Noah Hillman M.D. IPOKRaTES Conference Guadalajaira, Mexico August 23, PDF Free Download

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

AAP Policy Statement - 2002 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 - 2010 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

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

Steroids at <7 days Increases Cerebral Palsy Doyle LW et al. Cochrane Database Syst Rev. 2017 Oct 24;10

Steroids at <7 days Increases Death or Abnormal Neurologic exam Doyle LW et al. Cochrane Database Syst Rev. 2017 Oct 24;10

Table 1 Effects of postnatal corticosteroids on respiratory outcome, mortality and neurodevelopment BPD, bronchopulmonary dysplasia; CP, cerebral palsy. 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 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 Doyle LW et. al Cochrane Database Syst Rev. 2017 Oct 24;10

Steroids at >7 days No effect on Mental Disability Index < 2 SD Doyle LW et. al Cochrane Database Syst Rev. 2017 Oct 24;10

Steroids at >7 days No effect on Death and Cerebral Palsy Doyle LW et. al Cochrane Database Syst Rev. 2017 Oct 24;10

Meta-analysis of Steroid Trials and Neurologic Outcomes Doyle L et al Pediatrics March 2005

Gestational Age (Weeks) Birth weight Sex Race Postnatal Day Ventilator Type FiO 2 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 Systemic Early Inhaled Budesonide for the prevention of Bronchopulmonary Dysplasia Bassler 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 Systemic Early Inhaled Budesonide for the prevention of Bronchopulmonary Dysplasia Bassler et al. NEJM Oct 15, 2015

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia N 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 BPD Yeh et al. Am J Respir Crit Care Med. 2016 Jan 1;193(1):86-95.

Intra-tracheal administration of Budesonide/Surfactant to prevent BPD Yeh 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 injury 3 Surfactant treatment 2 Antenatal corticosteroids 4 Additional therapies have proven elusive Dexamethasone or cortisol given prior to the injury do not suppress the injury 4 The incidence of BPD has remained the same, despite advances in the field of Neonatology 5

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 Unpublished data Manuscript in preparation

Plasma Budesonide Levels Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

Physiologic Data OI = MAP x FiO2 / PaO2 VEI = 3800 / (ΔP x RR x PaCO2) Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

V o lu m e (m L /k g ) P r e s s u r e -V o lu m e C u r v e 1 5 0 S u rfa c ta n t 1 0 0 * * * * * * S u rfa c ta n t+ B u d 5 0 0 0 1 0 2 0 3 0 4 0 P re s s u re (c m H 2 O )

Pro-inflammatory Cytokines in the lungs Decreased Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

Liver and Brain mrna Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

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

Physiologic Data OI = MAP x FiO2 / PaO2 VEI = 3800 / (ΔP x RR x PaCO2) # = p < 0.05 vs Injury + Surf

Lung Parenchyma mrna # = p < 0.05 vs Injury + Surf

Brain and Liver mrna # = p < 0.05 vs Injury + Surf ; t = p < 0.05 vs Surf

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 1 st, 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

The Cohorts Historical Cohort: August 1 st, 2013 July 31 st, 2016 295 infants met inclusion criteria for study cohort Budesonide Cohort (as of April 20 th, 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 Data Historical 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% Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

3 Day Data Historical 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. Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

7 Day Data Historical 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 Death 3 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. Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

36 Week Data Discharged Infants Historical 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 Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

Discharge Data Historical 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 Discharged on Respiratory Support 41.6 + 6.4 Weeks 40.3 + 5.7 Weeks 0.002 49.4% 51.3% 0.82 Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

Secondary Outcomes Historical Cohort Budesonide Cohort p Value n 295 128 Presence of PDA (By Echocardiogram) Medical Treatment (of Patients with PDA) Surgical Ligation (of Patients with PDA) Retinopathy of Prematurity > Stage 3 Retinopathy of Prematurity 63.1% 53.1% 0.07 56.5% 44.1% 0.09 15.6% 4.4% 0.02 53.9% 45.8% 0.04 10.8% 10.8% 1 Kothe TB, Hillman NH et al. Unpublished data Manuscript in preparation

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

Conclusions 1. There is a role for postnatal steroids in management of infants at risk for BPD 2. Early steroid (<7 days) are associated with decreased BPD but increased risk of Cerebral Palsy and poor neurologic outcome 3. Later steroids are associated with improved BPD without increased risk of Cerebral Palsy 4. Stratification of risk for BPD (using NICHD BPD Calculator) can be used to determine infants that will benefit most from steroids 5. 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 sheep c) Decreased mechanical ventilation and postnatal dexamethasone in cohort study, but did not decreased BPD