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,Overview of presentation,Bronchopulmonary dysplasia: a moving target? Pathogenesis Strategies for pr
2、evention of BPD Strategies for management of BPD Outcome Appendix,BPD vs. CLD,Initially labeled “bronchopulmonary dysplasia” BPD 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 de
3、scribing the pathogenesis and that CLD is not a specific diagnosis or description,Introduction,Northway, Rosan, and Porter (1967) :BPD :premature infants who developed RDS, required prolonged mechanical ventilation with high pressures and FiO2. Classic clinical and radiographic course had four stage
4、s: 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,Introduct
5、ion,Definitions: 1980s: Oxygen dependence for 28 days or more after birth (Tooley WH. J Pediatr 95: 851-8, 1979) 1990s: 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%
6、PPV). 21st century: New physiologic definition of BPD,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. Development of a “room air test” to document the need for oxygen by the
7、 NICHD Neonatal Research Network What is O2 requirement (failure in test)? Saturation 88% for 5 continuous minutes Any saturation 80% on an accurate pulse oximeter reading,Study Design,Baseline phase x 5 min Oxygen reduction phase as per protocol every 10 min with continuous monitoring,O2 reduction
8、phase,Rapid Pass (15 min in RA96%),Rapid Fail (80-88% for 5 min (or) 80% immediate fail,Intermediate: 88-96% in first 15 min. Monitor for total 60 min.,No BPDBPDSome BPD Some No BPD,Incidence,Varies by definition, selection bias, survival Developed countries: NICHD Neonatal Network for 2001 BPD-36 U
9、AB All centers 401-1500g 11% (n=297) 23% (n=3589) 401-1000g 19% (n=154) 39% (n=1517) Developing countries: PGI: BPD-28: 1000g: 50% ; 1000-1249g: 8%; 1250-1499g: 2.3% (Indian Pediatrics Feb 2002),Incidence,UAB statistics (1998-1999) of all live births 34 w (excluding 10 deaths before admission)401-10
10、00 g (2001; n=154): 82% IMV, 73% surf, 16% steroids for BPD,Pathogenesis,Increased Airway Compliance,Pressure/ flow inhomogeneity,Immature cells,surfactant deficiency,DIFFUSE ALVEOLAR DAMAGE,BRONCHOPULMONARY DYSPLASIA,Barotrauma,Infection / Inflammation,RECOVERY,Barotrauma,Infection / Inflammation,P
11、DA O2 Toxicity,Protein leak,Retained fluid,PULMONARY IMMATURITY,Respiratory Distress Syndrome,Prevention of BPD,Ventilatory Strategies Selective intubation / Avoid IMV (Prophylactic IMV bad) Early CPAP Minimal (gentle”) ventilation Early extubation Pharmacologic Strategies Antenatal steroids Vitamin
12、 A supplementation Others Other management: PDA, Infection,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 (%),Non-ventilatory strategies for BPD prevention,Antenatal steroids V
13、itamin A supplementation (Tyson et al. NEJM 340:1962, 1999) 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 344:1966-72, 2001) Optimal fluid and electrolyte management: moderate water and sodium res
14、triction in first week of life (Tammela et al. Acta Paediatr 81:207-12,1992; Costarino et al. J Pediatr 120: 99-106, 1992; Hartnoll et al 82: F19-23, 2000),BPD Management,Treatment is directed towards major pathophysiology: Pulmonary edema = Diuretics Bronchoconstriction and airway hyperreactivity =
15、 Bronchodilators Airway inflammation = Steroids Cor pulmonale = Vasodilators Chronic lung injury and repair =Antioxidants, nutrition, prevention of infections,Management - Diuretics,DIURETICS: Furosemide + Thiazides When to consider :Babies 1-2 wks w/ mod-severe lung disease on ventilatorBPD w/ volu
16、me overload“Stalled” BPDBPD w/ inadequate nutrition due to fluid restriction,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 fo
17、r 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),Management - Bronchodilators,Types of Bronchodilators: Meth
18、ylxanthines ( Theophylline, caffeine ) Bronchodilator, diuretic, resp stimulant weak bronchodilator, increased side effects b-adrenergic agonists ( mainly b2, less b1 ) mainly smooth muscle relaxation, also enhance mucociliary transport, redistribute pulmonary blood flow Anticholinergics - Atropine,
19、 Ipratropium,Management - Bronchodilators,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 ? - b receptors in the brain. Is bron
20、choconstriction protective ? Focal bronchoconstriction may have protective action by limiting lung injury to distal units May maintain airway wall rigidity,Management - Vasodilators,VASODILATORS WHY ? Alveolar hypoxia leads to pulmonary vasoconstriction and structural remodeling of the pulmonary vas
21、cular bed. Oxygen a potent vasodilator, main vasodilator used in BPD. Keep PO2 60-80, SpO2 92-95%. 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, Ma
22、r 1999),Management - Steroids,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,AAP/CPS statement Pediatrics 109: 330-8 F
23、eb 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” “Outside the context of a randomized, controlled trial, the use of corticosteroids should be limited to exceptional clinical circumstan
24、ces (eg, an infant on maximal ventilatory and oxygen support).”,Summary of systemic dexamethasone for BPD,BPD and BPD/Death are decreased by steroids However, short-term risks are significant No improvement in survival Long-term neurodevelopment is worse in infants treated with steroids (about a 2-f
25、old increase in CP) Alternatives: Low doses of hydrocortisone ? Inhaled steroids ? Other steroids eg. Methylprednisolone ?,RCT OF VITAMIN A IN ELBW INFANTS,CLD or DeathCLD in SurvivorsHospital-acquired sepsisGrade 3/4 IVHDeath, 3/4 IVH, or PVL,Decreased Risk Increased Risk,0.6 0.7 0.8 0.9 1.0 1.1 1.
26、2 1.3,RR with 95% Cl,Tyson et al. NEJM 340:1962, 1999,Routine antisepsis and hand-washing precautions Routine infection control measures Specific prophylaxis (when available, depending on country): Palivizumab (Synagis): humanized monoclonal antibody to RSV Pneumococcal conjugate vaccine (7-valent,
27、Prevnar) Influenza vaccine,Prevention of infections,Treatment of infections,Postnatal sepsis associated with more BPD (Van Marter et al. J Pediatr 140:171-6, Feb 2002 ) Is Ureaplasma colonization associated with BPD? No (Heggie et al. PIDJ 20:854-9, Sept 2001) Only if persistently (+) (Castro-Alcara
28、z 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),Summary of BPD management,Prevention is better than treatment Oxygen therapy, avoidance of environmental and infectious hazards. Essential not to unde
29、rutilize or discontinue O2 too early (may lead to feeding difficulty, slow growth, bronchoconstriction, Pulmonary hypertension ) Optimize nutrition Bronchodilators and diuretics may lead to short-term improvements. Long-term effects unknown. Avoid steroids as far as possible Experimental management:
30、 Enzyme, Gene, Cytokine, Antioxidant, Antiprotease administration, Lung transplant,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
31、 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.,Outcome (contd.),Long-term outcome Lung function - Poor com
32、pliance,increased resistance,expiratory airflow limitation (bronchospastic and bronchomalacic),increased WOB, air trapping, reactive airway disease. May persist into adulthood.,Appendix,Introduction Indications for mechanical ventilation Ventilator variables for controlling mechanical ventilation BP
33、D Pathogenesis BPD Management,Introduction,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.)
34、23-26% of VLBW survivors in USA/Canada,Introduction,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 a
35、nd BPD curves downward”,Introduction (contd.),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.,Introduction (
36、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 th
37、e ventilator and oxygen therapy after weeks to months.,Introduction (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 fail
38、ure, cor pulmonale, or infections.,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
39、neonate,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,Indications for mechanical ventilation
40、,I. Clinical criteria: Respiratory distress : retractions (intercostal, subcostal, suprasternal) and tachypnea (rate 60-70/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),Indic
41、ations for mechanical ventilation,II. Laboratory criteria: Severe hypercapnia: arterial carbon dioxide tension (PaCO2) 60 mm Hg in early RDS or 70-80 mm Hg in resolving RDS, accompanied by a pH of less than 7.20 Severe hypoxemia: arterial oxygen tension (PaO2) 60-70%,Prophylactic mechanical ventilat
42、ion 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
43、-27) An individualized intubation strategy that restricted intubation and mechanical ventilation did not increase mortality or morbidity (Lindner W et al. Pediatrics 1999; 103: 961-967 ),Prophylactic mechanical ventilation is not beneficial (contd.),A significant part of the variation in BPD between
44、 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, 105:1194-1201),Ventilator controls,The ventilator controls on most pressure-controlled time-cycled ventilators are: Positive end expi
45、ratory pressure (PEEP) Peak inspiratory pressure (PIP) Ventilator rate (VR) Inspiratory time (TI), expiratory time (TE), or inspiratory-expiratory ratio (I:E) Inspired oxygen concentration (FiO2) Flow rate,Positive end expiratory pressure (PEEP),PEEP maintains or improves lung volume (functional res
46、idual capacity or FRC), prevents alveolar collapse, and improves V/Q matching PEEP, rather than PIP or TI, is the main determinant of FRC Low PEEP: atelectasis, low FRC, and low PaO2 High PEEP: low VT, high FRC, and high PaCO2 Optimal PEEP: between 3 - 6 cm H2O pressure,Peak Inspiratory Pressure (PI
47、P),Changes in PIP affect PaO2 by affecting the mean airway pressure and thus influencing V/Q matching. The level of PIP also affects the pressure gradient (DP) which determines the tidal volume PIP increases normally increase PaO2 and decrease PaCO2,Peak Inspiratory Pressure (PIP) contd.,Very high P
48、IP may lead to hyperinflation and decreased lung perfusion and cardiac output, leading to a decrease in oxygen transport despite an adequate PaO2 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 respir
49、atory system.,Peak Inspiratory Pressure (PIP) contd.,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
50、 accuracy (Aufricht et al. Am J Perinatol 10:139-142, 1993) Minimal effective PIP: start low (e.g. 15-20 cm H2O) and increase slowly (in steps of 1-2 cm H2O),Ventilator rate,The ventilator rate (frequency) determines alveolar minute ventilation and thereby PaCO2 alveolar minute ventilation = frequency x tidal volume dead space Relationship not linear: As ventilator rate increases and TI decreases below 3 time constants, VT decreases and minute ventilation falls (Boros et al. Pediatrics 74: 487-492, 1984) As time constant is low in RDS, rates 60/min can be used,
