Postnatal Steroids Use for Bronchopulmonary Dysplasia in 2018 · Noah Hillman M.D. IPOKRaTES Conference Guadalajaira, Mexico August 23, 2018 Postnatal Steroids Use for Bronchopulmonary

Noah Hillman M.D.

IPOKRaTES Conference

Guadalajaira, Mexico

August 23, 2018

Postnatal Steroids Use for Bronchopulmonary Dysplasia in 2018

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This statement is intended for health care professionals caring for neonates and young infants. The objectives of this statement are to review the short- and long-term effects of systemic and inhaled postnatal corticosteroids for the prevention or treatment of evolving or established chronic lung disease and to make recommendations for the use of corticosteroids in infants with very low birth weight.

• The routine use of systemic dexamethasone for the prevention or treatment of chronic lung disease in infants with very low birth weight is not recommended.

Pediatrics February 2002, VOLUME 109 / ISSUE 2

AAP Policy Statement - 2002

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

AAP Policy Statement - 2010

Steroids at <7 days – Decreases BPD

Doyle LW et al. Cochrane Database Syst Rev. 2017 Oct 24;10

Steroids at <7 days – Decreases Death or BPD


Steroids at <7 days – Increases Cerebral Palsy



Steroids at <7 days – Increases Death or Abnormal Neurologic exam

Outcome

Time of initiation of corticosteroid course

Early (<7 days) Moderately early Delayed

BPD ↓ ↓ ↓

Death or BPD ↓ ↓ ↓

Failure to extubate ↓ ↓ ↓

Mortality at 28 days No effect ↓ Not applicable

Mortality by discharge

No effect No effect No effect

Neurodevelopment Worse No different (?) ↑CP, ↓ mortality

Table 1 Effects of postnatal corticosteroids on respiratory outcome, mortality and neurodevelopment

BPD, bronchopulmonary dysplasia; CP, cerebral palsy.

Echinwald et al. Arch Dis Child Fetal Neonatal Ed. 2007 Sep

Steroids at >7 days – Decreases BPD

Doyle LW et. al Cochrane Database Syst Rev. 2017 Oct 24;10

Steroids at >7 days – Decreases Death and BPD


Steroids at >7 days –No effect on Mental Disability Index < 2 SD


Steroids at >7 days – No effect on Death and Cerebral Palsy


Outcome



BPD ↓ ↓ ↓










Outcome



BPD ↓ ↓ ↓










Doyle L et al Pediatrics March 2005

Meta-analysis of Steroid Trials and Neurologic Outcomes

Gestational Age (Weeks)

Birth weight

Sex

Race

Postnatal Day

Ventilator Type

FiO2

https://neonatal.rti.org/index.cfm

Dexamethasone Dosing?

Depends on institution and beliefs

1) Higher dose dexamethasone (0.5 mg/kg/day) likely do not give an advantage over lower dose regimens

2) The DART study used lower dose of steroids (0.15 mg/kg/day for 3 days, 0.10 mg/kg/day for 3 days, 0.05 mg/kg/day for 2 days, and 0.02 mg/kg/day for 2 days) Increased extubation success but had little effect on BPD or mortality

3) At our institution, we do:0.3 mg/kg/day for 3 days, 0.2 mg/kg/day for 3 days, 0.1 mg/kg/day for 3 days

Steroids to the Lung? - Instead of SystemicEarly Inhaled Budesonide for the prevention of Bronchopulmonary DysplasiaBassler et al. NEJM Oct 15, 2015

Randomized, placebo controlled trial of intubated infants

Infants with a gestational age of 23 weeks 0 days to 27 weeks 6 days Any form of positive-pressure support at 12 hours

Budesonide 400 μg every 12 hours in the first 14 days of life Then 200 μg every 12 hours from day 15 until the last dose of the study drug

Study drugs were administered until infants no longer needed supplemental oxygen and positive-pressure support or reached a postmenstrual age of 32 weeks 0 days

Steroids to the Lung? - Instead of SystemicEarly Inhaled Budesonide for the prevention of Bronchopulmonary DysplasiaBassler et al. NEJM Oct 15, 2015

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary DysplasiaN Engl J Med. 2018 Jan 11;378(2):148-157

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary DysplasiaN Engl J Med. 2018 Jan 11;378(2):148-157

Shinwell ES et al. Pediatrics. 2016 Dec;138(6).

Inhaled Corticosteroid vs Placebo

Steroids to the Lung? - Instead of Systemic

Intra-tracheal administration of Budesonide/Surfactant to prevent BPDYeh et al. Am J Respir Crit Care Med. 2016 Jan 1;193(1):86-95.

Intra-tracheal administration of Budesonide/Surfactant to prevent BPDYeh et al. Am J Respir Crit Care Med. 2016 Jan 1;193(1):86-95.

Surfactant plus Budesonide decreases lung and systemic inflammation over 24 hours

of mechanical ventilation in preterm sheep

T. Brett Kothe, Emily Royse, Matthew Kemp, Fabrizio Salomone, Gabrielle C Musk, Augusto

Schmidt, Alan Jobe, Noah Hillman

Background

• Mechanical ventilation with large tidal volumes causes acute phase activation, lung inflammation, and airway injury in preterm sheep• Can be decreased via several clinically relevant

interventions:• CPAP use during the stretch injury3

• Surfactant treatment2

• Antenatal corticosteroids4

• Additional therapies have proven elusive• Dexamethasone or cortisol given prior to the injury do not

suppress the injury4

• The incidence of BPD has remained the same, despite advances in the field of Neonatology5

Kothe TB, Hillman NH et al. Unpublished data – Manuscript in preparation

Plasma Budesonide Levels


Physiologic Data

OI = MAP x FiO2 / PaO2 VEI = 3800 / (ΔP x RR x PaCO2)


0 1 0 2 0 3 0 4 0

0

5 0

1 0 0

1 5 0

P r e s s u r e -V o lu m e C u r v e

P re s s u re (c m H 2 O )

Vo

lum

e (m

L/k

g)

S u rfa c ta n t

S u rfa c ta n t+ B u d**

*

* **

Pro-inflammatory Cytokines in the lungs – Decreased


Liver and Brain mRNA



Physiologic Data

# = p < 0.05 vs Injury + Surf

OI = MAP x FiO2 / PaO2 VEI = 3800 / (ΔP x RR x PaCO2)

Lung Parenchyma mRNA

# = p < 0.05 vs Injury + Surf

# = p < 0.05 vs Injury + Surf ; t = p < 0.05 vs Surf

Brain and Liver mRNA

Surfactant plus Budesonide for treatment of respiratory distress syndrome in very

low birth weight preterm infants: a cohort comparison

T. Brett Kothe, Farouk Sadiq, Howard Williams,

Nikki Burleyson, Connie Anderson, Noah Hillman

Objective

To evaluate the combination of Budesonide and surfactant for treatment of respiratory distress syndrome in very preterm infants.

Intervention• On August 1st, 2016 our NICU began combining

Budesonide (0.25 mg/kg) with surfactant (Survanta 4 mL/kg) to all infants < 1250 grams who were intubated and normally would have received surfactant alone

• Intervention could be given in the delivery room, in either of our 2 NICUs, or by transport team with first surfactant administration

• Infants who received Budesonide with surfactant were compared to historical cohort (August 2013 to July 2016)

• Data was extracted from EPIC using Microsoft SQL server and verified through chart review

• Exclusion criteria included:– Congenital anomalies or genetic disorders

– Gestational age less than 23 weeks 0 days

– Birth weight less than 500 grams

The Cohorts

• Historical Cohort:– August 1st, 2013 – July 31st, 2016– 295 infants met inclusion criteria for study cohort

• Budesonide Cohort (as of April 20th, 2018):– 151 infants meeting the inclusion criteria have received Budesonide and

surfactant– 133 have reached 36 weeks corrected gestational age– 128 have been discharged or died

• Data on the following slides are from discharged infants only

Demographic DataHistorical Cohort Budesonide Cohort p Value

n 295 151

Gestational Age 26.7 + 2.1 weeks 26.8 + 2.1 weeks

Birth Weight 845 + 205 grams 859 + 217 grams

5 Minute APGAR 6.2 + 1.9 6.5 + 1.8

Male 53.1% 54.8%

Caucasian 42.0% 37.7%

Antenatal Corticosteroids 83.0% 83.6%

Placental Inflammation 58.9% 51.8%


3 Day DataHistorical Cohort Budesonide Cohort p Value

n 295 151

Dose of Surfactant 1.9 + 0.5 2.0 + 0.7

Still Requiring Mechanical Ventilation

58.0% (167/288) 42.6% (63/148) <0.01

3. From online NICHD BPD Outcome Calculator, derived from work by Laughon et al in “Prediction of Bronchopulmonary Dysplasia by Postnatal Age in Extremely Premature Infants”. Am J Respir Crit Care Med. 2011 Jun 15; 183(12): 1715–1722.


7 Day DataHistorical Cohort Budesonide Cohort p Value

n 295 151

Dose of Surfactant 1.9 + 0.5 2.0 + 0.7 0.62

Still Requiring Mechanical Ventilation

48.2% 31.1% 0.001

Risk for Moderate/Severe BPD or Death3 57.9% 51.3% 0.02

Percent with Risk > 65%3 50.7% 38.7% 0.04

3. From online NICHD BPD Outcome Calculator, derived from work by Laughon et al in “Prediction of Bronchopulmonary Dysplasia by Postnatal Age in Extremely Premature Infants”. Am J Respir Crit Care Med. 2011 Jun 15; 183(12): 1715–1722.


36 Week Data – Discharged InfantsHistorical Cohort Budesonide Cohort p Value

n 295 151

BPD 71.2%(187/263) 66.7% (92/138) 0.39

BPD Plus Death 74.2% 69.3% 0.19

Mild BPD 47.7% 47.0% 0.91

Moderate BPD 19.7% 14.5% 0.25

Severe BPD 3.8% 3.4% 1

Moderate/severe/death 31.8%(93/295) 23.8% (36/151) 0.1


Discharge DataHistorical Cohort Budesonide Cohort p Value

n 295 128

Postnatal Dexamethasone 52.9% 36.7% 0.003

Required HFOV 44.4% 32.8% 0.03

Death 10.5% 8.6% 0.60

Length of Stay 104 + 51 Days 94 + 45 Days 0.03

Gestational Age at Discharge

41.6 + 6.4 Weeks 40.3 + 5.7 Weeks 0.002

Discharged on RespiratorySupport

49.4% 51.3% 0.82


Secondary OutcomesHistorical Cohort Budesonide Cohort p Value

n 295 128

Presence of PDA (By Echocardiogram)

63.1% 53.1% 0.07

Medical Treatment(of Patients with PDA)

56.5% 44.1% 0.09

Surgical Ligation(of Patients with PDA)

15.6% 4.4% 0.02

Retinopathy of Prematurity

53.9% 45.8% 0.04

> Stage 3 Retinopathy of Prematurity

10.8% 10.8% 1


Secondary Data

• No differences noted in multiple secondary outcomes, including:– Necrotizing enterocolitis– Spontaneous intestinal perforation– Intraventricular hemorrhage– Periventricular leukomalacia– VP shunt/Rickham reservoir placement– Pneumothoraces– Pulmonary interstitial emphysema– Pulmonary hemorrhage– Tracheostomy placement

Conclusions1. There is a role for postnatal steroids in management of infants

at risk for BPD2. Early steroid (<7 days) are associated with decreased BPD but

increased risk of Cerebral Palsy and poor neurologic outcome3. Later steroids are associated with improved BPD without

increased risk of Cerebral Palsy4. Stratification of risk for BPD (using NICHD BPD Calculator) can be

used to determine infants that will benefit most from steroids5. Inhaled steroids can decrease BPD, but could have effect on

mortality (No increase in meta-analysis of all trials)6. Combining surfactant with budesonide

a) Decreased BPD in a randomized trial of infants with severe RDS (Yeh et al)

b) Decreased lung and brain inflammation in sheepc) Decreased mechanical ventilation and postnatal

dexamethasone in cohort study, but did not decreased BPD

Documents

Postnatal Steroids Use for Bronchopulmonary Dysplasia in 2018 · Noah Hillman M.D. IPOKRaTES Conference Guadalajaira, Mexico August 23, 2018 Postnatal Steroids Use for Bronchopulmonary