMACOLOGICAL STRATEGIES
• EXOGENOUS SURFACTANT
• Early selective surfactant administration given to infants with RDS
requiring assisted ventilation leads to a decreased risk of acute
pulmonary injury and a decreased risk of neonatal mortality and
chronic lung disease compared to delaying treatment of such infants
until they develop worsening RDS.
• Early versus delayed selective surfactant treatment for
neonatal respiratory distress syndrome. Cochrane Neonatal
Group, 2012
• Significant decrese in the incidence of BPD in infants born at or after
30 weeks.

40. CORTICOSTEROIDS
• inflammation ----pathogenesis of BPD
• Two meta-analyses have divided these trials based upon the
timing of administration and their focus on either prevention or
treatment of established bronchopulmonary dysplasia (BPD)
• 1. administered glucocorticoid therapy up to and including seven days
of age to preterm infants at risk for BPD
• 2. administered dexamethasone to infants with evolving or established
chronic lung disease who were greater than seven days of life
• Cochrane Database Systematic Review 2014

41. • 1. Results showed that postnatal glucocorticoid therapy compared with placebo was
associated with earlier extubation and decreased incidence of BPD both at 28 and
36 weeks postmenstrual age (PMA). There were no differences in mortality or in the
proportion of survivors discharged home on oxygen.
• 2. Results showed that postnatal glucocorticoid therapy compared with placebo
reduced mortality at 28 days of age, but not at time of discharge. In addition, late
administration of glucocorticoid therapy was associated with a lower extubation
failure rate, incidence of BPD at 28 and 36 weeks PMA, and discharge on home
oxygen.

42. • Early glucocorticoid administration was associated with increased risk of cerebral
palsy and abnormal neurological examination at long-term follow-up. Late
administration was associated with trends in increased cerebral palsy or abnormal
neurological examination that were partly offset by trends in decreased mortality
• Short-term adverse effects -
● Hyperglycemia
● Hypertension
● Gastrointestinal bleeding
● Gastrointestinal perforation
● Infection
● Hypertrophic cardiomyopathy

43. DOSE
• Several cohort studies have reported an increasing risk of neurological impairment
with higher doses of glucocorticoid therapy
• In the EPICure study (a large English prospective cohort study of preterm infants
born <26 weeks gestation), postnatal glucocorticoid therapy was associated with an
increased risk for cerebral palsy (CP) in a dose-dependent fashion.
• Hydrocort vs Betamethasone – unclear.

44. 2010 REVISED AMERICAN ACADEMY PEDIATRICS
(AAP) POLICY STATEMENT
• In the absence of data from randomized control trials (RCT), high-
dose dexamethasone (about 0.5 mg/kg per day) cannot be recommended in the
management and prevention of BPD.
• Data are insufficient to make a recommendation in the use of low-
dose dexamethasone (<0.2 mg/kg per day) in the management of BPD.
• Data are insufficient to recommend early treatment with low-
dose hydrocortisone treatment (1 mg/kg per day) in the first two weeks of life, although
there may be a subpopulation of patients that may benefit from such therapy.
• Data are insufficient to recommend the use of higher dose hydrocortisone (3 to
6 mg/kg per day) after the first week of life in the management of BPD.

45. • select population of preterm infants in whom the benefits outweigh the risks of
postnatal glucocorticoids?
• Use of systemic glucocorticoid therapy for infants greater than two to three
weeks of age with severe BPD who require sustained ventilatory and oxygen
support - primary goal should be extubation
• Use of hydrocortisone (starting dose of 5 mg/kg per day) rather than
dexamethasone (Grade 2B) suggested
• clinical response (defined as a decrease in respiratory support) is typically seen
on the second or third day following initiation of treatment
• If response – treat with this dose for 24 – 48 hours f/b tapering dose for 7-10
days
• Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an
alternative to dexamethasone? Acta Paediatr 2003

46. DIURETIC THERAPY
• MOA: decreases interstitial and peribronchial fuid--- dec resistance and
improves compliance
• Thiazide diuretics – short term improvement
• Loop diuretics – chronic(PO/IV) awa single iv dose use in >3 weeks infants
improved pulmonary mechanics- hyponatremia, hypokalemia,
nephrocalcinosis, ototoxicity.
• Clinical/radiographic features of pulmonary edema in an infant with evolving
or established BPD
• Infants >2-3 weeks who remain ventilator dependent despite modest fluid
restriction – chlorthiazide 20-40 mg/kg/d

47. ROLE OF VITAMIN A
• Vitamin A ---integrity of respiratory tract epithelial cells.
• Very preterm infants are relatively deficient in vitamin A which has been
shown to associated with CLD.
• Vitamin A appears to be beneficial in reducing death or oxygen
requirement at one month of age and oxygen requirement at 36
weeks' postmenstrual age
• Cochrane Neonatal Group,2011
• 5000 units three times a week for 4 weeks from birth though oral absorption
reported to be satisfactory
• Vit E – antoxidant, no role in prevention of bpd

48. BRONCHODILATORS
• Routine use not recommended (1B)
• Reserved for acute resp decompensation

49. ACUTE EXACERBATIONS
• A/w infectios
• Severe airway rectivity
• Pulmonary air leaks
• Increased pulmonary edema
• ET tube displacement
• Tracheomalacia

50. LOOK FOR-
• Weight and fluid balance
• Lung examination – ronchi, decreased / absent breath sounds
• CXR – infection , pulmonary edema, air leak, et displacement
• Intermittent / single dose furosemide for acute worsening in ventilator dependent infants
– elctrolyte monitoring/ supplementation
• VAP
• Lab tests- cbc, ABGA,

51. CHRONIC COMPLICATIONS
• PAH
• Systemic HTN
• Neurodevelopmental delay
• Vision and Hearing
• Left ventricular hypertrophy

52. DETECTION OF COMPLICATIONS
• BP monitoring
• ECHO – 36-37 weeks
• Developmental screening
• Serial eye examinations
• Hearing screen

53. THANK YOU