4/20/2018 Disclosure • This presentation will reference the use of inhaled Post-discharge respiratory outcomes nitric oxide and calfactant for prevention of in extreme prematurity bronchopulmonary dysplasia (BPD), which is not approved for off-label use for this indication. Roberta L. Keller MD Benioff Children’s Hospital April 20, 2018 Outline • Bronchopulmonary dysplasia (BPD) • Post-discharge respiratory outcomes in former preterm infants • BPD as predictor of post-discharge respiratory outcomes • Other considerations in evaluations of post-discharge BRONCHOPULMONARY DYSPLASIA respiratory outcomes 1
4/20/2018 What is BPD? The origins What is BPD? The neonatologist’s perspective • Chronic lung disease of Normal outcome: GA + Abnormal outcome: PMA with prematurity mean PMA off O 2 ongoing supplemental O 2 GA (n) PMA off O 2 PMA Sensitivity Specificity PPV NPV • “Old” BPD 25 (31) 32.9 ± 3.3 31 88 31 36 85 Scarring and fibrosis of the lung, 26 (44) 33.3 ± 2.9 32 82 51 38 88 severe airway disease in surviving preterm babies in association with 27 (56) 31.2 ± 3.5 33 76 64 40 89 high ventilator pressure + FiO 2 28 (83) 30.7 ± 2.7 34 70 78 48 90 (Northway 1967) 29 (79) 30.8 ± 2.5 35 66 85 55 90 • “New” BPD 30 (70) 31.0 ± 1.7 36 63 91 63 90 Impaired lung and vascular development due to extreme 31 (49) 31.5 ± 1.2 37 51 95 71 89 prematurity (< 28-30 weeks’ 32 (37) 32.5 ± 1.1 38 43 97 77 87 gestation) (Jobe 1999) Cohort n=605: 119 with “abnormal” 1 y outcome (20%) Shennan 1988 What is BPD? The pathologist’s perspective What is BPD? The neonatologist’s perspective Pathology of BPD: Stages of lung development Normal outcome: GA + Abnormal outcome: PMA with Developmental arrest, alveolar simplification mean PMA off O 2 ongoing supplemental O 2 Term BPD GA (n) PMA off O 2 PMA Sensitivity Specificity PPV NPV 25 (31) 32.9 ± 3.3 31 88 31 36 85 Cannalicular 26 (44) 33.3 ± 2.9 32 82 51 38 88 27 (56) 31.2 ± 3.5 33 76 64 40 89 28 (83) 30.7 ± 2.7 34 70 78 48 90 29 (79) 30.8 ± 2.5 35 66 85 55 90 Saccular 30 (70) 31.0 ± 1.7 36 63 91 63 90 31 (49) 31.5 ± 1.2 37 51 95 71 89 32 (37) 32.5 ± 1.1 38 43 97 77 87 Cohort n=605: 119 with “abnormal” 1 y outcome (20%) Alveolar Shennan 1988 Hislop 2002 Bhatt 2001 2
4/20/2018 What is BPD? Current definition What is BPD? The pulmonologist’s perspective Former preterm infant (any of < 32 weeks’ GA the following): Assessed at 36 weeks’ PMA • Extended need for assisted Treatment with oxygen for at least 28d plus ventilation Mild Room air • Abnormal CXR Moderate < 30% (effective) FiO 2 • Discharged on oxygen Severe ≥ 30% (effective) FiO 2 or positive pressure • Symptomatic respiratory (PPV or NCPAP) disease after discharge Should reflect usual status for several days prior to and after 36 weeks’ PMA No requirement for abnormal CXR NICHD/NHLBI/ORD Workshop Summary June 1-2, 2000, Jobe and Bancalari, 2001 What is BPD? What is BPD? Physiologic/clinical trials definition Physiologic/clinical trials definition < 32 weeks’ GA < 32 weeks’ GA Assessed at 36 weeks’ PMA Assessed at 36 weeks’ PMA None Room air None Room air Moderate-to- Supplemental oxygen or positive Moderate-to- Supplemental oxygen or positive severe pressure severe pressure Physiologic challenge for nasal cannula with FiO 2 0.21 : Physiologic challenge for nasal cannula with FiO 2 0.21 : ~2/3 pass flow reduction challenge ~2/3 pass flow reduction challenge (~1/3 fail, unable to maintain oxygen saturation ≥ 90% off support): (~1/3 fail, unable to maintain oxygen saturation ≥ 90% off support): Walsh et al 2006: 7/22 fail Walsh et al 2006: 7/22 fail Poindexter et al 2015: 26/81 fail Poindexter et al 2015: 26/81 fail 3
4/20/2018 What is BPD? Physiologic/clinical trials definition < 32 weeks’ GA Assessed at 36 weeks’ PMA None Room air Moderate-to- Supplemental oxygen or positive severe pressure POST-DISCHARGE RESPIRATORY Physiologic challenge for nasal cannula with FiO 2 0.21 : OUTCOMES ~2/3 pass flow reduction challenge (~1/3 fail, unable to maintain oxygen saturation ≥ 90% off support): Walsh et al 2006: 7/22 fail Poindexter et al 2015: 26/81 fail How do we assess morbidity post- Outcomes: individual domains discharge? Hibbs 2008 Stevens 2014 Keller 2017 • No gold standard NO CLD SUPPORT TOLSURF – Pulmonary function tests? (12 mo) (18-22 mo) (12 mo) – What matters to families, patients? Any home O 2 /support 44% 23% 46% • Individual domains of morbidity/resource utilization Any respiratory medication 63% – home respiratory support Bronchodilator 47% 51% – hospitalization for respiratory cause – respiratory medication use Diuretic 24% 6% 21% – symptoms ( e.g ., wheeze, cough) Inhaled steroid 26% 26% 31% • Composite outcomes Systemic steroid 14% 9% 16% – multiple events and/or multiple time points Hospitalization 22% 31% 28% • Severity outcomes Cough 31% 44% – scale, weighted score Wheeze 53% 61% 52% 4
4/20/2018 Outcomes: composite Composite outcomes: distribution PROP = Prematurity + Respiratory Outcomes Program TOLSURF= Trial of Late Surfactant Study Adverse outcome Beneficial outcome • Quarterly parent surveys (3, 6, 9, 12 mos corrected age) PROP (n=724) PRD No PRD • Post-prematurity respiratory disease (PRD) 497 (69%) 224 (31%) – Primary outcome: PROP TOLSURF (n=439) Any PM No PM – At least one domain of morbidity on ≥ 2 surveys 329 (75%) 110 (25%) • No pulmonary morbidity (No PM) TOLSURF (n=426) Persistent PM No persistent PM – Co-primary follow up outcome: TOLSURF – No resource utilization through 12 mos 153 (36%) 273 (64%) • Persistent pulmonary morbidity (Persistent PM) Colorado (n=524) Late RD No Late RD – Resource utilization on ≥ 3 surveys 372/524 (71%) 152/524 (29%) Keller et al 2017; 2017; Morrow et al 2017 Keller et al J Peds 2017; 2017 Severity outcomes: count of morbidities Severity outcomes: count of morbidities NO CLD NO CLD respiratory medications, hospitalizations, home O 2 respiratory medications, hospitalizations, home O 2 Problems iNO (n=227) PLB (n=222) Total (n=449) Problems iNO (n=227) PLB (n=222) Total (n=449) 0 64 (28%) 40 (18%) 104 (23%) 0 64 (28%) 40 (18%) 104 (23%) 1 72 (32%) 65 (29%) 137 (31%) 1 72 (32%) 65 (29%) 137 (31%) 2 37 (16%) 44 (20%) 81 (18%) 2 37 (16%) 44 (20%) 81 (18%) 3 26 (11%) 24 (11%) 50 (11%) 3 26 (11%) 24 (11%) 50 (11%) 4 22 (10%) 27 (12%) 49 (11%) 4 22 (10%) 27 (12%) 49 (11%) 5 5 (2%) 14 (6%) 19 (4%) 5 5 (2%) 14 (6%) 19 (4%) 6 1 (0.4%) 8 (4%) 9 (2%) 6 1 (0.4%) 8 (4%) 9 (2%) P=0.01 for treatment effect P=0.01 for treatment effect NNT = 10 to prevent morbidity in 1 st year 5
4/20/2018 Severity score: CPQCC Severity score: CPQCC Clinical Factor Weight Clinical Factor Weight Severity n = 940 Clinical Factor Weight Clinical Factor Weight Severity n = 940 Supplemental O 2 2.5 Severe (5-8.5) 70 (7%) Supplemental O 2 2.5 Severe (5-8.5) 70 (7%) Respiratory 2.5 Respiratory 2.5 hospitalization hospitalization Diuretic therapy 1.5 Medium (2.1-4.9) 221 (24%) Diuretic therapy 1.5 Medium (2.1-4.9) 221 (24%) Daily bronchodilator 1.0 Intermittent 0.5 Low (0.1-2.0) 107 (11%) Daily bronchodilator 1.0 Intermittent 0.5 Low (0.1-2.0) 107 (11%) (BD) BD (BD) BD Daily inhaled 1.0 Intermittent 0.2 Daily inhaled 1.0 Intermittent 0.2 corticosteroids (ICS) ICS corticosteroids (ICS) ICS Chest PT 0 None (0) 542 (58%) Chest PT 0 None (0) 542 (58%) Score: 0-8.5, Higher score indicates more morbidity Score: 0-8.5, Higher score indicates more morbidity Gage 2015 Gage 2015 Severity scale: PROP Severity scales: distribution Respiratory morbidity severity (RMS) Severe Moderate/Mild Minimal/None CPQCC PROP TOLSURF <1500g, < 30 wks < 29 wks ≤ 28 0/7, Respiratory Sys Ster any BD ≥ 2 time points No ICS/SS/PV BPD 100% BPD ~43% intubated 7-14d medications Pulm Vasodil any Inhaled CS any (n=940) (n = 704) BPD ~65% Respiratory ≥ 2 any time 1 any time None (n = 454) hospitalizations Symptoms At 2 time points: At 2 time points: Wheeze/Cough Severe 7% 35% 45% Wheeze/Cough ≥ Wheeze/Cough ≥ < 1/wk or < 2 1/wk + ICS 1/wk time points Moderate/Mild 35% 38% 23% Home respiratory O 2 after 3 mos O 2 3 mos only None support Vent any time Trache without vent Minimal/None 58% 28% 31% Death due to X respiratory cause Keller et al J Peds 2017 6
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