Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of prematurity, is a chronic lung condition that can affect premature infants. It occurs as a result of lung injury from mechanical ventilation and oxygen therapy needed to treat respiratory distress syndrome. The incidence of BPD has increased with improved survival of very low birth weight infants. Risk factors include prematurity, infection, oxygen therapy, mechanical ventilation, and a patent ductus arteriosus. The pathogenesis involves oxidative stress, lung inflammation, and arrested alveolar development. Treatment focuses on preventing lung injury through gentle ventilation strategies, permissive hypercapnia/hypoxemia, nutrition support, and in some cases postnatal corticosteroids.

1. Bronchopulmonary dysplasia( chronic lung disease) Dr prathik

2. First defined by northway in 1967 Incidence In 1970 s----30-40% of neonates who received mechanical ventilation Recently incidence is increased – increased survival of VLBW babies Acc to NICHD database(2003) incidence is about < 1000 grams---23.2% 1000-1249 g---8.4% 1250-1499 g---5.4%

3. No indian database Study from PGI < 1000 grams---50% 1000-1249 g---8.1% 1250-1499 g---2.3%

4. DEFINITION Initially defined as continous oxygen dependency for first 28 days with compatible clinical and radiologic findings Bronchopulmonary dysplasia:clinicalpresentation. J Pediatr 1979 Later, it was proposed to use the need for supplemental oxygen at 36 weeks postmenstrual age (PMA) as the diagnostic criterion especially in preterm very low birth weight (VLBW) infants Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988

5. NIH DEFINITION < 32 weeks > 32 weeks Time point of assessment 36 weeks PMA or discharge* > 28 days but < 56 days postnatal age or discharge* Treatment with oxygen > 21% for at least 28 days > 21% for at least 28 days Mild Breathing room air at 36 weeks PMA or discharge Breathing room air at 56 days postnatal age or discharge* Moderate Need for <30% oxygen at 36 weeks PMA or discharge Need* for <30% oxygen at 56 days postnatal age or discharge Severe Need for > 30% oxygen and/or positive pressure (IMV/CPAP) at 36 weeks PMA or discharge Need for > 30% oxygen and/or positive pressure (IMV/CPAP) at 56 days postnatal age or discharge

6. Etiology Multifactorial The major risk factors include prematurity oxygen therapy, mechanical ventilation, infection( u urealyticum) patent ductus arteriosus (PDA) Excessive early intravenous fluid administration

7. genetic predisposition ( inadequate activity of antioxidant enzymes sod, catalase, glutathione peroxidase and ceruloplasmin --- predisposes to o2 toxicity) Familial airway hyperreactivity Increased inositol clearance

8. pathogenesis The most important factor in the pathogenesis of CLD is prematurity Exposure of immature lungs to high O2 concentrations and positive pressure ventilation results in oxidative stress and ventilator induced lung injury (barotrauma/volutruma)

9. Infection Intrauterine infection (chorioamnionitis) Inflammatory cytokines(IL-1,IL6 and TNF alfa) Lung injury and arrest of lung growth

10. U urealyticum is most commonly implicated Several large clinical studies have found a strong correlation between the presence of BPD and the development of late-onset sepsis, usually with organisms such as staphylococcus epidermidis

11. Barotrauma/Volutrauma The most immediate and frequent cause of BPD is the lung injury imposed by mechanical ventilatory support. positive-pressure mechanical ventilation Immature lung Surfactant def Injury to endothelium

12. increased permaebility of serum protiens Inhibition of surfactant Increased surface tension, unequal areation, collapse of alveoli Increased pressure to distend saccules->lung injury, PIP ,pneumothorax.

13. Studies have shown that overdistension of the lung (not increased pressure) is responsible for lung injury in the surfactant-deficient lung volutrauma and not barotrauma is the primary determinant of VILI.

15. Inflammation oxygen free radicals, pulmonary barotrauma, infectious agents attraction and activation of leukocytes. excessive oxygen free radicals ,tumour necrosis factor, interleukin-1, interleukin-8 (IL-8), and transforming growth factor (TGF)-1 breakdown of capillary endothelial integrity and leakage of macromolecules (e.g., albumin) into alveolar spaces.

16. Albumin leakage and pulmonary edema inhibit surfactant function The release of elastase and collagenase from activated neutrophils directly destroys the elastin and collagen framework of the lung.

17. Genetics neonates were more likely to develop BPD if there was a strong family history of atopy and asthma Nickerson found a positive family history of asthma in 77% of infants with RDS who subsequently developed BPD, compared with only 33% who did not . Clark and associates found that only infants with HLA-A2 developed BPD.

18. Clinical and radiologic features Respiratory signs in infants with CLD include fast but shallow breathing, retractions, and paradoxical breathing. Rales and coarse rhonchi are usually heard on auscultation Old BPD, as originally described by Northway, had four distinct stages:

19. Stage I Hyaline membrane. Alveolar and interstitial oedema. Necrosis of bronchial mucosa.

20. Stage II Areas of emphysema Atelectasis Areas of necrosis and repair of bronchial mucosa .

21. Stage III Cystic areas with hyperinflation. Bronchial metaplasia and hyperplasia. Interstitial oedema.

22. Stage IV Hyperinflation, Interstitial streak densities Flatter chest

23. Infants with new BPD show only haziness reflecting diffuse loss of lung volume or increased lung fluid. Occasionally they have dense areas of segmental or lobar atelectasis or pneumonic infiltrates, but they do not show severe over inflation.

24. Old vs New BPD OLD BPD is seen in infants who received aggressive ventilation and were exposed to high inspired oxygen concentration from birth emphysema, atelectasis and fibrosis, and marked epithelial metaplasia and smooth muscle hypertrophy in the airways and in the pulmonary vasculature.

25. NEW BPD occurs in infants who had only mild respiratory failure requiring shorter duration of ventilation and or oxygen therapy immediately after birth. Seen in VLBW infants, earlier stages of gestation , before alveolarization has been completed and associated with antenatal infection. Due to ARREST IN ALVEOLAR DEVELOPMENT

26. Histo-Pathologic characteristics of the ‘New BPD’ Decreased, large and simplified alveoli (alveolar hypoplasia) Decreased number and dysmorphic capillaries Variable interstitial fibroproliferation Negligible airway epithelial lesions Variable airway smooth muscle hyperplasia

27. Prevention of BPD BEFORE BIRTH Prenatal antibiotics and infection prevention Prompt treatment of chorioamnionitis with antibiotics.

28. Prevention of bpd Antenatal steroids Use of antenatal steroids in mothers at risk for delivering a premature infant reduces the incidence of neonatal deaths and RDS but does not reduce the incidence of CLD. Antenatal thyrotropin-releasing hormone (TRH) has not been effective in prevention of BPD. Cochrane Database Syst Rev 2004;

29. Practices in delivery room The goal in babies being resuscitated at birth,whether born at term or preterm, should be an oxygen saturation value in the interquartile range of preductal saturations These targets may be achieved by initiating resuscitation with air or a blended oxygen and titrating the oxygen concentration to achieve an SpO2 in the target range using pulse oximetry If blended oxygen is not available, resuscitation should be initiated with air If the baby is bradycardic (HR 60 per minute) after 90 seconds of resuscitation------ increase to 100 % o2. Use lower target inflation pressure range between 20- 25 cm h2o

30. Ventilatory strategies Continuous positive airway pressure (CPAP ): Early initiation of nasal CPAP has been shown to reduce the need for intubation and mechanical ventilation

31. Nasal intermittent positive pressure ventilation (NIPPV) NIPPV is a method of augmenting NCPAP by delivering ventilator breaths via the nasal prongs. Improves the tidal and minute volumes and decrease the inspiratory effort required by neonates as compared to nCPAP The Cochrane review that included three RCTs found a trend towards reduction in rates of chronic lung disease. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database of Systematic Reviews

32. Patient-triggered ventilation (PTV): Patient triggered modes (SIMV, assist-control, and pressure support ventilation) improve the infant-ventilator asynchrony. The Cochrane review concluded that though PTV is associated with shorter duration of ventilation, it does not reduce the incidence of BPD. Synchronized mechanicalventilation for respiratory support in newborn infants. Cochrane Database of SystematicReviews2008

33. High-frequency ventilation (HFV): Animal studies indicate that HFV could lead to less lung injury when compared to conventional ventilation A recent meta-analysis that included 17 RCTs of conventional versus high frequency ventilation found no significant difference in the incidence of BPD Ventilation strategies and outcome in Randomised Trials of High Frequency Ventilation Arch Dis Child. 2005

34. Volume targeted ventilation The Cochrane review that included four RCTs found significant reduction in the duration of ventilation and pneumothorax rates but only a borderline reduction in the incidence of BPD. Volume-targeted versus pressure-limited ventilation in the neonate. Cochrane Database of Systematic Reviews 2005

35. PERMISSIVE HYPERCAPNIA : Hypocapnia that occurs during assisted ventilation is an independent risk factor for BPD Co2 targets of 45-55 mm hg are now recommended in order to reduce the days of ventilation.

36. Permissive hypoxemia: A ccepting lower oxygen saturation values is associated with decreased incidences of CLD and ROP BOOST-trial and STOP-ROP trial indicate that maintaining higher oxygen saturation (>95%) is associated with increased need for oxygen at 36 weeks PMA and greater use of postnatal steroids and diuretics in premature infants (when compared to maintaining lower oxygen saturation of 89-94%). Spo2 b/w 85-93% ---- < 32 wks 87-94%---->32 wks

37. Fluid restriction The systematic review of studies on fluid restriction has not found any significant reduction in the incidence of BPD The amount of fluid restriction in VLBW infants is not definitely known. Fluid restriction for treatment of preterm babies with chronic lung disease. (Protocol) Cochrane Database of Systematic Reviews 2005;

38. Nutrition Aggressive parenteral nutrition and early enteral feeding decreases the incidence of BPD in VLBW infants ( The role of nutrition in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006 ) Enteral feeding is often delayed in these infants due to gastrointestinal immaturity, parenteral nutrition with proteins and lipids should be initiated as soon as possible after birth. .

39. Metabolic rate and energy expenditure are elevated in BPD Infants developing BPD require 20 to 40% more calories than their age-matched healthy controls . caloric requirement varies from 120 to 150 Kcal/kg/day More calories– lipids( mct oil)> carbohydrates, lowers respiratory quotient and decreases co2 production.

40. When enteral feeding is started --- give only EBM. Addition of HMF will also increase the calories and make up the deficiencies of protiens and minerals. Mct oil and glucose polymers can also be added.

41. Pharmacological strategies Exogenous surfactant Prophylactic surfactant therapy in infants born before 30 weeks of gestation has not been shown to reduce the incidence of BPD. However, surfactant treatment for established RDS ( ‘rescue therapy’) in infants born at or after 30 weeks of gestation is associated with significant reduction in the incidence of BPD American Academy of Pediatrics Committee on Fetus and Newborn.Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Pediatrics 2008;

43. Role of vit A Vitamin A ---integrity of respiratory tract epithelial cells. Very preterm infants are relatively deficient in vitamin A which has been shown to associated with CLD. large dose of intramuscular vitamin A (5000 units three times a week for 4 weeks from birth) decreases the incidence of CLD. (Cochrane Database Syst Rev 2007) All ELBW infants with respiratory distress requiring supplemental oxygen or mechanical ventilation at 24 hours of age should recieve vit A Vit E – antoxidant, no role in prevention of bpd

44. Role of superoxide dismutase : sod antioxidant --eliminates the free radicles Preterms – deficient in antioxidant enzymes and sucesptible to oxidant injury. A RCT enrolled around 300 infants proved the safe nature of the drug CuZnSOD, But did not find any difference in the primary outcome of BPD at 36 weeks PMA.

45. SOD treated infants-- fewer episodes of respiratory illness at I year of age. Cochrane review on this subject conclude that “The use of superoxide dismutase to prevent chronic lung disease of prematurity is not recommended”

46. Methylxanthines caffeine – reduced incidence of BPD . In a multicenter trial , infants < 1,250 g who received caffeine had lower BPD rates than infants who did not receive it. Duration of ventilaton, need for CPAP, and supplemental oxygen were reduced by caffeine administration. ( Adjunctive therapies in chronic lung disease:examining the evidence. Semin Fetal Neonatal Med 2008)

47. Another large RCT that used caffeine for these indications in infants with birth weights of 500-1250g has shown a significant decrease in the incidence of BPD. Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnoea of prematurity. N Engl J Med 2006 The authors attributed this rather unexpected finding to reduced duration of mechanical ventilation in the caffeine treated group

48. Indomethacin / Ibuprofen therapy for PDA: Patent ductus arteriosus is one of the major risk factors for BPD. prevention or treatment of PDA should ideally reduce its risk. However, prophylactic use of indomethacin in very low birth weight infants has failed to show any reduction in the incidence of BPD despite a significant reduction in the incidence of PDA (Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001)

49. Similar results are obtained with ibufrofen. Treatment of symptomatic PDA could possibly reduce the incidence of BPD . Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr. 1996

50. ROLE OF STEROIDS inflammation ----pathogenesis of BPD Early : During the first 96 hrs after birth Moderately early :Between postnatal days 7 and 14. Delayed :After 3 weeks of age Most commonly used steroid is :dexamethasone AMERICAN ACADEMY OF PEDIATRICS Committee on Fetus and Newborn

51. Systemic Early Postnatal Corticosteroid Therapy <96 Hours preterm, respiratory distress syndrome, and required mechanical ventilation with oxygen at the time of enrollment Corticosteroids (dexamethasone)intravenously within 96 hours after birth. The most commonly used dosages were 0.5 mg/kg of body weight per day for 3 days, followed by a tapering course

52. The combined outcome of death or CLD at 28 days PNA or at 36 weeks’PMA was significantly decreased by early corticosteroid treatment Weaning from mechanical ventilation was more successful in infants treated with dexamethasone. incidences of hypertension, hyperglycemia, insulin therapy for hyperglycemia, gastrointestinal bleeding or perforation, and hypertrophic obstructive cardiomyopathy were increased by early corticosteroid treatment. Borderline increased risk of PVL in steroid group

53. Moderately Early Postnatal Corticosteroid Therapy (7–14 Days PNA) The combined outcome of death or CLD was decreased at 28 days’ PNA and at 36 weeks’ PMA. There was increase in incidence of hyperglycemia, gastrointestinal bleeding, hypertrophic obstructive cardiomyopathy, and infection. AMERICAN ACADEMY OF PEDIATRICS Committee on Fetus and Newborn

54. Systemic Delayed Postnatal Corticosteroid Therapy (>3 Weeks) The incidence of CLD at 36 wks PMA was decreased by steroid therapy. Same side effects. AMERICAN ACADEMY OF PEDIATRICS Committee on Fetus and Newborn

55. The use of inhaled steroids, as well as the use of systemic steroids cannot be recommended as a part of standard practice for ventilated preterm infants to prevent CLD ( Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm Neonates Cochrane Database of Systematic Reviews 2008)

56. Inhaled nitric oxide pulmonary vasodilatation ,reduces lung inflammation and promotes lung growth iNO as rescue therapy for the very ill preterm infant does not appear to be effective. Early routine use of iNO in preterm infants with respiratory disease does not improve survival without BPD Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 12

57. Diuretic therapy: MOA: decreases interstitial and peribronchial fuid--- dec resistance and improves compliance Response: acute response – 1 hr, max clinical response– 1 wk Indication: clinical/radiographic features of pulmonary edema in an infant with evolving or established BPD Pharmacological strategies in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006

58. Dose: 0.5-1 mg/kg, stop after 24- 48 hours if no improvement in clinical condition. no effects on mortality or the incidence of BPD

59. Mast cell stabilizers Cromolyn sodium decrease neutrophil migration and activation ----minimizes inflammation in the lungs Dose: 10-20 mg 6-8 hr , nebulization. 2 trials– no benefit in prevention and treatment. Cromolyn sodium for the prevention of chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2001

60. Associted complications Cor pulmonale Systemic hypertension Systemic to pulmonary shunting Metabolic imbalance– sec to diuretics Infection-- urealasma and mycoplasma----rx with erythromycin Viral infections and fungal infections are also common

61. Cns dysfunction: a neurologic syndrome presenting with EPS signs has been described Hearing loss ROP Nephrocalcinosis Growth failure

62. Discharge planning Spo2 maintained > 92-94% No significant period of desaturation during feeding or sleep Good weight gain Stable respiratory status

63. Immmunization In addition to standard immunization , infants with CLD should receive penumocoocal, influenza and palivizumab AAP RECOMMENDATIONS FOR PALIVIZUMAB Administer monthly beginning in early november for 5 months Dose: 15mg/kg IM

64. OUTCOME MORTALITY: 10-20% in first year of life (infection) Morbidity: increased risk of reactive airway disease , bronchiolitis and pneumonia Rehospitalization rate is twice that of matched controls in first 2 yr of life Growth failure: delayed growth in 1/3 to 2/3 of these infants at 2 years.