Is There a Treatment for BPD?

Is There a Treatment for BPD? Amir Kugelman, Pediatric Pulmonary Unit and Department of Neonatology Bnai Zion Medical Center, Rappaport Faculty of Medicine Haifa, Israel

Conflict of Interest Our study was not funded. Teva supplied the QVAR and placebo, Trupharm supplied the Aerochambers.

BPD: Treatment??? Prevention Treatment

Antenatal Steroids and Poor Neonatal Outcome Rates (Kugelman et al. Arch of Pediatrics and Adolescent Medicine 2012) Combined poor outcome of death or severe morbidity by prenatal steroid therapy. Prenatal steroids and BPD - contervertial

Baud O, et al. Lancet. 2016

Baud O et al. Lancet. 2016

Bassler DN. NEUROSIS Trial Group. NEJM. 2015

No Magic Bullet Comprehensive Strategy to Prevent BPD Delivery Room or NICU Neopuff Endotracheal Intubation Caffeine INSURE Approach Surfactant Steroids- Selective use Nutrition Vitamin A? Immediate Extubation Extubation at RDS Resolution HFNC MIST NCPAP Nasal Respiratory Support Nasal Ventilation (NIPPV/SNIPPV) NAVA 1Permissive Hypercapnia 2Adequate Oxygenation Spontaneous Unsupported Breathing (Kugelman A. Ped Pulmonol 2011)

BPD: Treatment? Prevention Comprehensive approach Treatment

Introduction The evidence supporting inhaled steroids in spontaneously breathing infants with BPD is limited, and based on only two RCT with relative small number of infants (Cochrane, 2010). The Cochrane review concluded that these studies do not allow firm conclusions with regard to the efficacy of inhaled steroids in non-ventilated infants (Lister P et al. Cochrane 2010).

Introduction The "new" BPD involves the lungs more than the airways and is characterized by: Fewer but larger alveoli, Mild fibrosis, Persistent inflammation (Am J Respir Crit Care Med. 2003; Jobe AH. Am J Respir Crit Care Med. 2001, Jobe AH. Curr Opin Pediatr 2011).

Utilization of Inhaled Corticosteroids for Infants with BPD (Slaughter et al. PLoS One 2014) Retrospective Cohort Study. Evolving BPD. 15 US NICU Inhaled corticosteroid administration to infants with BPD is common in U.S. NICUs. Varies markedly between centers. This supports the need for further research.

Introduction Thus, there is a need to ascertain the role of inhaled steroids in infants with "new" BPD. Recent studies demonstrated the potential role of early use of systemic (Baud O et al. Lancet. 2016) or inhaled steroids in the prevention of "new" BPD (Bassler D, et al; N Engl J Med. 2015).

Introduction QVAR (extra-fine hydrofluoalkane-beclomethasone dipropionate [HFA-BDP]) is a new inhaled corticosteroid that is unique in its small particle size (1.1 micron) (Leach et al. Chest. 2002; de Vries et al. Respir Med. 2009). This results in higher lung deposition of QVAR (Devadason SG et al. Eur Respir J. 2003), and permits a reduction in the dosage relative to CFC-BDP (Vanden Burgt JA et al. J Allergy Clin Immunol. 2000).

Introduction These characteristics of the QVAR led to studies in models of ventilated and spontaneously breathing infants: Small airways, Obligatory nose breathers, Irregular breathing patterns. The studies showed better lung deposition of QVAR compared to CFC-BDP (Janssens HM et al. Chest. 2003; Cole CH et al. Arch Dis Child Fetal Neonatal Ed. 2004 ).

Introduction Compared with other inhaled steroids in asthma QVAR was found to be: At least as effective as or better Demonstrated similar safely profile (Fireman P et al. Ann Allergy Asthma Immunol. 2001; Worth H et al. Respiration. 2001; Price D et al. J Allergy Clin Immunol. 2010).

Study Aim To determine if inhaled QVAR will be effective in Reducing respiratory rehospitalizations Respiratory morbidities (within the NICU and 3 month post discharge) In infants with established moderate/ severe BPD compared with placebo.

Methods: Study Design This was a double blind, randomized placebocontrol, multi-center pilot study conducted at five university affiliated NICUs in Israel. (Meir, Ashkelon, Haemek, Laniado, Bnai Zion). The study was approved by the ethics committee of the Israeli Ministry of Health.

Methods: Study Design Our primary outcome measure was: To compare the rate of respiratory readmissions to the hospital during the study period between the QVAR and placebo groups. Secondary outcomes measures: Comparison of clinical, growth and safety parameters.

Methods: Patients Inclusion Criteria 1) Preterm infants (born <32 weeks) with moderate to severe BPD, - Moderate: O 2 <30% - Severe: O 2 >30% or with positive pressure support - At 36 weeks corrected gestational age, (Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001), 2) Parents signed an informed consent.

Methods: Patients Exclusion Criteria 1) Congenital malformation. 2) Unstable infants (Cardiac, neurological, or sepsis). 3) Unavailable F/U.

Methods: Study Procedure Eligible infants were randomized to Inhaled QVAR 100 microgram or Placebo Twice daily via Aerochamber with face mask (Neonatal Chamber, Trudell Medical International, London, ON, Canada). Treatment was given daily until 3 months post discharge.

Methods: Study Procedure Follow up visits were done at: Randomization Discharge Once a month until the end of the study. Patients were allowed to get other medication according to the decision of the attending Neonatologist or Pediatrician.

Methods: Study Procedure If the treating physician decided to add inhaled steroids during BPD exacerbation, he was allowed to give inhaled fluticasone, 125 microgram via Aerochamber twice daily until the exacerbation resolved. Oxygen was administered to keep pulse oximetry between 90-95%, and was stopped according to the treating Neonatologist. Analysis was done by intention to treat.

Results

Excluded 3 ½ months of systemic steroids Infants Enrollment QVAR n = 18 Discharge home Eligible Infants with moderate to severe BPD n=47 Included infants n = 38 Placebo n = 20 Included infants Infants excluded from the study n=9 Parental refusal = 4 Instability (Neurological, Cardiac ) = 4 Social problem = 1 Death before discharge n = 1 Lost in 2 nd month f/u n = 2 3 rd month f/u n = 1 n = 17 Finalized 3 months active follow up n = 14 n = 19 Finalized 3 months active follow up n = 19

Infants Characteristics

Infants Characteristics

Figure 2 A 15 10 5 Rehospitalizations (days) P=0.09 0 QVAR Placebo B 1.5 1 0.5 Rehospitalizations / infant P=0.13 0 QVAR Placebo C 30 20 10 Additive Steroids (days) P=0.63 P=1.00 P=0.28 0 Qvar Placebo Qvar Placebo Qvar Placebo Inhaled Steroids Systemic Steroids Inhaled Steroids or Systemic Steroids

Clinical Outcomes P = 0.796

Clinical and Safety Outcomes Out of the QVAR group: 1 infant was admitted to PICU for Parainfluenzae bronchiolitis Out of the placebo group: 1 infant died before discharge (sepsis), 2 infants were admitted to PICU for bronchiolitis (RSV and Parainfluenzae). Season at discharge: No significant difference study vs. placebo. There was no significant difference between the groups in urine cortisol/creatinine ratio at recruitment or at study end. No adrenal supresion.

Discussion Our study was unable to detect a significant effect of inhaled QVAR vs. placebo on the respiratory course of established BPD until discharge or during the following 3 months period. Rate of rehospitalizations, Use of oxygen (6.8+13.6 vs 14.8+27.6 days, NS) Tended to be lower in the QVAR group.

Discussion Our results may suggest modest benefits of QVAR that our study did not have the power to confirm (type II error). At the same time, there was a tendency towards higher use of additional steroids post discharge in the placebo group. This could mask possible benefits of QVAR. It is also possible that inhaled steroids, have no effect on established moderate/severe BPD.

Discussion Current Literature Yuksel et al (Thorax. 1992) in a prospective, cross over, randomized double-blind study treated 18 infants with BPD (???-wheezy preterm infants 10-24 month of age) with inhaled 200 microgram twice daily of chlorofluocarbon-beclomethasone dipropionate (CFC-BDP) via spacer and face mask for 6 weeks. They found in the treatment vs. the placebo group. 37% reduction in symptom score, Increase in bronchodilator free days Increase in functional residual capacity

Discussion Current Literature Beresford et al (Arch Dis Child Fetal Neonatal Ed. 2002), in a double blind prospective study that included 15 infants in each arm, treated with fluticasone 250 microgram twice daily vs. placebo for a year, found: No benefit with the treatment in terms of day or night symptoms (cough or wheeze). Treatment was safe in both studies. Early study termination: difficulty in recruitment

Fluticasone Inhalation in Moderate Cases of BPD (Dugas et al. Pediatrics 2005) 32 infants, moderate BPD were aged between 28 and 60 days were randomized. Fluticasone 125 mic twice daily for 3 weeks and once daily for a fourth week was delivered to infants who weighed between 500 and 1200 g. The dosage was doubled for infants who weighed >1200 g.

(Dugas et al. Pediatrics 2005) Results: No effect on duration of supplemental O 2 therapy. of ventilatory support. Conclusions: Fluticasone did not affect: - Supplemental O 2 use - Need for ventilatory support. However, fluticasone lowered chest radiograph scores. Trends on BP, adrenal supresion. Conclusion: The results of this investigation do not support the use of inhaled corticosteroids in the treatment of oxygen-dependent infants who have established moderate BPD.

Short-term Adverse Reactions We detected no short-term adverse reactions, Weight and height gain, Blood pressure Urine cortisol/creatinine ratio Comparable between the QVAR and the placebo groups. The placebo group tended to receive higher dose of additive steroids (flixotide), thus possible adverse effects of QVAR, could be obscured.

Study Strength Design: RCT double blind, multi-center study. Clinical significance Originality: New BPD, QVAR for BPD

Study Limitations Our study was underpowered. Relative short prospective F/U. No objective PFTs. Infants in the control group were allowed, and tended to receive more inhaled or systemic steroids, just masking a possible positive effect of QVAR.

Conclusions Our study was unable to detect a significant effect of inhaled QVAR vs. placebo on the respiratory course of established BPD. The study was underpowered.

Conclusions Possible benefits of QVAR could be masked by a tendency towards higher use of additional steroids in the placebo group. We detected no short-term adverse reactions. Our study is important for: Future RCT design on QVAR in established BPD Future meta-analyses.

Clinical Implications Currently, we cannot rule out or affirm whether inhaled steroids should be administered routinely. Inhaled steroids may be tried on individualized basis and continued according to the clinical response within 2-4 weeks.

BPD: Treatment? Prevention Comprehensive approach Treatment Not yet

Thank You All participating centers Parents