Bronchopulmonary Dysplasia

BPD in neonates

1. Bronchopulmonary Dysplasia

2. BPD Introduction Etiological factors Pathogenesis Clinical Features Management Preventive measures Treatment Newer / experimental modalities Long term outcome

3. Introduction Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) usually occurs in preterm infants who require mechanical ventilation and/or oxygen therapy for a primary lung disorder in early neonatal period. Incidence of CLD has largely remained unchanged over the years, although better treatment modalities are available now but the improved survival of more immature infants has led to increased numbers of BPD. The definition, pathophysiology , and management of bronchopulmonary dysplasia (BPD) has evolved significantly since first described by Northway almost 50 years ago. Northway, W.H., Jr.; Rosan , R.C.; Porter, D.Y. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. New Engl. J. Med. 1967, 276, 357–368.

4. Definition The earliest clinical definition of BPD was limited to oxygen requirement at 28 days with consistent radiologic changes.( Northway et al in 1967 ) These were originally modified to include continuing need for oxygen therapy at 36 weeks corrected gestational age(CGA). To address the inconsistencies in the diagnostic criteria, the United States National Institute of Health (NIH) organized a consensus conference in 2000 which suggested a new definition by incorporating many elements of previous definitions of BPD.

5. Definition The definition now takes into account total duration of oxygen supplementation, positive pressure requirements and gestational age , in addition to oxygen dependency at 36 weeks post menstrual age (PMA). As per oxygen need / ventilatory support severity of BPD was decided. American Thoracic Society. Copyright © 2016 American Thoracic Society. Jobe , A.H.; Bancalari , E.Bronchopulmonary Dysplasia. Am. J. Respir . Crit. Care Med. 2001, 163, 1723–1729. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

6. <32 weeks GA >32 weeks GA Treatment with oxygen >21% for at least 28 days >21% for at least 28 days Time point of assessment 36 weeks PMA or discharge* >28 days but <56 days postnatal age or discharge* Grade : 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* Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9 Definition of Bronchopulmonary Dysplasia: Diagnostic Criteria. Reprinted with permission of the American Thoracic Society. Copyright © 2016 American Thoracic Society. Jobe , A.H.; Bancalari , E.Bronchopulmonary Dysplasia. Am. J. Respir . Crit. Care Med. 2001, 163, 1723–1729. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. *- whichever comes first

7. limitations – Fails to classify infants with respect to airway issues (including tracheal or bronchomalacia and/or reactive airway disease) and pulmonary vascular disease. Infants who had intervals of off oxygen period in the first few weeks. Use of high- flow nasal cannula , is not addressed and can result in misclassification . Does not include morbidities in early infancy associated with BPD. Poindexter, B.B.; Feng , R.; Schmidt, B.; Aschner , J.L.; Ballard, R.A.; Hamvas , A.; Reynolds, A.M.; Shaw, P.A.;Jobe , A.H. Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program. Ann. Am. Thorac . Soc. 2015, 12, 1822–1830.

8. Incidence Few reports are available from the centers in India; one study from Chandigarh found the incidence of CLD (defined as need for oxygen at or beyond 28 days of life) to be 50% and 9% in ELBW and VLBW infants respectively. Narang A, Kumar P, Kumar R. Chronic Lung Disease in Neonates: Emerging problem in India. Indian Pediatr 2002; 39: 158-62 Recently, Ehrenkranz et al validated the consensus definition in a cohort of preterm (<32 weeks) extremely low birth weight (ELBW) infants and reported an incidence of 77% by the new criteria. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA,Wrage LA, Poole K; National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005;116:1353-60

9. Incidence In the NICHD Neonatal Network, the incidence of BPD at 36 weeks postmenstrual age in all infants weighing 501 to 1500 g (<32 weeks) at birth increased from 19% in 1990 to 22% in 2000, with another increase to 27% in 2003. Increased survival has been associated with these trends. The highest rates of BPD were in the smallest infants, 66% for those 501 to 750 g and 40% for those 751 to 1000 g birthweight , ( Fanaroff et al, 2007).

10. Risk factors Prematurity - The lung is most susceptible before alveolar septation begins (Near Term). Injury at this stage may lead to an arrest of alveolarization . Mechanical ventilation- pressure and volume trauma to growing lung Oxygen toxicity – high levels of free oxygen radicles damage lung tissues Patent ductus arteriosus (PDA)- fluid overload Pre- and postnatal infection & Inflammation - damage lung tissues Growth restriction or nutritional deficits - poor lung growth Genetic predisposition- history of hyperreactive lung disease in families Excessive early intravenous fluid administration- contributes to pulmonary edema

11. Stages of lung development: Embryonic stage (week:8) Pseudoglandular (weeks:8-16) Canalicular (weeks: 16-24) Saccular (weeks:24-near term) Alveolar (weeks: 34 weeks to postnatal period) The specific timing and duration of exposures influences the pattern of pulmonary damage.

12. Pathogenesis The etiology of BPD is clearly multifactorial and involves:- derangements in multiple aspects of lung function Surfactant production, Repair from injury (e.g., elastin deposition) and Growth and development (e.g., alveologenesis ).

13. Pathogenesis The phenotype seen with BPD is the end result of a complex multifactorial process in which various pre- and postnatal factors compromise normal development in the immature lung. Susceptible host with immature lung structure, Developmental deficiencies of factors crucial to lung development and function such as surfactant, nitric oxide, innate immune defense , and antioxidant capability Inadequate nutrition,resulting in postnatal growth failure,

14. Clinical and Radiological features Respiratory signs in infants with CLD include fast breathing, retractions, and paradoxical breathing. Rales and coarse rhonchi are usually heard on auscultation. Radiographic features of ‘old’ and ‘new’ BPD are quite different. New BPD shows haziness reflecting diffuse loss of lung volume. Occasionally they have dense areas of segmental or lobar atelectasis or pneumonic infiltrates, but they do not show severe overinflation . ‘Old’ BPD, as originally described by Northway, had four distinct stages.

15. Stages of ‘ old’BPD Stages of BPD (old BPD) features Stage- 1 consistent with hyaline membrane disease Stage-2 opaque lung fields with air bronchograms due to areas of atelectasis alternating with emphysema; / normal-low lung volume Stage-3 small radiolucent fields, streaky densities with early hyperinfl ation Stage-4 hyperinflated lungs with generalized cystic areas and dense fibrotic strands.

16. Old v/s New BPD Old BPD New BPD Etiology High O2 & mechanical ventilation Disorder of lung development Babies Originally reported by Northway in 1967, infants with a mean gestational age of 33 weeks and a birth weight of 2,000 g. mean gestational age under 28 weeks and birth weight under 1,000 g. Pathology emphysema, atelectasis and fibrosis, and marked epithelial metaplasia and smooth muscle hypertrophy in the airways and in the pulmonary vasculature. The major abnormalities are a decrease in alveolar number (referred to as alveolar hypoplasia ) and dysregulated microvascular growth (Bhatt et al, 2001; Burri , 1997; Coalson et al, 1999; De Paepe et al, 2006, 2008; Husain et al, 1998; Maniscalcoet al, 2002).

17. Preventive measures Antenatal steroids Probable benefits (indirect) Surfactant replacement therapy Probable benefits (indirect) Gentle ventilation and CPAP Needs more studies Fluid restriction Needs more studies Vitamin A Proven benefits Postnatal corticosteroids Proven benefits Antioxidant Therapy Needs more studies Inhaled nitric oxide Needs more studies Caffeine Probable benefits Azithromycin - Only in proven infection Early Entral / parentral nutrition

18. Prevention of BPD Management strategies are aimed at protecting against lung injury and the development of BPD. As the pathogenesis of disease is multifactorial , diverse approaches have been adopted including both ventilation and medical strategies.

19. Antenatal Steroids The effect of antenatal glucocorticoids on the incidence of BPD among survivors has been inconsistent. Some studies have demonstrated a benefit ( Gagliardi et al,2007; Van Marter et al, 1990). The inconsistent effect of antenatal steroids on BPD may be due to increased survival of less mature preterm infants. Antenatal steroids  less RDS/ HMDless BPD ( but more survival of less mature preterms  increased BPD)

20. Ventilation In spite of the development of numerous sophisticated ventilators for the newborn, there is still no clear advantage to any one approach to ventilating the preterm infant. Early initiation of nasal CPAP (other non invasive modes) has been shown to reduce the need for intubation and mechanical ventilation. Mechanical ventilation is major risk factors for, so use of early CPAP should logically reduce its incidence. If invasive ventilation is done, babies can be extubated more successfully if post extubation put on to nasal CPAP. ( Gupta et al 2009; Ho et al, 2002 ). The general approach should be one of preventing atelectasis , sustaining FRC, using a minimal tidal volume (usually 4 to 6 mL /kg), and allowing the infant to trigger his or her own ventilation as much as possible ( Carlo et al, 2002 ).

21. Saturation targets Specific to the outcome of BPD, the Surfactant, Positive Pressure and Oxygenation Randomization Trial ( SUPPORT) conducted in the US found slightly lower rates of BPD ( 38% vs. 41.7%) in the low-saturation group without statistical significance. (with low 85%–89% and high 91%–95%) The Canadian Oxygen Trial (COT) similarly identified a similar trend with BPD rates of 31.8% and 33.1% in the low- and high-saturation groups respectively. Despite the theoretical concerns for increased risk of oxidative lung injury and pulmonary vascular remodeling , many units now use higher saturation limits of 91%–95% based upon the collective finding of improved survival in multiple trials. Saugstad , O.D.; Aune , D. Optimal oxygenation of extremely low birth weight infants: A meta-analysis and systematic review of the oxygen saturation target studies. Neonatology 2014, 105, 55–63.

22. Surfactant Replacement Therapy Surfactant replacement therapy is clearly associated with decreased severity of RDS and its associated mortality. Although there is not substantial evidence that survivors have a decreased incidence of BPD. ( Engle and the Committee on Fetus and Newborn, 2008). In addition, it is possible that later replacement surfactant , during a period of secondary surfactant dysfunction ( Merrill et al, 2004 ), could be an effective way to prevent BPD in those infants who continue to require mechanical ventilation after the 1st week of life.

23. 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 gestation is associated with significant reduction in the incidence of BPD. Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn. Surfactant -replacement therapy for respiratory distress in the preterm and term neonate.Pediatrics 2008;121:419-32 The apparent lack of effect in the first group could probably be due to the increased survival of more immature infants ( similar to antenatal steroids ). Interestingly, both antenatal steroids and surfactant reduce rates of RDS and improve survival; however, neither has been shown to reduce incidence of BPD. Seger , N.; Soll , R. Animal derived surfactant extract for treatment of respiratory distress syndrome.Cochrane Database Syst. Rev. 2009.

24. Exogenous surfactant Meta-analysis of randomized clinical trials comparing prophylactic or early use of surfactant to initial support by continuous airway pressure (CPAP) have identified reduction in the combined outcome of death or BPD with avoidance of intubation. Still more evidence is needed in this regard before coming to any meaningful conclusion. Fischer, H.S.; Buhrer , C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: A meta-analysis. Pediatrics 2013, 132, e1351–e1360. [ CrossRef ] [ PubMed ] Schmolzer , G.M.; Kumar, M.; Pichler , G.; Aziz, K.; O’Reilly, M.; Cheung, P.Y. Non-invasive versus invasive respiratory support in preterm infants at birth: Systematic review and meta-analysis. BMJ 2013, 347, f5980. [ CrossRef ] [ PubMed ] Subramaniam , P.; Ho, J.J.; Davis, P.G. Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants. Cochrane Database Syst. Rev. 2016. [ CrossRef ]

25. Postnatal Corticosteroids Treatment with glucocorticoids does not appear to have a substantial impact on long-term pulmonary outcomes, such as duration of supplemental O2 requirement, length of hospital stay, or mortality. Currently, recommendations of the American Academy of Pediatrics and the Canadian Pediatric Society 2002 are that the use of postnatal steroids be restricted to randomized, controlled trials and, when these agents are given outside such trials, they be used only under exceptional circumstances of severity and after fully informing the parents of the potential problems with neurodevelopmental outcome.

26. Steroids: The DART study randomized 70 ventilator dependent infants with average birth weights less than 700g to a 10 day tapered dose of dexamethasone or placebo at a mean postnatal age of 23d. Treatment schedules of 0.2 mg/kg of dexamethasone or less tapered over 7 to 10d seem to avoid the hyperglycemia and hypertension frequently encountered with the higher doses and longer treatment schedules . Doyle LW, Davis PG, Morley CJ, et al. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial.  Pediatrics . 2006;117:75.  Prednisolone also has been used, but not evaluated in randomized trials Bhandari A, Schramm CM, Kimble C, et al. Effect of a short course of prednisolone in infants with oxygen-dependent bronchopulmonary dysplasia.  Pediatrics . 2008;121:e344.  [

27. Fluids Fluid restriction: old studies indicate that relative fluid restriction reduces incidence of BPD in preterm infants. However, the systematic review of studies on fluid restriction has not found any significant reduction. Barrington KJ, Al- Hazzani FN. Fluid restriction for treatment of preterm babies with chronic lung disease. (Protocol) Cochrane Database of Systematic Reviews 2005; (3):CD005389. Multiple studies suggest that fluid overload contributes to an increased risk of BPD ( Oh et al, 2005) However, extremely restrictive fluid administration contributes to the problem of undernutrition , thereby contributing to failure of alveologenesis . Moreover what represents fluid restriction in VLBW infants is not definitely known. Hence , no definite recommendation can be made regarding fluid restriction as a strategy for reducing the incidence of BPD.

28. Nutrition: Nutrition plays an important role in lung development and maturation. Aggressive parenteral nutrition and early enteral feeding may help decrease the incidence of BPD in VLBW infants. Biniwale MA, Ehrenkranz RA. The role of nutrition in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006;30:200-8 Ideally, nutritional management should begin as soon as posible after birth to minimize the respiratory morbidities. The initial management should meet the estimated fluid, protein, lipids and energy needs. Infants developing BPD require 20 to 40% more calories than their age-matched healthy controls. Their caloric requirement varies from 120 to 150 Kcal/kg/day.

29. Nutrition: This can be achieved by fortifying breast milk with human milk fortifier (HMF) or infant formula. For infants who require more calories, fat supplementation (e.g. MCT oil) is preferred. The role of specific nutrients (e.g. inositol , vitamin E, selenium, glutamine etc. except for vitamin A) however, remains speculative till now.

30. Vitamin A Vitamin A deficiency may predispose to chronic lung disease as it is a key regulator of normal lung growth . It plays a critical role in maintaining the integrity of respiratory tract epithelium and stored in the septal cells of the alveoli involved in alveolar septation ( Albertine et al, 1999) Vitamin A is accumulated predominantly in the third trimester, preterm infants have deficient liver stores of this vitamin ( Zachman , 1989 ). A number of clinical trials have investigated whether supplementation with vitamin A, typically by intramuscular injections, would result in a decrease in BPD.

31. Route of vitamin A administration I.V.- Vitamin A added to parenteral nutrition solutions is degraded by light and can adhere to the intravenous tubing, making it largely inaccessible. I.M .-Administration requires intramuscular injections which is associated with significant discomfort and potentially an increased risk of infection. Oral -A large trial is currently in progress evaluating the efficacy of oral vitamin A supplementation with hopes that a simpler route of administration may also be effective. Meyer, S.; Gortner , L.; NeoVitaA Trial investigators. Up-date on the NeoVitaA Trial: Obstacles, challenges,perspectives , and local experiences. Wien. Med. Wochenschr . 2016.

32. Vitamin A A large RCT of 807 infants with a birth weight of less than 1000 g has shown that a large dose of intramuscular vitamin A (5000 units three times a week for 4 weeks from birth) decreases the risk of CLD.A meta-analysis of seven RCTs has also confirmed this finding. Darlow BA, Graham PJ. Vitamin A supplementation for preventing morbidity and mortality in very low birth weight infants. Cochrane Database Syst Rev 2002; 4: CD000501. The largest study to date, by the NICHD Neonatal Network, also used one of the higher doses that has been studied and demonstrated a significant decrease in BPD or death at 36 weeks following treatment with vitamin A (55% vs. 62%) ( Tyson et al, 1999).

33. Antioxidant Therapy Superoxide dismutase is a naturally occurring enzyme that protects against oxygen free radical injury. Human studies have suggested that administration of intratracheal recombinant human superoxide dismutase ( rhSOD ) is well tolerated and might have beneficial effects on the lung ( Davis, 2002; Davis et al, 2003 ). Further trials of this intervention are needed before it can be recommended as useful in preventing BPD.

34. Nitric Oxide Most clinical studies in preterm infants with severe respiratory failure have not demonstrated any reduction in the risk of death or CLD with iNO . Recently, two large RCTs conducted in this regard indicate that iNO therapy might be beneficial in a select group of preterm infants. Expert review of the topic resulted in consensus opinions from both the NIH and the American Academy of Pediatrics do not recommend the routine use of iNO in premature infants. Despite these statements, off-label use of iNO in extremely premature infants remains on the rise . Ellsworth, M.A.; Harris, M.N.; Carey,W.A .; Spitzer, A.R.; Clark, R.H. Off-label use of inhaled nitric oxide after release of nih consensus statement. Pediatrics 2015, 135, 643–648. Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 2006;355:354-64

35. Nitric Oxide the appropriate dose, timing, duration, and more importantly, the subgroup of infants who are likely to benefit with this mode of therapy have not yet been clearly defined. Subsequent meta-analysis suggested no specific benefit with prematurity and stated routine use could not be recommended . Moreover, the prohibitive cost of iNO therapy precludes its use on a routine basis Barrington, K.J.; Finer, N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane DatabaseSyst . Rev. 2010. [ CrossRef ] 119. Askie , L.M.; Ballard, R.A.; Cutter, G.R.; Dani , C.; Elbourne , D.; Field, D.; Hascoet , J.M.; Hibbs , A.M.;Kinsella , J.P.; Mercier, J.C.; et al. Inhaled nitric oxide in preterm infants: An individual-patient data meta-analysis of randomized trials. Pediatrics 2011, 128, 729–739. Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PJ, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 2006;355:343-53

36. Others Indomethacin / Ibuprofen therapy for PDA: treatment of symptomatic PDA could possibly reduce the incidence of BPD. Patent ductus arteriosus is one of the major risk factors for BPD. No role of prophylactic indomethacin /ibuprofen for BPD. Caffine citrate- decrease incidence of apnea of prematurity and intubation/ventilation. Azithromycin - decrease the risk of developing BPD in infants with documented Ureaplasma colonization or infection. Cloherty

37. Treatment Ventilation Caffeine Inhaled Nitric oxide Diuretics Bronchodilator therapy Postnatal corticosteroids Nutrition

38. Ventilatory strategies Given that no ‘ ideal’ pharmacological agents are available for prevention of BPD, attention has now shifted to ‘optimal’ ventilatory strategies that would prevent/reduce lung injury and permit adequate lung development.

39. Ventilatory - Strategies: Minimizing ventilatory support Prefer non invasive ventilation, whenever it is possible CPAP/HHHFNC If invasive ventilation used: Volume targeted ventilation Patient triggered ventilation (SIMV) Low tidal volume (3-6 ml/kg) Moderate PEEP (4-5 cm H2o) Slightly high Ti (0.4-0.45) Permissive hypercapnea ( PaCO2 (45-55 mm Hg provided pH >7.25) Ambalavanan N, Carlo WA. Ventilatory strategies in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006;30:192-9 AIIMS protocol

40. Continuous positive airway pressure (CPAP): Non invasive ventilation is always better than invasive modalities. Numerous studies, mostly non-randomized, have reported the benefits of early CPAP in minimizing the need for mechanical ventilation and the incidence of chronic lung disease. Lemyre , B.; Davis, P.G.; De Paoli, A.G.; Kirpalani , H. Nasal intermittent positive pressure ventilation(NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.Cochrane Database Syst. Rev. 2014.

41. Patient-triggered ventilation (PTV): Patient triggered modes (SIMV, assist-control, and pressure support ventilation) improve the infant-ventilator asynchrony and reduce the risk of Ventilator induced lung injury. The Cochrane review concluded that though PTV is associated with shorter duration of ventilation, it does not reduce the incidence of BPD. Greenough A, Dimitriou G, Prendergast M, Milner AD. Synchronized mechanical ventilation for respiratory support in newborn infants. Cochrane Database of Systematic Reviews 2008;3: CD000456.

42. High-frequency ventilation (HFV): Animal studies indicate that HFV could lead to less lung injury when compared to conventional ventilation. However, randomized controlled trials comparing elective use of HFV with conventional ventilation in preterm infants have yielded conflicting results. A recent meta-analysis that included 17 RCTs of conventional versus high frequency ventilation found no significant difference in the incidence of BPD. Therefore, elective use of HFV cannot be recommended for preterm infants with RDS at present. Thome UH, Carlo WA, Pohlandt F. Ventilation strategies and outcome in Randomised Trials of High Frequency Ventilation. Arch Dis Child. 2005;90:F466-73

43. Volume targeted ventilation: The observation that volutrauma and not barotrauma is the primary determinant of V entilator I induced L ung I injury has enthused neonatologists to use volume controlled/targeted modes of ventilation in place of conventional pressure controlled modes. Only a few randomized trials are available in this regard till date. 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. McCallionN , Davis PG, MorleyCJ . Volume-targeted versus pressure-limited ventilation in the neonate. Cochrane Database of Systematic Reviews 2005;3: CD003666. More studies are needed to address the question of whether volume controlled ventilation would result in better long term respiratory outcomes.

44. Permissive hypercapnia Retrospective studies have suggested that hypocapnia that occurs during assisted ventilation is an independent risk factor for BPD. Subsequently, ‘minimal ventilation’ using smaller tidal volumes / less peak inflation pressures while accepting mild hypercapnia (PaCO2 45-55 mm Hg) was studied in preterm infants. One such study in preterm ELBW infants (target PaCO2 >52 mm Hg in study group) reported less need for mechanical ventilation but no reduction in the need for supplemental oxygen at 36 weeks PMA. Clearly , more studies are needed to prove the intended benefits of this promising strategy. Carlo WA, Stark AR, Wright LL, Tyson JE, Papile LA, Shankaran S, et al. Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-low-birth-weight infants. J Pediatr 2002;141:370-4

45. Permissive hypoxemia : Exposure to high oxygen concentration has long been recognized as an important factor in the pathogenesis of BPD. Preterm infants are more vulnerable to the harmful effects of free oxygen radicals. Surprisingly, there are few data to suggest either the optimal oxygen level required or the optimum target range for oxygen saturations (SpO2) in these infants. Observational studies suggest that in comparison with the more liberal oxygen therapy, the restrictive approach of accepting lower oxygen saturation values is associated with decreased incidences of CLD and ROP . Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. Oxygen-saturation targets and outcomes in extremely preterm infants. N Engl J Med 2003; 4;349:959-67

46. Permissive hypoxemia : Two RCTs have been conducted to see whether it is better to aim for high oxygen saturation in infants who are more than a few weeks old: BOOST-trial and STOP-ROP trial. Both these studies 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%). Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOPROP),a randomized, controlled trial. I: primary outcomes. Pediatrics.2000;105:295-310 Still, the uncertainty about ‘optimal’ oxygenation has led to wide variation of policies on oxygen-monitoring and therapy in neonatal nurseries.

47. Diuretic therapy: In infants with well-developed BPD, pulmonary edema is a major component of the illness. Diuretics help by increasing the reabsorption of fluid from the lungs. There is clear evidence that either daily or alternate-day therapy with furosemide improves lung mechanics and gas exchange in infants with established BPD. ( Hazinski , 2000 ) Thiazide type diuretics alone or in combination with spironolactone also have improved lung function in some studies. ( Rush et al, 2001 ).

48. Diuretics In view of the lack of data from randomized trials concerning effects on important clinical outcomes, routine or sustained use of systemic loop diuretics in infants with (or developing) CLD cannot be recommended based on current evidence. Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2003), MEDLINE (1966 to April 2003), EMBASE (1974 to 1998) However, diuretics can be used sparingly if there are clinical/radiographic features of pulmonary edema in an infant with evolving or established BPD.( Baveja R, Christou H. Pharmacological strategies in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006;30:209-18 ) An acute clinical response may be seen within 1 hour, although maximal effect may not be achieved until 1 week of therapy.

49. Diuretics Diuretics have not been shown to improve clinical outcomes such as duration of ventilator dependence, hospital length of stay, or long-term outcome. Still m ost centers use diuretics at some point in the management of infants with BPD. Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2003), MEDLINE (1966 to April 2003), EMBASE (1974 to 1998) Drugs- furosemide / chlorothiazide / spironolactone

50. Bronchodilator Therapy With established BPD, there is a significant increase in airway resistance, and there may also be persistent or intermittent wheezing may be related to increased airway tone or bronchospasm . Inhaled albuterol has been the most widely used agent. Systemic use of bronchodilators has been more restricted because of a high incidence of side effects and a very narrow therapeutic index ( DeBoeck et al, 1998 ).

51. Bronchodilator Therapy Infants with developing CLD may benefit as early as the second week of age. a. Albuterol nebulization every 6 to 8 hours S/E- tachycardia b. Ipratropium bromide- more potent bronchodilator . Combination therapy is more effactive compared to single agent.( Nelson, textbook of pediatrics -20 th edition ) Diuretics and bronchodilators can be used if the clinical condition warrants but should be stopped if no response occurs within 24-48 hours of initiation of therapy.

52. Mast cell stabilizers: Cromolyn sodium has been shown to decrease neutrophil migration and activation thus minimizing inflammation in the lungs. Two trials that have studied the possible role of cromolyn for prevention and treatment of BPD have not shown any benefit. Ng GY, Ohlsson A. Cromolyn sodium for the prevention of chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2001;(2):CD003059

53. Postnatal steroids: Inflammation plays a central role in the pathogenesis of BPD , steroids were thought to be a choice of management as anti-inflammatory agent. Conventionally, steroid therapy is categorized into 3 broad groups based on the timing of initiation: (I.V. Dexamethasone – DART study; Doyle 2000a ) early (during the first 96 hrs after birth), moderately early (between postnatal days 7 and 14), and delayed (after 3 weeks of age). Meta-analyses of RCTs of the first two regimes have shown a significant reduction in the incidence of BPD at 36 weeks PMA. Halliday HL, Ehrenkranz RA. Moderately early (7–14 days) postnatal corticosteroids forpreventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003; (1): CD001144.

54. Postnatal steroids: However, there are important concerns regarding both short-term (hypertension, gastrointestinal perforation, poor somatic growth) as well as long-term adverse effects ( neurodevelopmental outcomes including cerebral palsy). Rates of use of systemic steroids for prevention of BPD have markedly decreased following American Academy of Pediatrics (AAP) and Canadian Pediatric Society (CPS ) recommendations in 2002 against routine use. Specifically , rates of postnatal corticosteroids use declined from 20% in 1997–2000 to only 12% in 2001–2002 and then again to 8% in 2004 with no significant change thereafter . Fanaroff , A.A Korones , S.B.; Laptook , A.R.; et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am. J. Obstet. Gynecol. 2007, 196, 147.e1–147.e8.

55. Inhaled corticosteroids Based on this updated review, there is increasing evidence from the trials reviewed that early administration of inhaled steroids to VLBW neonates is effective in reducing the incidence of death or CLD at 36 weeks' PMA among either all randomised infants or among survivors. ( Cochrane review 2017) Further studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short- and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental  outcome. Clouse, B.J.; Jadcherla , S.R.; Slaughter, J.L. Systematic review of inhaled bronchodilator and corticosteroid therapies in infants with bronchopulmonary dysplasia: Implications and future directions. PLoS ONE 2016, 11, e0148188. [ CrossRef ] [ PubMed ] 105. Onland , W.; Offringa , M.; van Kaam , A. Late (7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst. Rev. 2012.

56. Caffeine Methylxanthines - increase respiratory drive/ decrease apnoea / improve diaphragmatic contractility/has diuretic effect/ decrease PVR & increase lung compliance probably through direct smooth muscle relaxation. In the recent randomized, multicenter Caffeine for Apnea of Prematurity (CAP) trial, early initiation of caffeine was found to result in lower incidence of BPD as well as a shorter course of respiratory support as compared to controls. Schmidt, B.; Roberts, R.S.; Davis, P.; Doyle, L.W.; Barrington, K.J.; Ohlsson , A.; Solimano , A.; Tin, W. Caffeinetherapy for apnea of prematurity. New Engl. J. Med. 2006, 354, 2112–2121 The specific mechanism by which caffeine protects against lung injury remains unclear, and improved outcomes may have been due to decreased incidence of apnea of prematurity. ( Schmidt et al,2006b ).

57. Strategies Proven benefits Promising (need more studies) Probable benefits (effects +/-) No benefit Ventilatory - NIPPV Volume targeted ventilation Permissive hypercapnea / hypoxemia Early CPAP Patient triggered mode HFO Fluid & nutrition - Aggressive early entral & parentral nutrition Fluid restriction - Pharmacological Vitamin A Postnatal steroids ( S/E +) Superoxide dysmutase Antenatal steroids Methylxanthines Surfactant Diuretics iNO Prophylactic indomethacin / ibupprofen Mastcell stabilizer AIIMS protocol

58. Long-Term Outcomes Long-term outcomes of BPD remain difficult to characterize as adult populations currently available to study represent survivors of outdated care. Mortality. Mortality is estimated at 10% to 20% during the fi rst year of life. The risk increases with duration of O2 exposure and level of ventilatory support. Death is frequently caused by infection. Jobe AH. The new bronchopulmonary dysplasia. Curr Opin Pediatr 2011;23(2):167–172. Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet 2006;367(9520):1421–1431.

59. Long term outcome Pulmonary functions- Numerous studies have evaluated long-term pulmonary function after premature birth alone. A meta-analysis including 59 articles identified that percent of predicted forced expiratory volume in 1 second (FEV1) is decreased in preterm-born survivors, even in patients who did not have a history of BPD. Evaluation of teenaged or young adult survivors of BPD specifically confirmed lower FEV1, as well as decreased forced vital capacity (FVC) and forced expiratory flow rate at 50% of FVC as compared to controls. Landry, J.S.; Chan, T.; Lands, L.; Menzies , D. Long-term impact of bronchopulmonary dysplasia on pulmonary function. Can. Respir . J. 2011, 18, 265–270.

60. Long term outcome Pulmonary defence – Premature infants have increased susceptibility to infection which persists into childhood. Common respiratory infections can result in severe morbidity and potential mortality in BPD survivors. Exposure to environmental insults including respiratory infections, tobacco and pollution may complicate resolution of BPD and prolong risks of pulmonary morbidity Beyond environmental insults, pulmonary morbidity in ex-preterm infants can be complicated by chronic reflux and microaspiration with risk of aspiration pneumonia and/or chronic inflammation. Collaco , J.M.; Aherrera , A.D.; Ryan, T.; McGrath-Morrow, S.A. Secondhand smoke exposure in preterm infants with bronchopulmonary dysplasia. Pediatr . Pulmonol . 2014, 49, 173–178.

61. Long term outcome Asthma like symptoms- Long-term follow-up of infants born <26 weeks gestation identified that 25% had an asthma diagnosis at 11 years of age and around 56% had evidence of abnormal spirometry . Many survivors of BPD demonstrate a component of reactive airway disease. While children with BPD have asthma-like symptoms, they are less likely to demonstrate airway hyper-responsiveness or response to bronchodilators as they may suffer a fixed peripheral airway narrowing. Fawke , J.; Lum , S.; Kirkby, J.; Hennessy, E.; Marlow, N.; Rowell, V.; Thomas, S.; Stocks, J. Lung function and respiratory symptoms at 11 years in children born extremely preterm: The epicure study. Am. J. Respir . Crit. Care Med. 2010, 182, 237–245.

62. Long term outcome Exercise intolerance -Significant risk of exercise-induced bronchoconstriction has been demonstrated in children with BPD consistent with concerns for reactive airway disease . Joshi, S.; Powell, T.; Watkins, W.J.; Drayton, M.; Williams, E.M.; Kotecha , S. Exercise-induced bronchoconstriction in school-aged children who had chronic lung disease in infancy. J. Pediatr . 2013, 162, 813–818.

63. Long term outcome Pulmonary artery hypertension Dysmorphic pulmonary vasculature and compromised angiogenesis with BPD results in risk of elevated pulmonary pressures or BPD-associated pulmonary hypertension (PH). Retrospective studies of infants with BPD suggested that 25%–37% of infants with BPD develop associated PH, but these data are limited by inconsistent definition and screening protocols. An, H.S.; Bae , E.J.; Kim, G.B.; Kwon, B.S.; Beak, J.S.; Kim, E.K.; Kim, H.S.; Choi , J.H.; Noh, C.I.; Yun , Y.S.Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Korean Circ. J. 2010, 40, 131–136.

64. Conditions may be associated with BPD System Morbidities Respiratory Oxygen dependency for hypoxia Airway obstructive disease Laryngo-tracheo-bronchomalacia Subglottic stenosis Respiratory viral infections Aspiration pneumonitis Cardio vascular Pulmonary hypertension Cor pulmonale G.I. system & growth GER Poor growth CNS Developmental abnormalities Behavioural problems Ophthalmology ROP Forfer & Arneil’s -7 th edition

65. Conclusion Advances in neonatal care have resulted in increased rates of survival of extremely premature infants leading to both a new set of management challenges as well as an emerging population of long-term survivors of BPD. Non invasive ventilation is preferred over invasive ventilation. During invasive ventilation - Volume controlled, patient triggered ventilation with moderate PEEP, low tidal volume and slightly high Ti is used to minimize ventilator induced lung injury.

66. Conclusion Interdisciplinary care to manage the complex pulmonary, nutritional and developmental needs of these patients is critical and may itself influence outcomes of severe BPD. Subclinical right ventricular dysfunction, obstructive lung disease, exercise intolerance, and asthma-like symptoms in survivors are frequent and should be evaluated and managed accordingly.

67. THANK YOU

68. The definition, pathophysiology , and management of bronchopulmonary dysplasia (BPD) has evolved significantly since first described by Northway almost 50 years ago.

69. Nasal intermittent positive pressure ventilation (NIPPV): In contrast, a Cochrane review including eight trials comparing NIPPV with CPAP identified less extubation failure with NIPPV, but no specific benefit with respect to risk of BPD . NIPPV is a method of augmenting NCPAP by delivering ventilator breaths via the nasal prongs. It is thought to improve the tidal and minute volumes and decrease the inspiratory effort required by neonates as compared to nCPAP . This should reduce the need for reintubation thus avoiding ventilator induced lung injury (VILI). The Cochrane review that included three RCTs found a trend towards reduction in rates of chronic lung disease (typical RR 0.73; 95% CI: 0.49, 1.07).16 However, more trials are required to document the safety and effectiveness of this relatively new modality. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB; COIN Trial Investigators. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008;14;358:700-8 Davis PG, Lemyre B, De Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation . Cochrane Database of Systematic Reviews 2001;3:CD003212

70. Ventilatory - Strategies Evolving BPD (2-4 weeks) Established BPD (>4 weeks) Minimizing ventilatory support (e.g. using nCPAP whenever possible) Tolerating slightly higher PaCO2 (45- 55 mm Hg provided pH >7.25) Target SpO2 : 88-93% If on IMV: Use PTVif possible Slow rates (25-40/min) Moderate PEEP (4-5 cm H2O) Moderate Ti (0.35-0.45 sec) Low tidal volume (3-6 mL /kg) Early extubation to CPAP Minimizing ventilatory support Tolerating higher PaCO2 (55-60 mm Hg provided pH >7.25) Target SpO2 : 89-94% If on IMV: Use PTVif possible Slow rates (20-40/min) Moderate PEEP (4-8 cm H2O) Longer Ti (0.4-0.7 sec) Larger tidal volume (5-8 mL /kg)

71. Continuous positive airway pressure (CPAP): Recently, a multi-centric study on CPAP versus intubation and ventilation in infants born at 25-28 weeks’ gestation found significant reduction in the need for oxygen at 28 days of life but not at 36 weeks PMA. Fischer, H.S.; Buhrer , C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: A meta-analysis. Pediatrics 2013, 132, e1351–e1360. Schmolzer , G.M.; Kumar, M.; Pichler , G.; Aziz, K.; O’Reilly, M.; Cheung, P.Y. Non-invasive versus invasive respiratory support in preterm infants at birth: Systematic review and meta-analysis. BMJ 2013, 347, f5980. Subramaniam , P.; Ho, J.J.; Davis, P.G. Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants. Cochrane Database Syst. Rev. 2016.