summer conference on neonatology avignon – sept. 2017 … · 2017. 11. 16. · 31-50% 2...
TRANSCRIPT
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Summer Conference on NeonatologyAvignon – Sept. 2017
Postnatal Risk Factors for BPD
Alan H. Jobe, MD, PhD
Cincinnati Children’s Hospital
University of Cincinnati
Cincinnati, Ohio
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Conflicts of Interest DeclarationSource: Purpose:
Grants B&M Gates Foundation Antenatal steroid studies
GSK (Matt Kemp) Steroid Pharmacokinetics
Gifts for Research Chiesi Surfactant
Merck Betamethasone
Consulting B&M Gates Foundation Infant mortality in low resource environments
Chiesi New treatments for BPD
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The Big Picture – Developmental Exposures that Degrade Lung Function in Later life
9 mos
Conception
Preconceptional
Exposures
Fetal
Exposures
Birth
Early Childhood
Exposures
Compounding Effects: Pre-conceptional + Fetal + Early
Childhood – Single Exposure – Different Exposures
Outcome
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Fetal Lung Development/Injury
- Prematurity
- Inflammation
- SGA
- Induced maturation, ANS
Injury
Repair
“Normal”
BPD
Oxygen
Inflammation
Ventilation
Fetal
Events
Resuscitation
Injury
Ongoing Injury Outcome
Months Minutes Months Years
What is BPD?
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BPD Pathogenesis - Complex
Wright & Kirpalani, Pediatrics, 2011
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Lung
Development
Injury
Repair
“Normal”
BPD
BPD is a Collision of 3 Programs
• Genetics
• Developmental Programming – epigenetics
• Stem cell populations
• Preconditioning to modulate response to a stimulus
• Systemic immune modulation
• Postnatal drug effects
• Nutrition
• Microbiome at Birth
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BPD by NIH Workshop Definition
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Prediction of BPD by Postnatal Age
• Postnatal risk factors• Gestational age
• Birth weight
• Sex
• Race and ethnicity
• Respiratory support
• FiO2
at 6 ages after birth
*Prediction improved with postnatal age
Web based model: https://neonatal.rti.org
Laughon, et al., AJRCCM, 2011
https://neonatal.rti.org/
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FiO2 to Day 14, and Frequency of BPD in 1340
Infants with GA
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A Brief Summary of the Clinical Landscape for Infants with GA
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What type of BPD do I want to prevent / treat?
• BPD is a continum of severity from “normal” lungs of VLBW infants at term to death before 36 weeks of respiratory failure.
• Definitions do not capture severity well.
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Proportionate Mortality at Postnatal
Ages for 22-28 Week GA Infants
Patel, et al., NEJM, 2015
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Conclusions First:
• Definition of BPD confounds insights into pathophysiology
• Variability in antenatal/postnatal exposures in infants confounds single therapies derived from animal models
• BPD in VLBW infants is much more complex than any of the animal models.
• Preconditioning phenomena contribute to variability in infants.
Animal Models of Pathophysiology
of BPD
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Elements of BPD that are the Focus of Animal Model Research
• Pathology• Septation abnormalities/alveolar simplification
• Microvascular injury and attenuation
• Pulmonary hypertension
• Primary Causes of Pathology• Oxygen
• Ventilation
• Inflammation
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Animal Models of BPDIntervention Weakness
Term rats and
mice
Preterm sheep
Preterm
monkeys/baboons
O2 or bleomycin causes
inflammation, septation
inhibition, and vascular
injury/pulmonary
hypertension
Can test mechanistic
pathways
Inexpensive and available
Can ventilate and expose to
oxygen – mimic clinical care
Can use fetal exposures
Can ventilated and expose to
oxygen – mimic clinical care
Primarily an oxidant injury
Chronic models are expensive
with limited availability
Acute and chronic models are
very expensive with very
limited availability
Ethical constraints
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Drug Therapies that Reverse Most of the Abnormalities of BPD in Animal Models
Agent/Intervention Clinical
Testing/Effectiveness
Growth factors – VEGF, KGF
Hepatocyte growth factor, anti-bombesin
Cox-2 inhibitors
Anti-TNF- antibodies
Elafin – elastase inhibitors
-catenin inhibitor
Stem cells
NT
No effect – not directly tested
NT
NT
NT
Possibly effective
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Drug Therapies that Reverse Most of the Abnormalities of BPD in Animal Models
Agent/Intervention Clinical
Testing/Effectiveness
Anti-inflammatory
Glucocorticoids
Granulocyte inhibitors –
CINC-1, Anti-CD-18, IL-1ra
Block Macrophages
Decrease BPD
NT
NT
*NT = Not Tested
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Drug Therapies that Reverse Most of the Abnormalities of BPD in Animal Models
Agent/Intervention Clinical
Testing/Effectiveness
Antioxidants -
Vitamin A
N-acetyl Cysteine
Small MW antioxidants – baboons
Peroxynitrite decomp. catalyst
Superoxide Dismutase
Inhaled NO- rodents, sheep, baboons
Modest decrease in BPD
No benefit
NT
NT
Possible benefit
No benefit
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Oxygen is harmful, but injury is decreased in:
• Newborns relative to adults
• Animals exposed to inflammation
• Animals pre-exposed to oxygen
• Corticosteroid treatment
Injury is increased by:
• Calorie deprivation
[All associations in animal models]
Sensitivity to oxygen is probably quite
variable in preterm infants
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Thoughts About Targeted Treatments for BPD Based on Animal Models
• Multiple pathways can be manipulated in animal models to decrease the BPD phenotype:• Block inflammatory cell recruitment to lung/inflammation• Antioxidants• iNO• Growth factors• Others
• Positive clinical results: Vit A and corticosteroids
• Targeting specific pathways may be ineffective (complex pathophysiology)
• Antioxidants may be of marginal benefit – corticosteroid effects are proof of principal that inhibition of inflammations can decrease BPD.
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Definitions of BPD - Clinical
• Supplemental O2 at 28d or for 28d
• Supplemental O2 at 36 wks (Shennan)
• Mild – 28d O2• Moderate – O2 use at 36 wks
• Severe - >30% O2 + Positive
Pressure
• Challenge of O2 need or Flow at 36 wks
NIH
Workshop
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Limitations to Definitions –“Facts” often Overlooked
• Preterm infants are abnormal.
• The lungs of VLBW infants develop abnormally. –independent of BPD
• The lungs of VLBW infants are abnormal at 36 weeks / term. – independent of BPD
• Comparison populations for incidence of BPD are abnormal – no “control” group.
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Problems with Definitions
• 36 wks is an arbitrary time on a continuum of disease.
• Defined by O2 or positive pressure – not pathophysiology, lab, radiology.
• Diagnosis occurs months after opportunities to prevent or treat.
• Patients are unclassifiable with newer therapies. • High flow nasal cannula – No O2• Very low flow - 100% O2
• Diagnosis poorly predicts long term outcomes.
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Poindexter, Annals ATS, 2015
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Severe Chronic Respiratory Disease of Prematurity
Primary Abnormalities:
• Parenchymal injury
• Airway injury
• Control of breathing abnormalities
• Pulmonary hypertension
• Others – Aspiration
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3 Populations to ConsiderRelative to a BPD Diagnosis
1. Infants that die of RDS + BPD before 36 wks.
2. Infants with “severe” BPD.
3. Infants that die with BPD after 36 wks
• Target populations for innovative therapies
• Who are these infants and how many are there?
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Associations of 6 Traditional Bronchopulmonary Dysplasia (BPD) Definitions With Adverse Outcomes at 18 to 21 Months of Age
Serious respiratory morbidity
Serious neurosensory impairment
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Association of Oxygen Use or Respiratory Support at 34 to 40Weeks’ Postmenstrual Age With Adverse Outcomes at 18 to 21 Months of Age
Serious respiratory morbidity Serious neurosensory impairment
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New Definitions of BPD
• International Neonatal Consortium – INC
• NICHD Workshop
• PROP Cohort – Judy Aschner
• Others
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Variables that Contribute to a BPD Diagnosis
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Variables that Contribute to a BPD Diagnosis
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Scoring for BPD at 36 or 40 weeks
Oxygen Use Respiratory Support
21% 0 None 0
21-30% 1 CPAP/Nasal Cannula 1
31-50% 2 Non-invasive Vent 2
>50% 3 Invasive Vent-PIP 20 4
My unvalidated attempt to quantify severity
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Conclusion: No BPD definition will meet all needs
• Define a population of interest
• Define the endpoints of interest
• Define a 36 or 40 week outcome –Primary outcome
• Define a 1 year respiratory outcome –Secondary outcome
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Summary of Recent Early Steroid Trials:
Inhaled SteroidBassler - 2015
10 day Hydrocortisone
Baud - 2016
Steroid + SurfYeh - 2016
Steroid Exposure Relatively targeted to lung, but higher dose
Very low dose,but systemic
Targeted to lung
Duration of Treatment Off support or 32 weeks
10 days Surfactant Treatments
Death Increased 3.3% Decreased 5 % Decreased 3 %
BPD Decreased 10.2 % Decreased 4 % Decreased 21 %
These results are a convincing proof of principle that early steroid treatments are effective.
Which treatment strategy do you prefer?
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BPD is 50 Years Old!