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 prevention 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 describing 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 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
Introduction Definitions: • 1980’s: Oxygen dependence for 28 days or more after birth (Tooley WH. J Pediatr 95: 851-8, 1979) • 1990’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). • 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 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 Rapid Pass (15 min in RA>96%) No BPD BPD Some BPD Some No BPD Rapid Fail (80-88% for 5 min (or) <80% immediate fail O2 reduction phase Intermediate: 88-96% in first 15 min. Monitor for total 60 min.
Incidence • Varies by definition, selection bias, survival • Developed countries: NICHD Neonatal Network for 2001 BPD-36 UAB 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) • 401-1000 g (2001; n=154): 82% IMV, 73% surf, 16% steroids for BPD
Pathogenesis PULMONARY IMMATURITY Increased Airway Compliance surfactant deficiency Pressure/ flow inhomogeneity Immature cells Retained fluid Barotrauma Protein leak Infection /Inflammation PDA O2 Toxicity Respiratory Distress Syndrome DIFFUSE ALVEOLAR DAMAGE RECOVERY Barotrauma Infection / Inflammation BRONCHOPULMONARY DYSPLASIA
Prevention of BPD • Ventilatory Strategies • Selective intubation / Avoid IMV (Prophylactic IMV bad) • Early CPAP • Minimal (‘gentle”) ventilation • Early extubation • Pharmacologic Strategies • Antenatal steroids • Vitamin A supplementation • Others • Other management: PDA, Infection
Poets and Sens Gitterman, et al Lindner, et al de Klerk and de Klerk Conservative Indication For CV and BPD Intubation BPD Percent (%) Adapted from Poets and Sens*, Gitterman et al., and Lindner et al, de Klerk and de Klerk*. *and/or mortality
Ventilatory strategies for BPD prevention • Conservative indications for assisted ventilation • Smallest possible tidal volume • Sufficient inspiratory and expiratory times • Moderate PEEP to prevent end expiratory alveolar collapse and maintain adequate lung volume • Early/prophylactic use of surfactant • Acceptance of hypercapnic acidosis • Aggressive weaning from assisted ventilation • Rescue with high frequency if air leak syndromes
Non-ventilatory strategies for BPD prevention • Antenatal steroids • Vitamin 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 restriction 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 => 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 ventilator • BPD w/ volume overload • “Stalled” BPD • BPD 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 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)
Management - Bronchodilators • Types of Bronchodilators: • Methylxanthines ( 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, 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 bronchoconstriction 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 vascular 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, Mar 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: 330-8Feb 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 circumstances (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-fold increase in CP) • Alternatives: • Low doses of hydrocortisone ? • Inhaled steroids ? • Other steroids eg. Methylprednisolone ?
RCT OF VITAMIN A IN ELBW INFANTS Decreased Risk Increased Risk CLD or Death CLD in Survivors Hospital-acquired sepsis Grade 3/4 IVH Death, 3/4 IVH, or PVL 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 RR with 95% Cl Tyson et al. NEJM 340:1962, 1999
Prevention of infections • 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, Prevnar) • Influenza vaccine
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-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)
Summary of BPD management • Prevention is better than treatment • Oxygen therapy, avoidance of environmental and infectious hazards. Essential not to underutilize 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: 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 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 compliance, • 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 • BPD 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.) • 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 and 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(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.
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 failure, 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 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 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 <85%) on oxygen by hood (head box) or continuous positive airway pressure (CPAP) at FiO2 > 60-70% • persistent apnea unresponsive to medical management (e.g. theophylline, caffeine, or CPAP)
Indications 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) < 40-50 mm Hg on oxygen by hood (head box) or CPAP at FiO2 > 60-70%
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: 961-967 )
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, 105:1194-1201)
Ventilator controls The ventilator controls on most pressure-controlled time-cycled ventilators are: • Positive end expiratory 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 residual 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 (PIP) • 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 PIP 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 respiratory 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 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)
Factors to be considered in selecting PIP Yes No Lung compliance Weight Blood gas derangement Resistance Chest rise Time constant Breath sounds PEEP Others Others
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
TI , TE , and I:E • The TI and TE are normally adjusted based on the time constant • Changes in I:E change MAP, and thus PaO2 • When corrected for MAP, changes in I:E are not as effective in improving PaO2 as changes in PIP or PEEP (Stewart et al. Pediatrics 67:474-81, 1981) • Higher ventilatory rates combined with a short TI decrease air leaks (Octave. Arch Dis Child 66:770-775, 1991; Pohlandt et al. Eur J Pediatr 151:904-909, 1992)
Gas exchange • MAP increases with increasing PIP, PEEP, TI to TE ratio, rate, and flow PIP Pressure Flow Rate TI PIP PEEP PEEP Time TI TE