1. Bronchopulmonary Dysplasia(BPD) Kumari Weeratunge M.D. PL - 2

2. Back ground  Develops in neonates treated with O2 & PPV.  Originally described by Northway in 1967 using clinical, radiographic & histologic criteria.  Bancalari refined definition using ventilation criteria, O2 requirement @ 28days to keep PaO2>50mmhg & abnormalities in chest x –ray.

3. Back ground  Shennan proposed in 1988 criteria of O2 requirement @ 36 weeks corrected GA.  Antenatal steroids, early surfactant Rx & gentle modes of ventilation minimize severity of lung injury.

4. Pathophysiology  Multifactorial  Major organ systems - lungs & heart  Alveolar stage of lung development - 36wks GA to 18 months post conception  Mechanical ventilation & O2 interferes with alveolar & pulmonary vascular development in preterm mammals.  Severe BPD  Pulmonary HT & abnormal pulmonary vascular development.

5. Stages of BPD  Defined by Northway in 1967  Stage 1 - similar to uncomplicated RDS  Stage 2 - pulmonary parenchymal opacities with bubbly appearance of lungs  Stage 3 & 4 – areas of atelectasis, hyperinflation & fibrous sheaths  Recently CT & MRI of chest – reveals more details of lung injury

6. Frequency of BPD  Dependent on definition used in NICU.  Using criteria of O2 requirement @ 28 days frequency range from 17% - 57%.  Survival of VLBW infants improved with surfactant  Actual prevalence of BPD has increased.

7. Mortality/Morbidity of BPD  Infants with severe BPD  Increased risk of pulmonary morbidity & mortality within the first 2 years of life.

8. Pulmonary Complications of BPD  Increased resistance & airway reactivity evident in early stages of BPD along with increased FRC.  Severe BPD  Significant airway obstruction with expiratory flow limitations & further increased FRC secondary to air trapping & hyperinflation

9. Volume trauma & Barotrauma  Rx of RDS – surfactant replacement, O2, CPAP & mechanical ventilation.  Increased PPV required to recruit all alveoli to Px atelectasis in immature lungs  Lung injury  Inflammatory cascade.  Trauma secondary to PPV-  Barotrauma  Volumetrauma  Lung injury secondary to excess TV from increased PPV.

10. Volume trauma & Barotrauma  Severity of lung immaturity & effects of surfactant deficiency  determines PPV.  Severe lung immaturity  Alveolar number is reduced  increased PP transmitted to distal bronchioles.  Surfactant deficiency  some alveoli collapse while others hyper inflate.

11. Volume trauma & Barotrauma  Increased PPV to recruit all alveoli  Compliant alveoli & terminal bronchioles rupture  leaks air in to interstium  PIE  Increase risk of BPD  Using SIMV compared to IMV in infants <1000g showed less BPD.

12. O2 & Antioxidants  O2 accept electrons in it’s outer ring  Form O2 free radicals  Cell membrane destruction  Antioxidants(AO)  Antagonise O2 free radicals  Neonates-Relatively AO deficient  Major antioxidants – super oxide dismutase, glutathione peroxidase & catalase

13. O2 & Antioxidants  Antioxidant enzyme level increase during last trimester.  Preterm birth  Increased risk of exposure to O2 free radicals

14. Inflammation  Activation of inflammatory mediators  In acute lung injury  Activation of leukocytes by O2 free radicals, barotrauma & infection  Destruction & abnormal lung repair  Acute lung injury  BPD  Leukocytes & lipid byproducts of cell membrane destruction  Activate inflammatory cascade

15. Inflammation  Lipoxigenase & cyclooxigenase pathways are involved in the inflammatory cascade  Inflammatory mediators are recovered in tracheal aspirate of newly ventilated preterm who later develops BPD  Metabolites of mediators  vasodilatation  increased capillary permeability  albumin leakage & inhibition of surfactant function  risk of barotrauma

16. Inflammation  Neutrophils – release collegenase & elastase  destroy lung tissue  Hydroxyproline & elastin recovered in urine of preterms who develops BPD  Di2ethylhexylphthalate(DEHP) degradation product of used ET tubes  lung injury  A study in 1996 found that increased interleukin 6 in umbilical cord plasma

17. Infection  Maternal cervical colonization/ preterm neonatal tracheal colonization of U.urealyticum associated with high risk of BPD

18. Nutrition  Inadequate nutrition supplementation of preterm compound the damage by barotrauma, inflammatory cascade activation & deficient AO stores  Acute stage of CLD  increased energy expenditure  New born rats  nutritionally deprived  decreased lung weight

19. Nutrition  Cu, Zn, Mn deficiency  predispose to lung injury  Vit A & E prevent lipid peroxidation & maintain cell integrity  Extreme prematurity – large amounts of H2O needed to compensate loss from thin skin

20. Nutrition  Increased fluid administration  increased risk of development of PDA & pulmonary edema(PE)  High vent settings & high O2 needed to Rx PDA & PE  Early PDA Rx – improve pulmonary function but no effect on incidence of BPD

21. Genetics  Strong family history of asthma & atopy increase risk of development & severity of BPD

22. CVS Changes  Endothelial cell proliferation  Smooth muscle cell hypertrophy  Vascular obliteration  Serial EKG – right ventricular hypertrophy  Echocardiogram – abnormal right ventricular systolic function & left ventricular hypertrophy

23. CVS Changes  Persistent right ventricular hypertrophy/ fixed pulmonary hypertension unresponsive to supplemental O2 leads to poor prognosis

24. Airway  Trachea & main stem bronchi - abnormalities depend on duration & frequency of intubation & ventilation  Diffuse or focal mucosal edema, necrosis/ulceration occur  Earliest changes from light microscopy  loss of cilia in columnar epithelium, dysplasia/necrosis of the cells

25. Airway  Neutrophils, lymphocyte infiltrate & goblet cell hyperplasia  increased mucus production  Granulation tissue & upper airway scarring from deep suctioning & repeated ET intubation results in laryngotracheomalacia, subglottic stenosis & vocal cord paralysis

26. Airway  Necrotizing bronchiolitis – results from edema, inflammatory exudate & necrosis of epithelial cells.  Inflammatory cells, exudates & cellular debris obstruct terminal airways  Activation & proliferation of fibroblasts  peribronchial fibrosis & obliterative fibroproliferative bronchiolitis

28. Radiologic Findings  Decreased lung volumes  Areas of atelectasis  Hyperinflation  Lung haziness  PIE

30. Histologic Findings  In 1996 Cherukupalli & colleagues described 4 pathologic stages  Acute lung injury  Exudative bronchiolitis  Proliferative bronchiolitis  Obliterative fibroproliferative bronchiolitis

33. Medical care in BPD  Prevention  Mechanical ventilation  O2 therapy  Nutritional support  Medications

34. Mechanical Ventilation  O2 & PPV life saving  Aggressive weaning to NCPAP eliminate need of PPV  Intubation primarily for surfactant therapy & quickly extubation to NCPAP decrease need for prolong PPV  If infant needs O2 & PPV gentle modes of ventilation employed to maintain pH 7.28 – 7.40, pCo2 45 – 65, pO2 50- 70

35. Mechanical Ventilation  Pulse oximetry & transcutaneous Co2 mesurements – provide information of oxygenation & ventilation with minimal patient discomfort  SIMV – provide information on TV & minute volumes which minimize O2 toxicity & barotrauma/volumetrauma  SIMV – allow infant to set own IT & rate

36. Mechanical Ventilation  When weaning from vent & O2 difficult – when adequate TV & low FiO2 achieved  trial of extubation & NCPAP  Commonly extubation failure  secondary to atrophy & fatigue of respiratory muscles  Optimization of nutrition & diuretics – contribute to successful weaning from vent  Meticulous nursing care – essential to ensure airway patency & facilitate extubation

37. O2 Therapy  Chronic hypoxia & airway remodeling  pulmonary HT & cor pulmanale  O2  stimulate production of NO  smooth muscle relaxation  vasodilatation

38. O2 Therapy  Repeated desats secondary to hypoxia results from- decreased respiratory drive - altered pulmonary mechanics - excessive stimulation - bronchospasm  Hyperoxia  worsen BPD as preterms have a relative deficiency of AO

39. O2 Therapy  O2 requirement increase during stressful procedures & feedings  therefore wean O2 slowly  Keep sats 88% - 92%  High altitudes  may require O2 many months  PRBC transfusion  increase O2 carrying capacity in anemic(hct<30%) preterms

40. O2 Therapy  Study in 1988 found increased O2 content & systemic O2 transport, decreased O2 consumption & requirement after blood Tx  Need for multiple Tx & donor exposures decreased by  erythropoetin, iron supplements & decreased phlebotomy requirements

41. Nutritional Support  Infant with BPD- increased energy requirements  Early TPN – compensate for catabolic state of preterm  Avoid excessive non N calories  increase CO2 & complicate weaning  Early insertion of central lines  maximize calories in TPN

42. Nutritional Support  Rapid & early administration of increased lipids  worsen hyperbillirubinemia & BPD through billirubin displacement from albumin & pulmonary vascular lipid deposition respectively.  Excessive glucose load  increase O2 consumption, respiratory drive & glucoseuria.

43. Nutritional Support  Cu, Mn, & Zn essential cofactors in AO defenses  Early initiation of small enteral feeds with EBM, slow & steady increase in volume  facilitate tolerance of feeds  Needs 120 – 150 Kcal/kg/day to gain weight

44. Medical Therapy  Diuretics  Systemic bronchodilators

45. Diuretics  Furesemide (Lasix) Rx of choice  Decrease PIE & pulmonary vascular resistance  Facilitate weaning from PPV, O2 /both  Adverse effects – hyponatremia, hypokalemia, hypercalciuria, cholelithiasis, nephrocalcinosis & ototoxicity

46. Diuretics  Careful parenteral & enteral supplements  compensate adverse effects  Thiazide & spiranolactone for long term Rx

47. Systemic Bronchodilators  Methylxanthines – increase respiratory drive, decrease apnea, improve diaphragmatic contractility  Smooth muscle relaxation – decrease pulmonary vascular resistance & increase lung compliance  Exhibit diuretic effects

48. Systemic Bronchodilators  Theophyline – metabolized primarily to caffeine in liver  Adverse effects – increase heart rate, GER, agitation & seizures

49. Prognosis  Pulmonary function slowly improves  secondary to continued lung & airway growth & healing  Northway- Airway hyperactivity, abnormal pulmonary functions, hyperinflation in chest x ray persists in to adult hood  A study in 1990 found gradual decrease in symptom frequency in children 6 – 9 yrs