Management of Severe BPD
PPHN
Medications

 Airways are free of epithelial
metaplasia, smooth muscle
hypertrophy and fibrosis
 Fewer, larger more simplified
alveoli
 Decreased septation (less
alveolar complexity)
 Dysregulated pulmonary
vascular development
New BPD: arrest of development of the small and
large airways *
Image: public domain
Hussain A, Human Pathology 1998;29:710-717
Coalson JJ, Seminars in Perinatology 2006;30:179-184
Coalson JJ, Path Chronic Lung dis, New York, Marcel Decker, 2000.
Jobe AJ, Pediatric Research 1999; 46(6):641

The phenotype depends largely on the stage of lung
development at the time of delivery.
Reprinted from Pharmacology and Therapeutics, Vol 114 (Kajekar
R, Pharmacol Therap 2007;114:129–145)
 Vasculogenesis parallels
alveolar/saccule
development
 Interstitial extracellular
matrix (scaffolding) also
develops during this period
 Thus, injury alters normal
lung development and
architecture

Established BPD
Established BPD :A
different disease
needing a different
approach to treatment
Evolving BPD

Maldistribution of ventilation in
Severe BPD
Fast compartment: low R, normal or high C
Slow compartment - high R, normal or low C

With advances in care, a more “severe” BPD phenotype has emerged…
Despite use of antenatal steroids and postnatal surfactant…
 More survivors
 More tracheostomies
 More home ventilation and complex care
 Outcomes occur across treatment modalities
 No obvious modality that prevents BPD
Baraldi E and Filippone M, NEJM, 2007
Jobe A, Bancalari E Bronchopulmonary Dysplasia 2001
Coalson JJ, Pathology of BPD 2006

4 Phases of BPD Management
Clinical Trajectory of severe phenotype BPD

Principles of chronic care
1. Minimal impact respiratory support
2. Optimal nutrition for growth and repair
3. Prevention of infection
4. Prevention of cor pulmonale
5. Optimal nutrition for growth and repair
6. Intensive neurodevelopmental assistance lead by a team of nursing,
OT, PT, massage and speech therapists

Pro-growth state
Inadequate respiratory
support
Inflammation
Unbalanced
fluid/nutrient supply
Stress
Infection/Illness
Improved
nutritional status
Respiratory
progress
Developmental
progress
Improved state
regulation
Linear growth
Parent
involvement/
Environment
Interdisciplinary
care
Barriers to achieving a
pro-growth state
Outcomes of a
pro-growth state
Logan JW, Curtiss J, et al. Ped
Resp Reviews 2018 (in press)

Transdisciplinary Model of Care
• Develop communication loops for mapping
progress with cares and developmental
activities
• Is the baby able to do age- matched
activities? What are the barriers?
• Does child have enough reserve?
Incorporate feedback on stability into PACE
of medical care plans/weaning
Abman SH, J. of Pediatrics 2017;181:12-28
Shepherd EG, J Perinatology 2012;32:33–38

An adequately supported infant
with severe BPD:
 Quiet and alert
 Good eye contact
 No evidence of resp distress
 Stable O2 saturations
 Good growth (linear)
Clinical exam is important!

BPD with PPHN: Emerging entity

PPHN: Components in BPD
• Dynamic ( reactive/ vascular) component: Depends of the number of
alveoli recruited, mechanics of ventilatory support, age of the baby,
exacerbating factors such as viral infections, atelectasis etc
• Fixed( interstitial) Component: Right ventricular pressure overload:
concentric hypertrophy of RV septal flattening Increased
pulmonary artery pressures

Risk factors for association of PPHN with BPD
• History of IUGR
• History of SGA status.
• Increased risk from 36 weeks - 52 weeks, when the developmental demands
of the infant require tolerance to more handling and PO feeding, and
therefore increased metabolic needs.

Screening ECHO
• At 36 weeks for all babies needing Fi02 >30%
• Findings
• RA enlargement
• Tricuspid regurgitation
• R to L shunting at PFO and/or PDA
• Septal flattening, interventricular septum at end-systole
• RV pressure/systemic pressure: round <50%,
• Flat = 50-100%, Bowing to LV ≥100%

Management: Dynamic Component
• Dynamic component: Needs to be addressed promptly
 Optimizing fluid management (Restrict to a goal : 130 ml/kg)
 Optimizing pH ( 7.25- 7.35)
 Oxygenation ( Zero tolerance to desaturations); Target sats > 95% at
all times
 Treat the precipitation factors:
Sepsis/dehydration/Aspiration/Agitation
 Sedation: Use with caution
Keslar et al 2001

Management: Fixed component
• Primarily responds only to medications: Slow to
reverse

BMC Pediatrics 2019; Choi et al

PPHN and Neurodevelopmental outcomes
Choi et al, BMC Pediatrics 2019

Al Ghanem et al,
Canada; JOP 2017
PPHN and Neonatal outcomes

Inhaled NO in animals with BPD
Causes:
Decreased airway muscle & resistance
Improved compliance
Decreased inflammation
Improved surfactant function
Protection against hyperoxic injury
Improved lung growth
Increased angiogenesis
Enhanced alveolar formation

Inhaled NO and Sildenafil

• More than 3000 preterm infants in at least
11 clinical trials
• Used for:
• Early respiratory failure < 3 days:
• rescue iNO for sick infants ------------ 7
trials
• routine iNO for intubated infants ---- 2
trials
• Late iNO (>3 days)
• To prevent CLD ------------------------- 2 trials
Clinical trials of iNO in preterm
infants

Mortality

2. Nutrition: Achieving a PRO-GROWTH State
• Balancing factors that promote growth while avoiding exposures that
interfere with it
• Achieving LINEAR growth correlates with both pulmonary and
neurodevelopmental outcomes.
• LINEAR growth is a helpful measure of balance in the
support/environment fit
Sanchez-Solis M, et al. Pediatr Pulmon 2016;51(9):936-42

3. Avoid / minimize
stress
• Minimize lab draws, loud noise, inconsistent
caregivers
• Cares with containment/comfort
• Encourage and support parent
comfort/involvement/touch and presence (bed in
room?)
• “Stress” and ICU environment leads to growth
suppression and limited ND gains
• Encourage kangaroo care, touch, family
recordings, containment w/ painful stimuli-
(encourage neuro-regulation)

Pharmacotherapy in Severe BPD

What are the target areas for drug therapy
Large airway disease
Small airway disease
Neural Control

Bronchodilators

Mechanism of Action
Decreases small airway resistance
Improve compliance
? Sustained benefit in sBPD

Clouse et al 2016

Ongoing trial….CHOP

Indications:
• ? Acute decrease in oxygen saturations: one time use to assess
response
• Active or audible wheezing appreciated, decreased breath sounds or
active exhalation

Diuretics

Mechanism of Action

• In preterm infants > 3 weeks of age with CLD, a four-week treatment
with thiazide and spironolactone improved lung compliance and
reduced the need for furosemide.
• Thiazide and spironolactone decreased the risk of death and tended
to decrease the risk for remaining intubated after eight weeks in
infants who did not have access to corticosteroids, bronchodilators or
aminophylline.
• However , there is little or no evidence to support any benefit of
diuretic administration on need for ventilatory support, length of
hospital stay, or long-term outcome in patients receiving current
therapy.
Brion LP et al 2002
Use of distal diuretics for established or evolving CLD

• The only loop diuretic used in the studies that met the selection
criteria was furosemide
• In preterm infants < 3 weeks of age developing CLD, furosemide
administration has either inconsistent effects or no detectable effect.
• In infants > 3 weeks of age with CLD, a single intravenous dose of 1
mg/kg of furosemide improves lung compliance and airway resistance
for one hour. Chronic administration of furosemide improves both
oxygenation and lung compliance
• No reports on long term outcomes or survival available
Brion LP et al 2002
Use of loop diuretics for established or evolving CLD

Summary
• Insufficient data to recommend routine use of loop diuretics but may
be used in a case to case basis
• Diuretics may help to reduce the need of excessive fluid
restriction(<130 ml/ kg/ day) and potentially avoid nutritional
deficiencies

Nebulized diuretics

J Pediatr Pharmacol Ther 2011

Glucocorticoids
• Systemic: Dexa/ Hydrocortisone
• Inhaled: Budesonide

Low-Dose Dexamethasone Facilitates Extubation Among Chronically
Ventilator-Dependent Infants: A Multicenter, International, Randomized,
Controlled Trial. DART
Low-dose dexamethasone > 7 days PNA
facilitated extubation; Doyle et al 2006

Late steroids: Cochrane 2009
• Late >7days
• 19 trials, n=1345
• Reductions in BPD (28%), extubation failure, home oxygen therapy,
death (at day 28)
• Trend to increase CP offset by trend to increase death before late
follow up in the control group
• Benefits may not outweigh

Halidey L et al Pediatrics March 2018

Hydrocortisone for BPD
Rademaker KJ, Arch. Dis. Child. Fetal Neonatal Ed. 2008

Long-TermEffectsof InhaledBudesonide forBronchopulmonary
Dysplasia ( Inhaled steroids vs Placebo)
NeJM 2018

Long-TermEffectsof InhaledBudesonide for
BronchopulmonaryDysplasia

Few studies on Established BPD
Haliday et al 2014

Best to avoid Systemic steroids
unless…

Airway Edema and Planned Extubation
Peri extubational Dexamethasone, for infants with history of failed
extubation attempts, or known to have significant airway edema with
stridor following a planned extubation.
• 0.5 mg/kg/dose (max dose 10 mg flat dose) IV q 8 hours x 3 doses
• First 2 doses given prior to extubation
• Third dose to be given following extubation
• Consider maximum dose delivery of 2 mg/kg for therapy course

Exacerbation of RAD/BPD
• Prednisolone when optimal medical management has failed to
alleviate symptoms.
• Prednisolone burst, 2 mg/kg PO/FT once 24 hours later,
0.5mg/kg/dose PO/FT, q 12 hours, for 4 days
• Hydrocortisone stress dose may be used with weaning protocol over
next few days
• Methyl Prednisolone is optional

Stress dosing:
• For babies who have been on steroids for >2 weeks? And undergoing
either of the following
a. Elective surgery
b. Emergency surgery
c. Emergency interventions
d. Systemic sepsis
e. Exacerbations?