1. Bronchopulmonary Dysplasia John Salyer RRT-NPS, MBA, FAARC Director Respiratory Therapy Seattle Children’s Hospital and Research Institute

2. A Little History Originally described by Northway in 1967 Report of a series of 32 patients in NEJM, average gestational age 32 weeks All were treated with 100% oxygen, then prolonged mechanical ventilation with 80- 100% oxygen Before mechanical ventilation was available the usual course of RDS was several days of severe lung disease to which the infant either succumbed or recovered completely in 7-10 days

3. History (cont.) The addition of mechanical ventilation led to appearance of a new syndrome –Stage I, days 1-3, HMD (RDS) –Stage II, days 4-10, opacification of lungs, with bronchiolar and alveolar necrosis –Stage III, days 10-20, transition to a CXR with a reticular network of small rounded areas of radiolucency, emphysematous and atelectatic airspaces, with pulmonary fibrosis –Stage IV, hyperexpanded and cystic lungs. cor pulmonale

4. Definition Shennan noted that if oxygen requirement at 36 weeks used as threshold over 50% of infants would have abnormal pulmonary follow-up (Shennan, 1988) Now usually defined as requirement for supplemental oxygen at: –36 weeks postmenstrual age if born at or before 32 weeks’ gestational age –4 weeks of age if born after 32 weeks’ gestational age

5. Physiologic Test BPD if at 35-37 weeks post menstrual age: –receiving mechanical ventilation, or –CPAP, or –>30% oxygen with saturation <96% –If infant is receiving 96% then: Wean O2 to room air No BPD if saturation > 90% in room air for 30 minutes

6. Pathology Classic BPD Airway injury Epithelial metaplasia with type II cell hyperplasia Smooth muscle hypertrophy Parenchymal fibrosis, alternating with emphysema Capillary dysplasia

7. Low power view of lung from infant who died from BPD at 2.5 months of age. Note alternating areas of emphysema and atelectasis, and strands of fibrosis.

8. Smooth Muscle Hyperplasia

9. Preterm spontaneously breathing lambs supported with N-HFV or intubation/MV (n=16) N-HFV group had greater oxygenation (p<0.05) at a lower FiO 2 and improved alveolarization

10. Albertine et al., Am J Respir Crit Care. 2008 Preterm spontaneously breathing lambs supported with N-HFV or intubation/MV (n=16) N-HFV group had greater oxygenation (p<0.05) at a lower FiO 2 and improved alveolarization Histology of BPD

11. Classic BPD

13. Classic vs. New BPD Much of the histologic findings of “old BPD” seen in animal models with oxygen toxicity New epidemiology –Most common in ELBW infants –Risk factors: low gestational age, postnatal infection, maternal chorioamnionitis, PDA, mechanical ventilation –Some ELBW infants do not have RDS, with minimal early oxygen or mechanical ventilation

15. Clinical Presentation “New” BPD Hazy lungs on CXR, with minimal cystic emphysema, or hyperinflation Less airway reactivity Less pulmonary hypertension (blue spells, “twits”) Pathology –Minimal fibrosis, minimal airway injury –Decreased alveolar septation and microvascular development

16. CXR New BPD Old BPD

17. Division of Respiratory Bronchioles 20 to 32-36 weeks 3 generations of saccular septations, forming 524,000 respiratory bronchioles Hypothesized that the further septation of respiratory bronchioles disrupted by inflammation/injury in new BPD

18. Pathology New BPD Arrest of Alveolarization Increased saccular diameters, fewer saccules (alveoli) Collagen network disrupted, elastin not localized to fibers for secondary septation No severe inflammation Saccules lined with dysplastic type II cells Seen in post-natal mice and rats exposed to inflammation or hyperoxia

19. Pathogenesis “New” BPD: Overview Immaturity of structure and function before about 32 weeks’ gestation –Poorly developed airway supporting structures –Surfactant deficiency –Decreased compliance –Underdeveloped antioxidant mechanisms –Inadequate fluid clearance Inflammation –Mechanical ventilation –Oxygen toxicity –Infection

20. Pathogenesis: Mechanical Injury Over-distension of airways and airspaces (Volutrauma) –Excessively large tidal volumes, not pressure (Hernandez, 1989) –Association of decreased PCO2 with increased risk BPD (Garland, 1995) –Maximum end-inspiratory volume more important than tidal volume or FRC (Dreyfuss, 1993) –As few as 6 large manual inflations was enough to increase the lung damage premature lambs (Bjorklund, 1997) –Positive pressure causes bronchiolar lesions (Nilsson, 1978)

21. Pathogenesis: Oxygen Toxicity Safe FiO2 level and duration are unknown Cell damage from reactive oxygen metabolites –Cell enzyme inactivation Preterm infants may have inadequate antioxidant defenses –Nutrient deficiencies –Immature enzyme development

22. Pathogenesis: Infection Four-fold increase in BPD incidence with sepsis (Rojas, 1995) Due to increased concentration of proinflammatory cytokines in amniotic fluid? Association with Ureaplasma urealyticum (Hannaford, 1999) Maternal chorioamnionitis associated with decreased RDS, but increased risk of BPD

23. Pathogenesis: Inflammation Macrophages, lymphocytes, platelets in lung will release inflammatory mediators –Cytokines –Lipid mediators –Platelet factors (Ozdemir, 1997) Complement activation Increased vascular permeability Protein leakage Mobilization of neutrophils into interstitial and alveolar compartments –Release of reactive oxygen radicals, elastase, collagenase –Increased MIP-1 and IL-8, reduced IL-10 (Jobe 2001)

24. Normal Alveolus Injured Alveolus (Acute Phase) Alveolar air space Type I cell Surfactant Layer Type II cell Interstitium Capillary Alveolar macrophage Sloughing bronchial epithelium Edema fluid Necrotic or Apoptotic Type I cell Red cell Cellular debris Hyaline membrane Fibrin Widened, edematous interstitium (interstitial pneumonia) TNF IL Red cell Inactivated surfactant Activated neutrophil

25. Cardiopulmonary function in BPD Decreased tidal volume Increased airway resistance Decreased dynamic lung compliance Uneven airway obstruction –Gas trapping –Hyperinflation –Abnormal distribution of ventilation Bronchomalacia

26. Pulmonary Edema in BPD Reduced cross sectional area of pulmonary vessels causes increased pulmonary vascular resistance Alveolar hypoxia induces local vasoconstriction Intact vessels must accept remaining pulmonary blood flow, which leads to –elevated pressure and RV afterload –increased fluid filtration in interstitium

27. Clinical Course of BPD Most: gradual improvement over weeks or months Some: marked pulmonary instability in first few weeks followed by weeks or months of ventilator dependence Few: pulmonary hypertension and cor pulmonale

28. Prevention of BPD Antenatal glucocorticoid steroids - lead to decreased incidence RDS, but only modest decrease in BPD Nutrition – although poor growth is associated with BPD, no studies show impact of nutrition in altering risk for BPD Vitamin A – Slight decrease in BPD with IM supplementation in ELBW infants (Darlow, 2011), UW study showed increased sepsis with IM vit A (48.5% vs. 12%), but no decrease BPD Surfactant – decreases risk of pneumothorax, improves survival, decreases need for oxygen and ventilation, but no decrease in rate of BPD.

29. Prevention of BPD (cont.) Limited oxygen – SUPPORT trial with lower oxygen targets saw decreased incidence of ROP, but increased mortality and no decrease in BPD Permissive hypercapnea – Target of pCO2>52 vs. <48 not associated with decreased BPD in ELBW, but decreased ventilation at 36 wks (Carlo, 2002) HFOV – not associated with decreased BPD compared to modern conventional ventilation

30. Prevention of BPD (cont.) PDA treatment – incidence of PDA goes up with ligation (Chorne, 2007) Inhaled Nitric Oxide – NO-CLD trial showed decreased BPD in treatment group. Survival without BPD 43.9% vs. 36.8% (Ballard, 2006)

31. Ventilation Strategy for CLD Settings 1.Slow Respiratory Rates –< 40 breaths/min 2.PIP (lowest required) –target V T 5-10 mL/kg –Not ECLS candidate 3.PSV/VG 4.PEEP –5-6 (up to 12 for bad TM) 5.Short Inspiratory Times –0.4-0.7 s Blood Gases 1.Permissive Hypercapnea –pCO 2 levels 45-65* –pH 7.25-7.35 2.Less Aggressive Oxygenation Goals –paO 2 45-55* –Saturations 85-92%

32. p=< 0.05

33. Management of established BPD: Bronchodilators Beta-2 agonists (albuterol, terbutaline) acutely decrease airway resistance and increase compliance Only one controlled clinical study of outcomes (Denjean, 1992) –173 infants < 31 weeks, vent at 10 days –No effect on survival, severity of BPD, duration of vent or oxygen use

34. Management of established BPD: Bronchodilators Recommendation (not evidenced-based!) –Use albuterol for short-term effects or to treat acute deterioration –Discontinue if no improvement in gas exchange, work of breathing, or number of respiratory decompensations –Watch for tachycardia, arrhythmia, hypokalemia, irritability

35. Management of established BPD: Acute Exacerbations Consider viral infections (usually not bacterial) Consider tracheitis if purulent secretions Obtain CXR (although rarely helpful) Culture and gram stain of tracheal secretions if purulent (often misleading) Try dose of furosemide Try inhaled albuterol, and if poor response, try ipratropium Consider inhaled corticosteroids Consider systemic corticosteroids for 5 days, esp. if at term corrected age

36. Web Resources for Parents http://www.nhlbi.nih.gov/health/dci/Diseases/Bpd/Bpd_WhatIs.h tmlhttp://www.nhlbi.nih.gov/health/dci/Diseases/Bpd/Bpd_WhatIs.h tml –Excellent description of BPD for lay audience from the National Heart Lung and Blood Institute http://www.nlm.nih.gov/medlineplus/ency/article/001088.htm –Very brief review of BPD from National Library of Medicine’s Medline Plus website http://depts.washington.edu/growing/Assess/BPD.htm –Description of BPD with emphasis on home care and nutritional issues from Donna Johnson at the University of Washington

37. The End