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Bronchopulmonary Dysplasia: Prevention and Management Namasivayam Ambalavanan M.D. Assistant Professor, Division of Neonatology, Department of Pediatrics,

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Presentation on theme: "Bronchopulmonary Dysplasia: Prevention and Management Namasivayam Ambalavanan M.D. Assistant Professor, Division of Neonatology, Department of Pediatrics,"— Presentation transcript:

1 Bronchopulmonary Dysplasia: Prevention and Management Namasivayam Ambalavanan M.D. Assistant Professor, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham Feb 2003

2 Overview of presentation Bronchopulmonary dysplasia: a moving target? Bronchopulmonary dysplasia: a moving target? Pathogenesis Pathogenesis Strategies for prevention of BPD Strategies for prevention of BPD Strategies for management of BPD Strategies for management of BPD Outcome Outcome Appendix Appendix

3 BPD vs. CLD Initially labeled “bronchopulmonary dysplasia” [BPD] Initially labeled “bronchopulmonary dysplasia” [BPD] Later called “neonatal chronic lung disease” or “chronic lung disease of infancy” [CLD] Later called “neonatal chronic lung disease” or “chronic lung disease of infancy” [CLD] Many experts now believe the term “bronchopulmonary dysplasia” is more accurate in describing the pathogenesis and that CLD is not a specific diagnosis or description Many experts now believe the term “bronchopulmonary dysplasia” is more accurate in describing the pathogenesis and that CLD is not a specific diagnosis or description

4 Introduction  Northway, Rosan, and Porter (1967) :BPD :premature infants who developed RDS, required prolonged mechanical ventilation with high pressures and FiO 2. Classic clinical and radiographic course had four stages : I : RDS, II: dense parenchymal opacification, III: bubble-like pattern, IV: hyperlucency of bases with strands of radiodensity in upper lobes.  Currently, a milder form of BPD is more commonly seen in tiny premies who have only mild pulmonary disease not requiring high ventilatory support

5 Introduction Definitions: Definitions: ’s: Oxygen dependence for 28 days or more after birth (Tooley WH. J Pediatr 95: 851-8, 1979) ’s: Oxygen dependence at 36 wks’ corrected age (Shennan et al. Pediatrics 82:527-32, 1988) More correlated with abnormal pulmonary outcome at 2 years (63% PPV) vs. 28 d definition (38% PPV). More correlated with abnormal pulmonary outcome at 2 years (63% PPV) vs. 28 d definition (38% PPV) st century: New physiologic definition of BPD

6 Physiologic definition of BPD Problem with previous definitions: The decision to administer oxygen is not uniform and the definition of acceptable saturation (85-98%) varies. Problem with previous definitions: The decision to administer oxygen is not uniform and the definition of acceptable saturation (85-98%) varies. Development of a “room air test” to document the need for oxygen by the NICHD Neonatal Research Network Development of a “room air test” to document the need for oxygen by the NICHD Neonatal Research Network What is O 2 requirement (failure in test)? What is O 2 requirement (failure in test)?  Saturation <88% for 5 continuous minutes  Any saturation <80% on an accurate pulse oximeter reading

7 Study Design Baseline phase x 5 min Baseline phase x 5 min Oxygen reduction phase as per protocol every 10 min with continuous monitoring Oxygen reduction phase as per protocol every 10 min with continuous monitoring O 2 reduction phase Rapid Pass (15 min in RA>96%) Rapid Fail (80-88% for 5 min (or) <80% immediate fail Intermediate: 88-96% in first 15 min. Monitor for total 60 min. No BPD BPD Some BPD Some No BPD

8 Incidence Varies by definition, selection bias, survival Varies by definition, selection bias, survival Developed countries: NICHD Neonatal Network for 2001 Developed countries: NICHD Neonatal Network for 2001 BPD-36UAB All centers g11%(n=297)23% (n=3589) g19% (n=154)39% (n=1517) Developing countries: Developing countries:  PGI: BPD-28: <1000g: 50% ; g: 8%; g: 2.3% (Indian Pediatrics Feb 2002)

9 Incidence UAB statistics ( ) of all live births <34 w (excluding 10 deaths before admission) g (2001; n=154): 82% IMV, 73% surf, 16% steroids for BPD GA n Survival(%) BPD(%)

10 Pathogenesis Increased Airway Compliance Pressure/ flow inhomogeneity Immature cells surfactant deficiency DIFFUSE ALVEOLAR DAMAGE BRONCHOPULMONARY DYSPLASIA Barotrauma Infection / Inflammation RECOVERY Barotrauma Infection / Inflammation PDA O2 Toxicity Protein leak Retained fluid PULMONARY IMMATURITY Respiratory Distress Syndrome

11 Prevention of BPD Ventilatory Strategies Ventilatory Strategies  Selective intubation / Avoid IMV (Prophylactic IMV bad)  Early CPAP  Minimal (‘gentle”) ventilation  Early extubation Pharmacologic Strategies Pharmacologic Strategies  Antenatal steroids  Vitamin A supplementation  Others Other management: PDA, Infection Other management: PDA, Infection

12 Conservative Indication For CV and BPD Intubation BPD Adapted from Poets and Sens*, Gitterman et al., and Lindner et al, de Klerk and de Klerk*. *and/or mortality Percent (%) Poets and Sens Gitterman, et al Lindner, et al de Klerk and de Klerk

13 Ventilatory strategies for BPD prevention 1.Conservative indications for assisted ventilation 2.Smallest possible tidal volume 3.Sufficient inspiratory and expiratory times 4.Moderate PEEP to prevent end expiratory alveolar collapse and maintain adequate lung volume 5.Early/prophylactic use of surfactant 6.Acceptance of hypercapnic acidosis 7.Aggressive weaning from assisted ventilation 8.Rescue with high frequency if air leak syndromes

14 Non-ventilatory strategies for BPD prevention Antenatal steroids Antenatal steroids Vitamin A supplementation (Tyson et al. NEJM Vitamin A supplementation (Tyson et al. NEJM 340:1962, 1999) Avoidance of infections Avoidance of infections Closure of PDA (but TIPP trial did not show a difference in BPD despite a decrease in PDA from 50 to 24%. Schmidt et al. NEJM 344: , 2001) Closure of PDA (but TIPP trial did not show a difference in BPD despite a decrease in PDA from 50 to 24%. Schmidt et al. NEJM 344: , 2001) Optimal fluid and electrolyte management: moderate water and sodium restriction in first week of life ( Tammela et al. Acta Paediatr 81:207-12,1992; Costarino et al. J Pediatr 120: , 1992; Hartnoll et al 82: F19-23, 2000 ) Optimal fluid and electrolyte management: moderate water and sodium restriction in first week of life ( Tammela et al. Acta Paediatr 81:207-12,1992; Costarino et al. J Pediatr 120: , 1992; Hartnoll et al 82: F19-23, 2000 )

15 BPD Management  Treatment is directed towards major pathophysiology:  Pulmonary edema => Diuretics  Bronchoconstriction and airway hyperreactivity => Bronchodilators  Airway inflammation => Steroids  Cor pulmonale => Vasodilators  Chronic lung injury and repair =>Antioxidants, nutrition, prevention of infections

16 Management - Diuretics  DIURETICS: Furosemide + Thiazides  When to consider : 1 Babies >1-2 wks w/ mod-severe lung disease on ventilator 2 BPD w/ volume overload 3 “Stalled” BPD 4 BPD w/ inadequate nutrition due to fluid restriction

17 Management - Diuretics  How?  Therapeutic trial (Lasix): Give 1 mg/kg iv or 2 mg/kg po/og x 4-5 doses. If no improvement, increase dose. If improvement, give long term. If no improvement, no long term. Eval weekly.  Monitor for side effects: Fluid-electrolyte balance/ alkalosis/ osteopenia / ototoxic / gall stones. Alternate day Rx may decrease side effects. No evidence to support any long-term benefit (Brion et al. Cochrane Database Syst Rev (1):CD001817, 2002) No evidence to support any long-term benefit (Brion et al. Cochrane Database Syst Rev (1):CD001817, 2002)

18 Management - Bronchodilators Types of Bronchodilators: Types of Bronchodilators:  Methylxanthines ( Theophylline, caffeine )  Bronchodilator, diuretic, resp stimulant  weak bronchodilator, increased side effects   -adrenergic agonists ( mainly , less  1 )  mainly smooth muscle relaxation, also enhance mucociliary transport, redistribute pulmonary blood flow  Anticholinergics - Atropine, Ipratropium

19 Management - Bronchodilators Results: Results:  Bronchodilators improve pulmonary function in the short-term.  No studies on long-term efficacy  Inhaled salbutamol did not prevent BPD in a RCT (Denjean et al. Eur J Pediatr 157:926-31, Nov 1998)  Long term safety ? -  receptors in the brain. Is bronchoconstriction protective ? Is bronchoconstriction protective ?  Focal bronchoconstriction may have protective action by limiting lung injury to distal units  May maintain airway wall rigidity

20 Management - Vasodilators VASODILATORS VASODILATORS  WHY ?  Alveolar hypoxia leads to pulmonary vasoconstriction and structural remodeling of the pulmonary vascular bed.  Oxygen a potent vasodilator, main vasodilator used in BPD. Keep PO , SpO %.  Hydralazine, Diltiazem, Nifedipine used in very small trials showed hemodynamic improvement.  Nitric Oxide (NO) improves oxygenation in some infants (Pilot study by Banks et al. Pediatrics 103:610-8, Mar 1999)

21 Management - Steroids STEROIDS - Widespread use, different regimens STEROIDS - Widespread use, different regimens  HIGH RISK: Use is not recommended  WHY ?  Anti-inflammatory properties (early)  Modulate lung repair (late)  HOW ?  Early vs Late use  Short-term vs Long-term course  PO/IV vs Inhaled route

22 AAP/CPS statement Pediatrics 109: Feb 2002 “The routine use of systemic dexamethasone for the prevention or treatment of chronic lung disease in infants with very low birth weight is not recommended” “The routine use of systemic dexamethasone for the prevention or treatment of chronic lung disease in infants with very low birth weight is not recommended” “Outside the context of a randomized, controlled trial, the use of corticosteroids should be limited to exceptional clinical circumstances (eg, an infant on maximal ventilatory and oxygen support). ” “Outside the context of a randomized, controlled trial, the use of corticosteroids should be limited to exceptional clinical circumstances (eg, an infant on maximal ventilatory and oxygen support). ”

23 Summary of systemic dexamethasone for BPD BPD and BPD/Death are decreased by steroids BPD and BPD/Death are decreased by steroids However, short-term risks are significant However, short-term risks are significant No improvement in survival No improvement in survival Long-term neurodevelopment is worse in infants treated with steroids (about a 2-fold increase in CP) Long-term neurodevelopment is worse in infants treated with steroids (about a 2-fold increase in CP) Alternatives: Alternatives:  Low doses of hydrocortisone ?  Inhaled steroids ?  Other steroids eg. Methylprednisolone ?

24 RCT OF VITAMIN A IN ELBW INFANTS CLD or Death CLD in Survivors Hospital-acquired sepsis Grade 3/4 IVH Death, 3/4 IVH, or PVL Decreased Risk Increased Risk RR with 95% Cl Tyson et al. NEJM 340:1962, 1999

25 Routine antisepsis and hand-washing precautions Routine antisepsis and hand-washing precautions Routine infection control measures Routine infection control measures Specific prophylaxis (when available, depending on country): Specific prophylaxis (when available, depending on country):  Palivizumab (Synagis): humanized monoclonal antibody to RSV  Pneumococcal conjugate vaccine (7-valent, Prevnar)  Influenza vaccine Prevention of infections

26 Treatment of infections Postnatal sepsis associated with more BPD Postnatal sepsis associated with more BPD (Van Marter et al. J Pediatr 140:171-6, Feb 2002 ) Is Ureaplasma colonization associated with BPD? Is Ureaplasma colonization associated with BPD?  No (Heggie et al. PIDJ 20:854-9, Sept 2001)  Only if persistently (+) (Castro-Alcaraz et al. Pediatrics 110:e45, Oct 2002)  Even if associated with BPD, erythromycin treatment may not be effective (Buhrer et al. Drugs 61:1893-9, 2001)

27 Summary of BPD management Prevention is better than treatment Prevention is better than treatment Oxygen therapy, avoidance of environmental and infectious hazards. Essential not to underutilize or discontinue O 2 too early (may lead to feeding difficulty, slow growth, bronchoconstriction, Pulmonary hypertension ) Oxygen therapy, avoidance of environmental and infectious hazards. Essential not to underutilize or discontinue O 2 too early (may lead to feeding difficulty, slow growth, bronchoconstriction, Pulmonary hypertension ) Optimize nutrition Optimize nutrition Bronchodilators and diuretics may lead to short-term improvements. Long-term effects unknown. Bronchodilators and diuretics may lead to short-term improvements. Long-term effects unknown. Avoid steroids as far as possible Avoid steroids as far as possible Experimental management: Enzyme, Gene, Cytokine, Antioxidant, Antiprotease administration, Lung transplant Experimental management: Enzyme, Gene, Cytokine, Antioxidant, Antiprotease administration, Lung transplant

28 Outcome Short-term outcome Short-term outcome  Mortality in first year is high ( Respiratory failure, sepsis, or intractable cor pulmonale) : 11-73% (23%)  Respiratory infections not more frequent, but earlier and more severe. 22% risk of hospitalization in first yr for resp illness, 40-50% for all causes.  Higher risk of growth and developmental delay  Gradual improvement in pulmonary function and cor pulmonale usual, with adequate nutrition, growth and control of infection.

29 Outcome (contd.) Long-term outcome Long-term outcome  Lung function -  Poor compliance,  increased resistance,  expiratory airflow limitation (bronchospastic and bronchomalacic),  increased WOB, air trapping, reactive airway disease.  May persist into adulthood.

30 Appendix Introduction Introduction Indications for mechanical ventilation Indications for mechanical ventilation Ventilator variables for controlling mechanical ventilation Ventilator variables for controlling mechanical ventilation BPD Pathogenesis BPD Pathogenesis BPD Management BPD Management

31 Introduction Factors influencing incidence: Factors influencing incidence:  Definition used  Nature of patient population (Race, Sex, Antenatal steroid use, Infection incidence etc.)  Wide variation between different centers (Avg: 4% of the babies req vent, 15% of RDS req vent >3 d & surviving 30 days.)  23-26% of VLBW survivors in USA/Canada

32 Introduction Factors influencing incidence: Factors influencing incidence:  Survival statistics in patient population  Developing nations have very low CLD since most ELBWs die within 28 days  Surfactant improves survival of smaller babies, but overall incidence of BPD same [“Shift of survival and BPD curves downward”]

33 Introduction (contd.) Clinical presentation: Clinical presentation:  Progression of XRay findings through 4 stages (Northway) now rarely seen :  I: RDS,  II: dense parenchymal opacification,  III: bubble-like pattern,  IV: hyperlucency of bases with strands of radiodensity in upper lobes.

34 Introduction Introduction (contd.) Clinical presentation (contd.) Clinical presentation (contd.)  Many premies have mild disease initially, but after a few days or weeks, chronic lung disease appears - maybe triggered by infection, PDA or barotrauma.  Survivors show slow but steady improvement in their lung function and XRay changes and can be weaned from the ventilator and oxygen therapy after weeks to months.

35 Introduction (contd.) Clinical presentation (contd.) Clinical presentation (contd.)  After extubation, retractions, tachypnea, and crackles persist for variable periods. Atelectasis occurs frequently.  Infants with more severe lung damage may die of progressive respiratory failure, cor pulmonale, or infections.

36 Goals of mechanical ventilation  To achieve adequate gas exchange with minimal lung injury and other adverse effects  The definitions of “adequate gas exchange” and “minimal lung injury” will depend on the underlying pathophysiology and the clinical condition of the neonate

37 Adequate Gas Exchange  The definition of adequate gas exchange will determine:  the indications for the initiation of mechanical ventilation  the desired blood gas values  the ventilator adjustments to maintain the blood gas values within the desired ranges

38 Indications for mechanical ventilation I. Clinical criteria:  Respiratory distress : retractions (intercostal, subcostal, suprasternal) and tachypnea (rate > /min)  Central cyanosis (cyanosis of oral mucosa or an oxygen saturation of 60-70%  persistent apnea unresponsive to medical management (e.g. theophylline, caffeine, or CPAP)

39 Indications for mechanical ventilation II. Laboratory criteria:  Severe hypercapnia: arterial carbon dioxide tension (PaCO 2 ) > 60 mm Hg in early RDS or > mm Hg in resolving RDS, accompanied by a pH of less than 7.20  Severe hypoxemia: arterial oxygen tension (PaO 2 ) 60-70%

40 Prophylactic mechanical ventilation is not beneficial  Prophylactic mechanical ventilation not beneficial, even for extremely premature neonates  A decrease in the rates of intubation and mechanical ventilation for very low birth weight (VLBW) neonates reduced bronchopulmonary dysplasia (BPD) ( Poets CF, Sens B:Pediatrics 1996;98: 24-27)  An individualized intubation strategy that restricted intubation and mechanical ventilation did not increase mortality or morbidity (Lindner W et al. Pediatrics 1999; 103: )

41 Prophylactic mechanical ventilation is not beneficial (contd.)  A significant part of the variation in BPD between two centers could be explained by an increased incidence of BPD in the center with more frequent use of mechanical ventilation ( Van Marter LJ et al. Pediatrics 2000, 105: )

42 Ventilator controls The ventilator controls on most pressure-controlled time-cycled ventilators are: The ventilator controls on most pressure-controlled time-cycled ventilators are: Positive end expiratory pressure (PEEP) Positive end expiratory pressure (PEEP) Peak inspiratory pressure (PIP) Peak inspiratory pressure (PIP) Ventilator rate (VR) Ventilator rate (VR) Inspiratory time (TI), expiratory time (TE), or inspiratory-expiratory ratio (I:E) Inspiratory time (TI), expiratory time (TE), or inspiratory-expiratory ratio (I:E) Inspired oxygen concentration (FiO 2 ) Inspired oxygen concentration (FiO 2 ) Flow rate Flow rate

43 Positive end expiratory pressure (PEEP) PEEP maintains or improves lung volume (functional residual capacity or FRC), prevents alveolar collapse, and improves V/Q matching PEEP maintains or improves lung volume (functional residual capacity or FRC), prevents alveolar collapse, and improves V/Q matching PEEP, rather than PIP or T I, is the main determinant of FRC PEEP, rather than PIP or T I, is the main determinant of FRC Low PEEP: atelectasis, low FRC, and low PaO 2 Low PEEP: atelectasis, low FRC, and low PaO 2 High PEEP: low V T, high FRC, and high PaCO 2 High PEEP: low V T, high FRC, and high PaCO 2 Optimal PEEP: between cm H 2 O pressure Optimal PEEP: between cm H 2 O pressure

44 Peak Inspiratory Pressure (PIP) Changes in PIP affect PaO 2 by affecting the mean airway pressure and thus influencing V/Q matching. Changes in PIP affect PaO 2 by affecting the mean airway pressure and thus influencing V/Q matching. The level of PIP also affects the pressure gradient (  P) which determines the tidal volume The level of PIP also affects the pressure gradient (  P) which determines the tidal volume PIP increases normally increase PaO 2 and decrease PaCO 2 PIP increases normally increase PaO 2 and decrease PaCO 2

45 Peak Inspiratory Pressure (PIP) contd. Very high PIP may lead to hyperinflation and decreased lung perfusion and cardiac output, leading to a decrease in oxygen transport despite an adequate PaO 2 Very high PIP may lead to hyperinflation and decreased lung perfusion and cardiac output, leading to a decrease in oxygen transport despite an adequate PaO 2 High levels of PIP also increase the risk of “volutrauma”, air leak syndromes, and lung injury High levels of PIP also increase the risk of “volutrauma”, air leak syndromes, and lung injury PIP required depends mainly on the compliance of the respiratory system. PIP required depends mainly on the compliance of the respiratory system.

46 Peak Inspiratory Pressure (PIP) contd. Clinical indicator of adequate PIP is gentle chest rise with every ventilator-delivered breath, similar to spontaneous breathing. Clinical indicator of adequate PIP is gentle chest rise with every ventilator-delivered breath, similar to spontaneous breathing. The degree of observed chest wall movement during the ventilator-delivered breaths indicates the compliance with fair accuracy The degree of observed chest wall movement during the ventilator-delivered breaths indicates the compliance with fair accuracy (Aufricht et al. Am J Perinatol 10: , 1993) Minimal effective PIP: start low (e.g cm H 2 O) and increase slowly (in steps of 1-2 cm H 2 O) Minimal effective PIP: start low (e.g cm H 2 O) and increase slowly (in steps of 1-2 cm H 2 O)

47 Factors to be considered in selecting PIP Yes No Yes No Lung complianceWeight Blood gas derangementResistance Chest rise Time constant Breath soundsPEEP OthersOthers

48 Ventilator rate The ventilator rate (frequency) determines alveolar minute ventilation and thereby PaCO 2 The ventilator rate (frequency) determines alveolar minute ventilation and thereby PaCO 2 alveolar minute ventilation = frequency x [tidal volume – dead space] alveolar minute ventilation = frequency x [tidal volume – dead space] Relationship not linear: As ventilator rate increases and T I decreases below 3 time constants, V T decreases and minute ventilation falls Relationship not linear: As ventilator rate increases and T I decreases below 3 time constants, V T decreases and minute ventilation falls (Boros et al. Pediatrics 74: , 1984) As time constant is low in RDS, rates > 60/min can be used As time constant is low in RDS, rates > 60/min can be used

49 T I, T E, and I:E The T I and T E are normally adjusted based on the time constant The T I and T E are normally adjusted based on the time constant Changes in I:E change MAP, and thus PaO 2 Changes in I:E change MAP, and thus PaO 2 When corrected for MAP, changes in I:E are not as effective in improving PaO 2 as changes in PIP or PEEP (Stewart et al. Pediatrics 67:474-81, 1981) When corrected for MAP, changes in I:E are not as effective in improving PaO 2 as changes in PIP or PEEP (Stewart et al. Pediatrics 67:474-81, 1981) Higher ventilatory rates combined with a short T I decrease air leaks Higher ventilatory rates combined with a short T I decrease air leaks (Octave. Arch Dis Child 66: , 1991; Pohlandt et al. Eur J Pediatr 151: , 1992)

50 Gas exchange MAP increases with increasing PIP, PEEP, T I to T E ratio, rate, and flow MAP increases with increasing PIP, PEEP, T I to T E ratio, rate, and flow PEEP PIP TITI Rate Flow Pressure Time TITI TETE PEEP PIP

51 Inspired oxygen concentration (FiO 2 ) Changes in FiO 2 alter PaO 2 directly by changing the A-a DO 2 Changes in FiO 2 alter PaO 2 directly by changing the A-a DO 2 Insufficient data to compare the roles of O 2 - induced versus pressure-associated (or volume- associated) lung injury in the neonate Insufficient data to compare the roles of O 2 - induced versus pressure-associated (or volume- associated) lung injury in the neonate Generally believed that risk of O 2 toxicity is less than that of volutrauma with FiO 2 < Generally believed that risk of O 2 toxicity is less than that of volutrauma with FiO 2 < Frequent FiO 2 changes are required, based on pulse oximetry rather than occasional blood gases Frequent FiO 2 changes are required, based on pulse oximetry rather than occasional blood gases

52 Inspired oxygen concentration (FiO 2 ) During early RDS, FiO 2 first increased to 0.6 to 0.7 before additional increases in MAP During weaning, first decrease PIP to relatively safe levels, then decrease FiO 2 below 0.4 to 0.5 Maintenance of an adequate MAP and V/Q matching may permit a reduction in FiO 2 Reduce MAP before a very low FiO 2 (<0.3) is reached, to reduce the risk of air leaks.

53 Flow rate As long as a sufficient flow is used, there is minimal effect on the pressure waveform or on gas exchange As long as a sufficient flow is used, there is minimal effect on the pressure waveform or on gas exchange Higher flow leads to a more “square wave” pressure waveform, which increases MAP, turbulence, and risk of air leaks Higher flow leads to a more “square wave” pressure waveform, which increases MAP, turbulence, and risk of air leaks A minimum flow rate of about 3 times the infant’s minute ventilation is usually required, and 6-10 L/min is usually sufficient A minimum flow rate of about 3 times the infant’s minute ventilation is usually required, and 6-10 L/min is usually sufficient

54 Ventilator settings In view of the low compliance, short time constant, low FRC, and risk for air leaks, it is usually preferred to use   rapid rates (>60/min)   moderate PEEP (4-5 cm H 2 O)   low PIP (10-20 cm H 2 O)   T I of s V T is generally mL/kg body weight

55 Ventilator settings Randomized controlled trials have shown that a rapid rates and short T I (versus slow rates and long T I ) decrease air leaks (Octave. Arch Dis Child 66: , 1991; Pohlandt et al. Eur J Pediatr 151: , 1992) Animal models also show that rapid, shallow ventilation produce less lung injury than slow, deep breaths ( Albertine et al. Am J Respir Crit Care Med 159: , 1999)

56 Clinical estimation of optimal T I and T E Short T I Optimal T I Long T I Inadeq V T Short insp. plateau Long plateau Short T E Optimal T E Long T E Air trapping Short exp. plateau Long exp. plateau Chest Wall Motion Time Chest Wall Motion

57 Weaning off ventilator When good spontaneous ventilatory attempts are present and mechanical ventilation contributes only minimally to total ventilation Normally done when ventilator rates are 15/min or less, at a PIP <15 cm H 2 O and a FiO 2 < 40%. Extubation from low rates is more successful as compared to extubation from endotracheal CPAP ( Davis and Henderson-Smart. Cochrane Rev. CD , 2000)

58 BPD Pathogenesis Features of the immature lung increasing susceptibility: Features of the immature lung increasing susceptibility:  Barotrauma : Poorly compliant airspaces, but highly compliant airways  Hyperoxia : Poorly developed antioxidant defenses  Infection : Altered airway clearance, immature macrophages & WBC  Inflammation : Poorly developed anti-oxidant, antiproteolytic and antielastolytic systems  Increased permeability of the alveolo-capillary membrane with decreasing gestational age.

59 BPD Pathogenesis Complications of Hyperoxia: Complications of Hyperoxia:  Cytotoxicity epithelium & endothelium Pulmonary edema and hemorrhage  Cytotoxicity on airway lining & macrophages Poor airway clearance and increased infection  Pulmonary edema + inhibition of surfactant synthesis leads to worsening compliance  Inhibition of pulmonary vascular response to hypoxia leads to shunting, V/Q mismatch  Inhibition of normal lung repair, healing by fibroblast proliferation  Inhibition of normal lung development, decreased alveolarization  Loss of pulmonary endothelial functions

60 Lung Injury During Mechanical Ventilation 1. Chest wall restriction limits pressure-induced lung injury (Hernandez, et al., 1988) 2.Overexpansion of the thorax with negative pressures causes lung injury (Dreyfus, et al. 1988)

61 Changes in intubation rates in relation to outcome in VLBW infants p value n=665n=664n=672 Intubated (%)787866<0.05 O 2 at 28d (%)212017<0.05 Death or O 2 at 28d (%)322927NS Death or O 2 in < 1.0 kg (%)625452<0.05 Death or O 2 in kg (%)14129<0.05 CPAP (%)456NS Poets and Sens. Pediatrics 98:24, 1996

62 Ventilator-Associated Lung Injury (VALI) Likely mechanisms Volume rather than pressures End expiratory volume rather than V T or FRC Transalveolar pressure and reopening of alveoli Repeated collapse and reopening of alveoli Very low positive end expiratory pressure Oxidant injury

63 A B Time A High V T B Normal V T, high PEEP Volutrauma Zone Volume Which Volumes Cause Lung Injury?

64 EFFECT OF TIDAL VOLUME ON LUNG COMPLIANCE Age (min) 32 cc/kg 16 cc/kg 8 cc/kg Compliance (cc/cmH 2 Okg) Bjorklund et al. Pediatr Res 39:326A, 1996

65 Early CPAP: prophylactic or rescue? Prophylactic CPAP (before onset of respiratory distress) practiced at some centers. Prophylactic CPAP (before onset of respiratory distress) practiced at some centers. Rescue CPAP (after onset of distress): Rescue CPAP (after onset of distress):  Often combined with an dose of surfactant given by a brief intubation  May decrease the need for mechanical ventilation and improve respiratory failure and reduce mortality  May increase risk of pneumothorax (Ho et al. Cochrane Rev 2000 ;(4): CD ) (Verder et al. Pediatrics 1999;103: E24 )

66 1.Maintenance of normocapnia in some patients with severe respiratory failure necessitates high ventilatory support. 2.Compensated respiratory acidosis is generally well tolerated and may reduce lung injury. Permissive Hypercapnia: Background

67 Relative Risk for BPD VariableNRelative risk (95% CI) Highest PaCO 2 at 48 or 96 hr > 50 mm Hg21Reference group mm Hg (0.95, 1.90) < 40 mm Hg (1.04, 2.01) Kraybill et al., J Pediatr 115: , 1989

68 Risk for BPD in Neonates with RDS: Variables in Logistic Regression OddsConfidence RatioInterval VE Index < a/A Ratio < Low PaCO 2 (< 29 vs 40) (30-39 vs >40) Birthweight < 1000 grams C/S Due to Fetal Distress Garland et al. Arch Pediatr Adolesc Med , 1995

69 Volume vs. Pressure in Lung Injury Pulm.Epith.HyalineLymphFiltr. VolumePressureEdemaInjuryMemb. Flow Coef. IPPVHighHighYesYesYes Yes Yes IPPVHighHighYesYesYes Yes Yes Iron LungHighLowYesYesYes N/A N/A Iron LungHighLowYesYesYes N/A N/A StrappingLowHighNoNoNo No No StrappingLowHighNoNoNo No No Dreyfus et al, 1988; Bshouty et al, 1988; Hernandez et al, 1989; Corbridge et al, 1990; Carlton et al 1990

70 CPAP at Birth in VLBW Infants CPAPControl n=70n=57p value Intubated (%)3053<0.05 Dur. intubation (d)6(3-9)4.5(3-7)NS O 2 at 28 days (%)3032NS Nosocomial infection (%)2137<0.05 Gitterman et al. Eur J Pediatrics. 156:384, 1997

71 CPAP at Birth in VLBW Infants 2 Gitterman et al. Eur J Pediatrics. 156:384, 1997 Percent (%)

72 CV vs CPAP at Birth in ELBW Infants CPAP Routine Intubationp value CPAP Routine Intubationp value N=67N=56 DR intubation (%)4084<0.01 Intubated (%)6593<0.01 Mortality (%)2227NS O 2 at 36 weeks (%)1232<0.05 IVH > 2 (%) (%)1638<0.01 Lindner et al. Pediatrics 103:961, 1999

73 2 CV VS CPAP at Birth in ELBW Infants Lindner et al. Pediatrics 103:961, 1999 Percent (%)

74 CPAP in Infants Kg CPAPControlp value n=59n=57 Intubated (%)1465 <0.001 Surfactant (%)1240<0.001 Ventilation (d)26<0.05 Oxygen suppl (d)24<0.01 O 2 at 28d (%)011<0.05 O 2 at 28d or death (%)316<0.05 O 2 at 36w or death (%) de Klerk and de Klerk. J Paedr Child Health 37:161:201

75 CPAP in Infants Kg de Klerk and de Klerk. J Paedr Child Health 37:161:201 2 Percent (%)

76 Demographic Characteristics of ELBW and BPD Without BPDWith BPD Characteristic(n=50)(n=97) Gestational age (wk) * Birth weight (gm) Sex (% male)34 60* Race (% white)3243 Roentgenographic score * *p<0.005 Kraybill et al., J. Pediatr 115: , 1989

77 Treatment Variables of ELBW infants and BPD Without BPDWith BPD Characteristic(n=29)(n=90) Pressure management PIP (cm H 2 O) At 48 hr At 96 hr Paw (cm H 2 O) At 48 hr At 96 hr Kraybill et al., J. Pediatr 115: , 1989

78 Treatment Variables of ELBW infants and BPD Without BPDWith BPD Characteristic(n=29)(n=90) Oxygen management FiO 2 (%) At 48 hr At 96 hr PaO 2 (mmHg) At 48 hr At 96 hr PA-aO 2 (mmHg) At 48 hr At 96 hr Kraybill et al., J. Pediatr 115: , 1989

79 Relative Risk for BPD VariableNRelative risk (95% CI) Highest PaO 2 at 48 or 96 hr < 70 mm Hg30Reference group mm Hg (0.60, 1.07) mm Hg (0.72, 1.13) > 100 mg Hg (0.57, 1.01) Kraybill et al., J Pediatr 115: , 1989

80 Logistic Regression Model to Predict BPD Independent Variable p r Sex (male)< PaCO 2 at 48 hr< Roentgenographic score Gestational age Race Kraybill et al., J. Pediatr 115: , 1989

81 RANDOMIZED TRIAL OF PERMISSIVE HYPERCAPNIA IN PRETERM INFANTS G Mariani, J Cifuentes, WA Carlo Department of Pediatrics, University of Alabama at Birmingham Pediatrics 104: , 1999

82 p = Log rank test Duration of MV (hours) Infants on MV (%) Normocapnia Permissive hypercapnia

83 EFFECTS OF MINIMAL VENTILATION IN A MULTICENTER RANDOMIZED CONTROLLED TRIAL OF VENTILATOR SUPPORT AND EARLY CORTICOSTEROID THERAPY IN EXTREMELY LOW BIRTH WEIGHT INFANTS The Steroid And VEntilation (SAVE) Trial NICHD Neonatal Research Network Carlo et al. J Pediatr 141: 370-4, Sept 2002 SAVE Trial

84 Centers and Principal Investigators Univ of Alabama at BirminghamWally Carlo, MD Harvard UniversityAnn Stark, MD Emory UniversityBarbara Stoll, MD Case Western Reserve UniversityAvroy Fanaroff, MB, BCh Yale UniversityRichard Ehrenkranz, MD University of Tennessee-MemphisSheldon Korones, MD UT Southwestern Medical Center-DallasJon Tyson, MD Wayne State UniversitySeetha Shankaran, MD Brown UniversityWilliam Oh, MD University of MiamiCharles Bauer, MD University of CincinnatiEd Donovan, MD Stanford UniversityDavid Stevenson, MD University of New MexicoLu-Ann Papile, MD Research Triangle InstituteKen Poole, PhD NICHDLinda Wright, MD SAVE Trial

85 Hypothesis A strategy of minimal ventilation support (defined as a PCO 2 goal > 52 mmHg) in infants 501 to 1000 grams, initiated within 12 hours of birth and maintained as long as mechanical ventilation is needed during the first 10 days, reduces by at least 20% the incidence of death or chronic lung disease at 36 weeks postmenstrual age. A strategy of minimal ventilation support (defined as a PCO 2 goal > 52 mmHg) in infants 501 to 1000 grams, initiated within 12 hours of birth and maintained as long as mechanical ventilation is needed during the first 10 days, reduces by at least 20% the incidence of death or chronic lung disease at 36 weeks postmenstrual age.

86 Sample Size 1200 infants 1200 infants Ventilator strategy Ventilator strategy MinimalRoutine Stress Dose Placebo Steroid strategy SAVE Trial

87 Study Design Multicenter Multicenter Randomized-stratified by center and birth weight group Randomized-stratified by center and birth weight group 2 x 2 Factorial design 2 x 2 Factorial design Interventions Interventions  Corticosteroid/Placebo  Minimal/Routine ventilation SAVE Trial

88 Ventilatory Intervention (Continued) Pressure-limited, time-cycled ventilation with or without SIMV is preferred; HFV is discouraged. Pressure-limited, time-cycled ventilation with or without SIMV is preferred; HFV is discouraged. The preferred ventilator strategy for infants in the minimal ventilator support group is to use the smallest possible tidal volume with the conventional ventilator. The preferred ventilator strategy for infants in the minimal ventilator support group is to use the smallest possible tidal volume with the conventional ventilator. Ventilator strategy is maintained for ten days unless extubation occurs sooner. Ventilator strategy is maintained for ten days unless extubation occurs sooner. SAVE Trial

89 Methods - Ventilatory Management Goals: Minimal ventilation group-PCO 2 > 52 mmHg Goals: Minimal ventilation group-PCO 2 > 52 mmHg Routine ventilation group -PCO2 < 48 mmHg In both groups: In both groups:  Priority was given to decrease tidal volume by decreasing peak inspiratory pressure (PIP) or increasing rate  Tidal volume was measured daily  The same extubation criteria (rate 7.25) were used SAVE Trial

90 Ventilatory Intervention Routine ventilator support Routine ventilator support(Normocapnia) PCO 2 goal: < 48 mmHg PaO 2 goal: mmHg O 2 sat goal: 88-95% pH goal:  7.20 Minimal ventilator support Minimal ventilator support (Permissive hypercapnia) PCO 2 goal: > 52 mmHg PaO 2 goal: mmHg O 2 sat goal: 88-95% pH goal:  7.20 SAVE Trial

91 Results - Primary Outcome Measure MinimalRoutine VentilationVentilationRRCI (N=109)(N=111) Mortality or CLD (%) ( ) Mortality (%) ( ) CLD (%) ( ) SAVE Trial

92 Results - Secondary Analyses Minimal Routine Minimal Routine VentilationVentilation RR CI NNT VentilationVentilation RR CI NNT CLD or death in gm (%) ( )* gm (%) ( )* 6 Ventilation at 36 wk (%) ( )* 7 36 wk (%) ( )* 7 O 2 /CPAP/Vent at 36 wk (%) ( ) — at 36 wk (%) ( ) —*p<0.05 SAVE Trial

93 PCO 2 While on a Ventilator Study Day Weighted PCO 2 (mmHg)

94 Compliance (cc/cmH 2 Okg) Age ( min ) TIMING OF SURFACTANT AND LUNG VOLUTRAUMA Ingirmarsson et al. Pediatr Res 41:255A, “Rescue” Surfactant Prophylactic Surfactant

95 Surfactant: which one to use? Natural surfactants reduce ventilatory requirements faster, decrease pneumothorax and mortality risk (Soll & Blanco. Cochrane Rev 4, 2001) Natural surfactants reduce ventilatory requirements faster, decrease pneumothorax and mortality risk (Soll & Blanco. Cochrane Rev 4, 2001) Natural surfactants: Bovine origin (e.g. Survanta, Infasurf) or Porcine origin (e.g. Curosurf) Natural surfactants: Bovine origin (e.g. Survanta, Infasurf) or Porcine origin (e.g. Curosurf) Infasurf and Curosurf have a longer duration of action and may slightly decrease ventilator requirements compared to Survanta (Bloom et al. Pediatrics 100; 31-38, 1997; Speer et al. Arch Dis Child Fetal Neonatal Ed;72:F8-13, 1995) Infasurf and Curosurf have a longer duration of action and may slightly decrease ventilator requirements compared to Survanta (Bloom et al. Pediatrics 100; 31-38, 1997; Speer et al. Arch Dis Child Fetal Neonatal Ed;72:F8-13, 1995)

96 Surfactant use: repeat doses Repeat doses are given depending on the clinical status and the ventilatory settings Higher threshold (>40% FiO 2 with a MAP > 7 cm H 2 O) for uncomplicated RDS Lower threshold (>30% FiO 2 ) may reduce mortality in infants with RDS complicated by perinatal compromise or sepsis ( Kattwinkel et al. Pediatrics 106: , 2000)

97 Surfactant use: how many doses? Multiple doses of surfactant are normally required for moderate to severe RDS. Multiple doses of natural surfactant (e.g. Survanta):  improve oxygenation  reduce ventilator requirements  reduce pneumothorax (RR 0.51)  tend to reduce mortality (RR 0.63) (Dunn et al. Pediatrics;86: , 1990; Speer et al Pediatrics. 89:13-20, 1992; Soll. Cochrane Rev. (2): CD000141, 2000)

98 Surfactant use: how many doses? Synthetic surfactant (e.g. Exosurf): Synthetic surfactant (e.g. Exosurf):  Two doses as good as 3-4 doses ( OSIRIS. Lancet 340:1363-9,1992)  Three doses better than one dose (lower mortality, ventilator requirement, need for HFV) ( American Exosurf Neonatal Study. J Pediatr;126:969-78, 1995)

99 BPD Management - difficulties in study  Definition ; objective assessment of severity ; variable status  confounding effect of multiple risk factors  limited number of patients per center ; difference between centers in patient population  historical controls / retrospective studies of little use since rapid changes in management techniques  Technical limitation of PFTs ; data dropout due to death, discharge or extubation

100 Elective HFOV: Meta-analysis of 8 studies Elective HFOV: Meta-analysis of 8 studies (Henderson-Smart: Cochrane Rev 4, 2001) No difference in mortality Trends toward decreases in BPD in survivors at weeks (RR 0.73 (0.57, 0.93) and death or CLD at weeks Significant increase in severe (grades 3 & 4) IVH and in any air leak [RR 1.19 (1.03, 1.38)] in the HFOV group 2 trials with neurodevelopmental F/U : more survivors in the HFOV group are abnormal [RR 1.26 (1.01, 1.58)] (Ogawa 93, HiFi 89) Sub-group with high volume strategy did not have increased IVH or PVL Not currently recommended

101 Elective HFJV: Meta-analysis of 3 studies Carlo 90, Wiswell 96, Keszler 97 Carlo 90, Wiswell 96, Keszler 97 HFJV is associated with a reduction in BPD at 36 weeks PMA in survivors [RR 0.58 (0.34, 0.98), NNT 7 ] HFJV is associated with a reduction in BPD at 36 weeks PMA in survivors [RR 0.58 (0.34, 0.98), NNT 7 ] Increase in PVL in the trial by Wiswell [RR 5.0 (1.19, 21.04), NNH 4.0 (2.3,14.5)] where a ‘high volume strategy' was not the standard protocol Increase in PVL in the trial by Wiswell [RR 5.0 (1.19, 21.04), NNH 4.0 (2.3,14.5)] where a ‘high volume strategy' was not the standard protocol Requires more investigation Requires more investigation (Bhuta and Henderson-Smart. Cochrane Rev 4, 2001)

102 Rescue HFOV Only one good trial (HIFO Study Group. J Pediatr 1993;122: ) Reduction in new air leak [RR 0.73 (0.55,0.96; NNT 6] Mortality and the use of IPPV at 30 days was similar in the HFOV and CV groups. The rate of IVH of any grade increased with HFOV [RR 1.77 (1.06,2.96), NNH 6] Insufficient evidence for conclusions at present (HIFO Study Group. J Pediatr 1993;122: ; Bhuta and Henderson-Smart. Cochrane Rev 4, 2001)

103 Newer modes of ventilation Patient-triggered ventilation (PTV) / Synchronized IMV (SIMV) Patient-triggered ventilation (PTV) / Synchronized IMV (SIMV)  May shorten duration of IMV and weaning (Greenough et al. Cochrane Rev 4, 2001) Proportional Assist Ventilation (PAV) Proportional Assist Ventilation (PAV) (Schulze et al. J Pediatr 135: ,1999) Continuous tracheal gas insufflation (CTGI) Continuous tracheal gas insufflation (CTGI) (Dassieu et al. Intensive Care Med 24: ,1998) Perflurocarbon assisted gas exchange (PAGE) Perflurocarbon assisted gas exchange (PAGE) (Wolfson et al. Pediatr Pulmonol 26:42-63,1998)

104 Surfactant use: prophylactic vs. selective use Multiple clinical trials and meta-analyses performed Multiple clinical trials and meta-analyses performed ( Dunn 1991, Kendig 1991, Merritt 1991, Egberts 1993, Kattwinkel 1993, Walti 1995, Bevilacqua 1996 and 1997; Soll and Morley. Cochrane Rev 4, 2001) Prophylaxis decreases the risk of pneumothorax, PIE, mortality, and BPD or death associated with prophylactic surfactant administration. Prophylaxis decreases the risk of pneumothorax, PIE, mortality, and BPD or death associated with prophylactic surfactant administration. Meta-analysis : For every 100 infants treated prophylactically, there will be 2 fewer pneumothoraces, and 5 fewer deaths. Meta-analysis : For every 100 infants treated prophylactically, there will be 2 fewer pneumothoraces, and 5 fewer deaths.

105 Management - Diuretics  DIURETICS  WHY ?  Clinical, XRay & Histologic evidence of interstitial & peribronchiolar pulmonary edema  Abnormal regulation of water balance ; hypervolemia  Acute and short term diuretics improve pulmonary function and occasionally gas exchange  Benefit unrelated to urine output

106 Management - Diuretics  DIURETICS:  Types: Loop diuretics: Furosemide Thiazides : Chloro/Hydrochlorothiazide Spironolactone  Results with Thiazides and Spironolactone conflicting, though blinded studies did show some improvement  Furosemide also increases vasodilator PG synthesis, causes systemic and pulmonary vasodilation, increases surfactant synthesis and decreases Cl - transport in the airway epithelium

107 Management - Bronchodilators  BRONCHODILATORS Pathways controlling airway smooth muscle tone : 1. Parasympathetic cholinergic : contraction, increase mucus 2. Beta-adrenergic : relaxation 3. Nonadrenergic, noncholinergic (NANC) or Peptidergic :  Bronchoconstrictor : Substance P  Bronchodilator : VIP (possibly deficient in Asthma)

108 Management - Bronchodilators  WHY ?  Sufficient bronchial smooth muscle, even in tiny premies  Hyperplastic smooth muscle and metaplastic epithelium in BPD  Correlation with family history of Asthma

109 Management - Bronchodilators Bronchodilators - How ? Bronchodilators - How ?  Albuterol 50  g q 4-6 hrs for 2-3 days. If improvement noted, continue, and reassess weekly.

110 Early steroids (<96 Hours of Age) BPD or BPD/Death at 28 d and 36 w were decreased by steroids (NNT =10), and weaning from ventilator was faster. BPD or BPD/Death at 28 d and 36 w were decreased by steroids (NNT =10), and weaning from ventilator was faster. Increase in short-term complications (hypertension, hyperglycemia, GI bleeds, perforation). No change in NEC, IVH, severe ROP, or infection. Borderline increase in PVL (1.41 [ ]) Increase in short-term complications (hypertension, hyperglycemia, GI bleeds, perforation). No change in NEC, IVH, severe ROP, or infection. Borderline increase in PVL (1.41 [ ]) Long-term outcome worse with steroids, with increased risk of CP in larger studies (Shinwell et al 2000: RR 3.2; Yeh et al 1998: RR 2.32) Long-term outcome worse with steroids, with increased risk of CP in larger studies (Shinwell et al 2000: RR 3.2; Yeh et al 1998: RR 2.32)

111 Moderately early steroids (7-14 days) BPD or BPD/Death at 28 d and 36 w were decreased by steroids (NNT =7 for BPD 28 and 4 for BPD 36 ), and weaning from ventilator was faster. BPD or BPD/Death at 28 d and 36 w were decreased by steroids (NNT =7 for BPD 28 and 4 for BPD 36 ), and weaning from ventilator was faster. Duration of hospital stay same. No difference in severe ROP, IVH, or NEC. Increase in hypertension. Duration of hospital stay same. No difference in severe ROP, IVH, or NEC. Increase in hypertension. Increase in CP in steroid group in one study (O’Shea et al 1999: 12 of 48 in steroid vs. 3 of 45 in placebo; RR 3.75, CI ) Increase in CP in steroid group in one study (O’Shea et al 1999: 12 of 48 in steroid vs. 3 of 45 in placebo; RR 3.75, CI )

112 Delayed Steroids (>3 weeks) BPD and BPD/Death at 36 w were decreased by steroids, but not survival or duration of hospital stay. BPD and BPD/Death at 36 w were decreased by steroids, but not survival or duration of hospital stay. No difference in NEC, GI bleeding, or infection. No difference in NEC, GI bleeding, or infection. Steroids led to poor weight gain or weight loss. Steroids led to poor weight gain or weight loss. Long-term outcome similar in one large study (Jones et al 1995: RR for CP 1.21, CI ), but full neurodevelopmental evaluation was not done in this trial. Long-term outcome similar in one large study (Jones et al 1995: RR for CP 1.21, CI ), but full neurodevelopmental evaluation was not done in this trial.

113 Inhaled steroids Beclomethasone and Flunisolide have been tried by nebulization. May decrease Beclomethasone and Flunisolide have been tried by nebulization. May decrease  need for systemic steroids  side effects Beclomethasone did not decrease BPD in RCTs (Denjean et al. Eur J Pediatr 157:926-31, Nov 1998; Cole et al. 340(13): , Apr 1999) Beclomethasone did not decrease BPD in RCTs (Denjean et al. Eur J Pediatr 157:926-31, Nov 1998; Cole et al. 340(13): , Apr 1999) Type, dosage, and delivery methods still need to be optimized Type, dosage, and delivery methods still need to be optimized

114 Other medications: Vitamin A Vitamin AControl (N=405)(N=402) Birth weight (grams)770   138 Gestational age (weeks)27  227  2 Mean airway pressure (cm H 2 O)7  37  2 FiO   0.20 Baseline retinol (µg/dL)16  616  6 Tyson et al. NEJM 340:1962, 1999

115 Other antioxidants No benefit demonstrated with Vit E supplementation (Watts et al. Eur Respir J 4: , 1991) No benefit demonstrated with Vit E supplementation (Watts et al. Eur Respir J 4: , 1991) No benefit shown with Superoxide Dismutase (SOD) (Suresh et al. Cochrane Database Syst Rev (1): CD , 2001) No benefit shown with Superoxide Dismutase (SOD) (Suresh et al. Cochrane Database Syst Rev (1): CD , 2001) Catalase, Glutathione peroxidase etc are under investigation. Catalase, Glutathione peroxidase etc are under investigation.

116 Outcome (contd.) Long-term outcome (contd) Long-term outcome (contd)  Cor pulmonale - usually resolves  Reactive Airway disease - 50% will have exercise induced bronchospasm  SIDS ? - BPD spells ?- acute obstructive episodes. Some reports of increased SIDS incidence.

117 Outcome (contd.)  Long-term outcome (contd)  Growth failure common. – 50% < 10th centile at 6 mo. – Only 7% > 50th at 2 yrs. Resistance to oral stimulation, Resistance to oral stimulation, forcing food, forcing food, increased caloric consumption increased caloric consumption

118 Outcome (contd.)  Long-term outcome (contd) – Studies on developmental outcome inconclusive. Most show no relation to BPD but to prematurity and other risk factors. Relationship to time hospitalized, but not with time ventilated. – Short stature and airflow obstruction persist into adulthood ( Northway’s 23 yr follow-up )


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