Care of Infants with Bronchopulmonary Dysplasia Jatinder Bhatia, MD, FAAP Professor and Chief, Division of Neonatology Vice Chair, Clinical Research Department of Pediatrics Medical College of Georgia Georgia Regents University Augusta, GA

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Learning Objectives Define bronchopulmonary dysplasia (BPD). List the risk factors for BPD. Identify current strategies to prevent BPD. Describe current management of BPD. Discuss implications for the practicing pediatrician.

Definition Originally defined by Northway Clinical, radiological, and pathologic changes Prolonged mechanical ventilation High inspiratory oxygen levels Subsequently, BPD defined by clinical characteristics present at 1 month in association with radiological changes Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy in hyaline membrane disease: bronchopulmonary dysplasia. N Engl J Med. 1967;276(7):357–368.

Births in the United States Number of births: 3,932,181 Birth rate: 12.4 per 1000 population Percent born low birthweight: 8% Percent born preterm (<37 weeks gestation): 11.4% Martin JA, Hamilton BE, Osterman MJK, et al. Births: final data for 2013. Natl Vital Stat Rep. 2015;64(1):1–65.

National Institutes of Health Consensus Definition of BPD Gestational age <32 weeks >32 weeks Time at assessment 36 weeks PMA or discharge to home, whichever comes first >28 days but <56 days postnatal age or discharge to home, whichever comes first Treatment with oxygen >21% for at least 28 days PLUS Mild BPD Breathing room air at 36 weeks PMA or discharge, whichever comes first Breathing room air by 56 days postnatal age or discharge, whichever comes first Moderate BPD Need* for <30% oxygen and/or positive pressure (PPV or NCPAP) at 36 weeks PMA or discharge, whichever comes first Need* for <30% oxygen and/or positive pressure (PPV or NCPAP) at 56 days postnatal age or discharge, whichever comes first Severe BPD Need* for >30% oxygen and/or positive pressure (PPV or NCPAP) at 36 weeks PMA or discharge, whichever comes first Need* for >30% oxygen and/or positive pressure (PPV or NCPAP) at 56 days postnatal age or discharge, whichever comes first Abbreviations: BPD, bronchopulmonary dysplasia; NCPAP, nasal continuous positive airway pressure; PMA, postmenstrual age; PPV, positive pressure ventilation. *Physiologic test of oxygen requirement required. Adapted from Bancalari E, Claure N. Definitions and diagnostic criteria for bronchopulmonary dysplasia. Semin Perinatol. 2006;30(4):164–170.

Physiologic Test for Diagnosis of BPD Infants receiving <30% O2 or >30% O2 with oxygen saturations >96% O2 progressively weaned to 21% (room air) No BPD if saturations remain >90% in room air for 30 minutes Reduces the incidence of the diagnosis of BPD Walsh MC, Yao Q, Gettner P, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics. 2004;114(5):1305–1311.

Incidence of BPD Birthweight (g) Incidence (%) 501-750 46 751-1000 33 1001-1250 14 1251-1500 6

Lung development – Pathology Kajekar R. Environmental factors and developmental outcomes in the lung. Pharmacol Ther. 2007;114(2):129–232. Copyright 2007, with permission from Elsevier.

Risk Factors for BPD Genetic predisposition, male gender, Caucasian Peripartum infection Mechanical ventilation Fluid management Excessive fluids in the first few days Patent ductus arteriosus (PDA) Left to right symptomatic PDA

Role of Mechanical Ventilation Major role Barotrauma, volutrauma Use of excessive inflation pressures Not allowing permissive hypercapnea (as long as pH is satisfactory) Even a small number of inflations (for example, bagging) and use of high oxygen concentrations soon after birth can affect surfactant deficient lungs: implications for delivery room management

Risk Factors for BPD Monte LF, Silva Filho LV, Miyoshi MH, Rozov T. Displasia broncopulmonar (bronchopulmonary dysplasia). J Pediatr (Rio J). 2005;81(2):99–110.

Other Factors Oxygen toxicity (use current targeted oxygen saturations) Nutrient deficiencies Vitamin A Immature antioxidant systems Superoxide dismutase Glutathione peroxidase Infections, inflammation Sepsis: bacterial and fungal

Symptoms of BPD Rapid, shallow breathing Continued need for oxygen or ventilatory support Peripheral cyanosis Intercostal retractions Use of accessory muscles of respiration

Other Issues Trouble feeding Increased work of breathing Delayed growth Development of pulmonary hypertension Cor pulmonale

Representative X-Ray LearningRadiology. Bronchopulmonary Dysplasia: Chronic Lung Disease of Infancy. Published with permission from LearningRadiology.com. http://learningradiology.com/archives2013/COW%20538-BPD/bpdcorrect.html/. Accessed July 17, 2015.

Diagnosis Premature infants, especially those <30 weeks, and still requiring oxygen therapy at original due date Mild, moderate, or severe Chest x-ray findings: infiltrates/atelectasis Blood gas: low O2, high pCO2, low (initially) and later normal pH with compensation

Treatment Goals Prenatal steroids to reduce respiratory distress syndrome Reduce lung injury by minimizing ventilatory support Appropriate oxygen saturation targets Appropriate nutrition to promote growth and prevent extra uterine growth failure/restriction Aggressive treatment of infections

Treatment Goals: Drugs that Prevent BPD Vitamin A: Intramuscular vitamin A* (5000 IU, IM, 3 x week, over 4 weeks) Relative risk of death or BPD at 36 weeks PMA: 0.91, 95% CI 0.83,1.00 Relative risk of reducing death or O2 requirement at 1 month of age: 0.93, 95% CI 0.88,0.99 Oxygen requirement at 36 weeks, 0.87, 95% CI 0.77-0.99 Meta-analysis confirmed the reduction of BPD with vitamin A *Would be considered a therapeutic dose. Tyson JE, Wright LL, Oh W, et al. Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1999;340(25):1962–1968; and Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev. 2011;10:CD000501.

Treatment Goals Caffeine citrate Caffeine for apnea trial: 2006 infants treated for apnea with primary outcome of death, cerebral palsy, cognitive delay, deafness, or blindness at 18-21 months corrected age Secondary analysis: BPD, retinopathy of prematurity, and necrotizing enterocolitis Infants treated with caffeine had lower risk of BPD than placebo: relative risk 0.63, 95% CI 0.52,0.73 Caffeine citrate use in premature infants resulted in a significant reduction in BPD with few side effects. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006;354(20):2112–2121; and Picone S, Bedetta M, Paolillo P. Caffeine citrate: when and for how long. A literature review. J Matern Fetal Neonatal Med. 2012;25(S3):11–14.

Treatment Goals: Other Drugs Late steroids: may have a role Inositol Azithromycin/Clarithromycin (eradication of Ureaplasma urealyticum) reduced BPD: does not have FDA-labeled instructions Inhaled nitric oxide Other Ballard HO, Shook LA, Bernard P, et al. Use of azithromycin for the prevention of bronchopulmonary dysplasia in preterm infants: a randomized, double-blind, placebo controlled trial. Pediatr Pulmonol. 2011;46(2):111–118; Beam KS, Aliaga S, Ahlfeld SK, Cohen-Wolkowiez M, Smith PB, Laughon MM. A systematic review of randomized controlled trials for the prevention of bronchopulmonary dysplasia in infants. J Perinatol. 2014;34(9):705–710; Hallman M, Bry K, Hoppu K, Loppi M, Pohjavuori M. Inositol supplementation in premature infants with respiratory distress syndrome. New Engl J Med. 1992;326(19):1233–1239; Ozdemir R, Erdeve O, Dizdar EA, et al. Clarithromycin in preventing bronchopulmonary dysplasia in Ureaplasma urealyticum–positive preterm infants. Pediatrics. 2011;128(6):e1496–e1501; and Doyle LW, Ehrenkranz RA, Halliday HL. Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2014;5:CD001145.

Nutrition and Other Total energy needs may be increased: need to provide energy and protein to satisfy growth requirements Fluid restriction often required, necessitating calorically dense feedings Diuretics: electrolyte imbalance; little evidence that they improve outcome Adams JM, Stark A. Management of bronchopulmonary dysplasia, UpToDate. June 2015; Gianni ML, Roggero P, Colnaghi MR, et al. The role of nutrition in promoting growth in pre-term infants with bronchopulmonary dysplasia: a prospective non-randomised interventional cohort study. BMC Pediatr. 2014;14:235; and Lai NM, Rajadurai SV, Tan K. Increased energy intake for preterm infants with (or developing) bronchopulmonary dysplasia/chronic lung disease. Cochrane Database Syst Rev. 2006;3:CD005093.

Prevention Vitamin A Caffeine Involved in regulation of lung development and repair Prophylactic vitamin A decreases incidence of BPD Need to treat ~14-15 infants to have 1 infant survive without BPD Caffeine Reduces BPD; mechanism not known

Prevention Corticosteroids High-dose prolonged therapy with dexamethasone used to be standard therapy for BPD. Increase in adverse neurodevelopment AAP policy statement recommends limited use under “exceptional clinical circumstances.”a When given after 14 days of life, corticosteroids may have short- and long-term benefits that need to be confirmed in larger trials. a Watterberg KL and American Academy of Pediatrics Committee on Fetus and Newborn. Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics. 2010;126(4):800–808.

BPD and the Pediatrician Abnormal lung function through school age and beyond More respiratory symptoms, asthma treatment Pulmonary and systemic hypertension, cor pulmonale

BPD and the Pediatrician Poor neurodevelopmental outcome Language delays Fine and gross motor impairment Other Feeding difficulty Gastroesophageal reflux Increased energy expenditure Growth failure

Outpatient Management Home oxygen to maintain saturations >90%* Home mechanical ventilation* Nutritional support Appropriate fortification of breastmilk Appropriate formulas Routine immunizations, including against influenza Respiratory syncytial virus prophylaxis by AAP criteria Developmental follow up and intervention* *Use of a multidisciplinary group or consultation suggested.

Approach to Caring for an Infant with BPD Shepherd EG, Knupp AM, Welty SE, Susey KM, Gardner WP, Gest AL. An interdisciplinary bronchopulmonary dysplasia program is associated with improved neurodevelopmental outcomes and fewer rehospitalizations. J Perinatol. 2012;32(1):33–38.

Conclusions BPD is a known complication in premature infants with initial lung disease. Incidence increases with decreasing gestational age. Prenatal steroids reduce the incidence of RDS; effects on incidence of BPD are not shown. Appropriate resuscitation, judicious use of positive pressure ventilation, and targeted oxygen saturations reduce the incidence of BPD.

Conclusions Vitamin A has a preventative role. Early and sustained appropriate nutrition to support growth may reduce BPD. Caffeine therapy in high-risk infants has been shown to reduce BPD. Post-natal growth failure is common in infants with BPD. Post-discharge attention to nutrition can ameliorate the growth failure.

Conclusions A multidisciplinary team approach, including a nutritionist, cardiology/pulmonary specialists, speech therapist, and developmentalists, is recommended. Adjunctive therapy should be tailored to individual cases: postnatal steroids, diuretics, and bronchodilators. Complications, including pulmonary artery and systemic hypertension, should be addressed.

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