Bronchopulmonary Dysplasia: Prevention and Management

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 g 11% (n=297) 23% (n=3589) g 19% (n=154) 39% (n=1517) Developing countries: PGI: BPD-28: <1000g: 50% ; g: 8%; g: 2.3% (Indian Pediatrics Feb 2002)

Incidence UAB statistics (1998-1999) of all live births <34 w
(excluding 10 deaths before admission) g (2001; n=154): 82% IMV, 73% surf, 16% steroids for BPD GA 23 24 25 26 27 28 29 30 31 32 33 34 n 52 50 62 63 82 87 85 100 168 158 160 Survival (%) 35 48 95 89 97 94 99 98 BPD 19 14 4 2 1

Pathogenesis PULMONARY IMMATURITY surfactant deficiency Increased
Airway Compliance Pressure/ flow inhomogeneity Immature cells surfactant deficiency 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 Pharmacologic 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

Conservative Indication For CV and BPD
Poets and Sens Gitterman, et al Lindner, et al de Klerk and de Klerk 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: , 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)

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

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

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
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)

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 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” “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 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 > /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) The usual indications for the initiation of mechanical ventilation in neonates are Clinical criteria: respiratory distress, as manifested by retractions (intercostal, subcostal, suprasternal) and tachypnea (respiratory rate of more than 60-70/min) And 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 an oxygen concentration (FiO2) of more than % Or persistent apnea unresponsive to medical management such as 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 > mm Hg in resolving RDS, accompanied by a pH of less than 7.20 Severe hypoxemia: arterial oxygen tension (PaO2) < mm Hg on oxygen by hood (head box) or CPAP at FiO2 > 60-70% II: Laboratory criteria include Severe hypercapnia: arterial carbon dioxide tension (PaCO2) > 60 mm Hg in neonates with early respiratory distress syndrome or > mm Hg in resolving respiratory distress syndrome, accompanied by a pH of less than 7.20. Or Severe hypoxemia: arterial oxygen tension < mm Hg on oxygen by hood (head box) or CPAP at a FiO2 of more than 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: ) Prophylactic mechanical ventilation may not be beneficial, even for extremely premature neonates. Poets and Sens showed that a decrease in the rates of intubation and mechanical ventilation for very low birth weight (VLBW) neonates reduced the incidence of bronchopulmonary dysplasia (BPD) in a population based study. In another retrospective study, an individualized intubation strategy that restricted intubation and mechanical ventilation did not increase mortality or morbidity.

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: ) Van Marter et al also showed that 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

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 The ventilator controls on most pressure-controlled time-cycled ventilators are: 1. Positive end expiratory pressure (PEEP) 2. Peak inspiratory pressure (PIP) 3. Ventilator rate (VR) 4. Inspiratory time (TI), expiratory time (TE), or inspiratory- expiratory ratio (I:E) 5. Inspired oxygen concentration (FiO2) 6. Flow rate In addition, most new ventilators offer additional modes, as well as mechanisms to detect respiratory efforts and synchronize the ventilator tidal volume with the spontaneous breaths. Some ventilators also offer graphical displays of dynamic pulmonary function testing by analyzing flow and airway pressures. Although these often more expensive devices have not been proven to improve survival or other important outcomes, they may improve our understanding of pathophysiology in individual patients. The expertise of the clinician in optimizing the ventilation for the individual neonate is particularly important as improved hardware and software have become available.

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 cm H2O pressure PEEP maintains or improves lung volume (functional residual capacity or FRC), prevents alveolar collapse, and improves ventilation perfusion or VQ matching PEEP, rather than peak inspiratory pressure or inspiratory pressure, is the main determinant of FRC At low levels of PEEP,atelectasis, low lung volumes, and impaired oxygenation can result, At high PEEP, overdistension of the lung and decreased lung compliance can lead to decreased tidal volumes, high lung volumes, and impaired carbon dioxide elimination. Other possible hazards of high PEEP are an increase in pulmonary vascular resistance, decreased venous return with a decrease in cardiac output, and possibly a higher incidence of air leak syndromes In general, optimum PEEP levels are between 3 and 6 cm H2O pressure. Early in the course of RDS, when micro-atelectasis due to surfactant deficiency is a concern, PEEP levels of 4-5 cm H2O are often used. Later, during the weaning process, a PEEP level of 3-4 cm H2O may be more appropriate.

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 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. 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: , 1993) Minimal effective PIP: start low (e.g cm H2O) and increase slowly (in steps of 1-2 cm H2O) 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: , 1993) The Minimal effective PIP must be used. One must start low (e.g cm H2O) and increase slowly (in steps of 1-2 cm H2O) to avoid volutrauma.

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: , 1984) As time constant is low in RDS, rates > 60/min can be used The ventilator rate (frequency) determines alveolar minute ventilation and thereby PaCO2 alveolar minute ventilation = frequency x [tidal volume – dead space] This relationship is not linear. As ventilator rate increases and inspiratory time decreases below 3 time constants, tidal volume decreases and minute ventilation plateaus and later falls with ventilator rates above certain levels The exact frequencies at which tidal volume will decrease with increasing rate and at which minute ventilation decreases will depend on the time constant of the respiratory system. As compliance is low and resistance is not usually significantly increased in RDS, the time constant is low and higher rates (>60/min) can be used in the acute and resolving phase of RDS (Chan V, Greenough A, Hird MF. Comparison of different rates of artificial ventilation for preterm infants ventilated beyond the first week of life. Early Hum Dev 26: ,1991).

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: , 1991; Pohlandt et al. Eur J Pediatr 151: , 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

Inspired oxygen concentration (FiO2)
Changes in FiO2 alter PaO2 directly by changing the A-a DO2 Insufficient data to compare the roles of O2- induced versus pressure-associated (or volume- associated) lung injury in the neonate Generally believed that risk of O2 toxicity is less than that of volutrauma with FiO2 < Frequent FiO2 changes are required, based on pulse oximetry rather than occasional blood gases

Inspired oxygen concentration (FiO2)
During early RDS, FiO2 first increased to 0.6 to 0.7 before additional increases in MAP During weaning, first decrease PIP to relatively safe levels, then decrease FiO2 below 0.4 to 0.5 Maintenance of an adequate MAP and V/Q matching may permit a reduction in FiO2 Reduce MAP before a very low FiO2 (<0.3) is reached, to reduce the risk of air leaks.

Flow rate 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 A minimum flow rate of about 3 times the infant’s minute ventilation is usually required, and L/min is usually sufficient

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 H2O) low PIP (10-20 cm H2O) TI of s VT is generally mL/kg body weight

Ventilator settings Randomized controlled trials have shown that a rapid rates and short TI (versus slow rates and long TI) 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)

Clinical estimation of optimal TI and TE
Short TI Optimal TI Long TI Inadeq VT Short insp. plateau Long plateau Chest Wall Motion Time Short TE Optimal TE Long TE Air trapping Short exp. plateau Long exp. plateau Chest Wall Motion

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 H2O and a FiO2 < 40%. Extubation from low rates is more successful as compared to extubation from endotracheal CPAP (Davis and Henderson-Smart. Cochrane Rev. CD , 2000)

BPD Pathogenesis 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.

BPD Pathogenesis 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

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)

Changes in intubation rates in relation to outcome in VLBW infants
p value n=665 n=664 n=672 Intubated (%) <0.05 O2 at 28d (%) <0.05 Death or O2 at 28d (%) NS Death or O2 in < 1.0 kg (%) <0.05 Death or O2 in kg (%) <0.05 CPAP (%) NS Poets and Sens showed in a population based study that over the 3 years, the proportion of patients not intubated and mechanically ventilated increased from 7% to 14% in infants less than 1000 g and from 28% to 44% in those more than 1000 g . There was an increase in the proportion of infants less than 1000 g who survived without BPD and a decrease in the proportion of infants more than 1000 g in whom BPD developed. This observational study, however, cannot define whether a more selective approach to the intubation of VLBW infants will ultimately result in a better outcome. A randomized, controlled trial would be required to answer this clinically important question. Poets and Sens. Pediatrics 98:24, 1996

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

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

EFFECT OF TIDAL VOLUME ON LUNG COMPLIANCE 1 2 3 8 cc/kg (cc/cmH2O•kg)
1 2 3 8 cc/kg (cc/cmH2O•kg) Compliance Comments: In this study, only a handful of large breaths were sufficient to cause persistent lung injury, manifested as decreased lung compliance. 16 cc/kg 32 cc/kg 60 120 180 240 Age (min) Bjorklund et al. Pediatr Res 39:326A, 1996

Early CPAP: prophylactic or rescue?
Prophylactic CPAP (before onset of respiratory distress) practiced at some centers. 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 ) Prophylactic CPAP (before onset of respiratory distress) is practiced at some centers. We will look at the evidence behind this. Early “rescue” use of nasal CPAP after the onset of respiratory distress, often when combined with an dose of surfactant given by a brief intubation, may be more effective in decreasing the need for mechanical ventilation and in improving respiratory failure and reducing mortality, although with an increased risk of pneumothorax

Permissive Hypercapnia: Background
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. This is a practice note slide. Let’s see if this works

Relative Risk for BPD Variable N Relative risk (95% CI)
Highest PaCO2 at 48 or 96 hr > 50 mm Hg 21 Reference group 40-49 mm Hg (0.95, 1.90) < 40 mm Hg (1.04, 2.01) Kraybill et al., J Pediatr 115: , 1989

Risk for BPD in Neonates with RDS: Variables in Logistic Regression
Odds Confidence Ratio Interval VE Index < a/A Ratio < Low PaCO2 (< 29 vs 40) (30-39 vs >40) Birthweight < 1000 grams C/S Due to Fetal Distress Garland et al. Arch Pediatr Adolesc Med , 1995

Volume vs. Pressure in Lung Injury
Pulm. Epith. Hyaline Lymph Filtr. Volume Pressure Edema Injury Memb. Flow Coef. IPPV High High Yes Yes Yes Yes Yes Iron Lung High Low Yes Yes Yes N/A N/A Strapping Low High No No No No No Dreyfus et al, 1988; Bshouty et al, 1988; Hernandez et al, 1989; Corbridge et al, 1990; Carlton et al 1990

CPAP at Birth in VLBW Infants
CPAP Control n=70 n=57 p value Intubated (%) <0.05 Dur. intubation (d) 6(3-9) 4.5(3-7) NS O2 at 28 days (%) NS Nosocomial infection (%) <0.05 Gitterman et al. Eur J Pediatrics. 156:384, 1997

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

CV vs CPAP at Birth in ELBW Infants
CPAP Routine Intubation p value N=67 N=56 DR intubation (%) <0.01 Intubated (%) <0.01 Mortality (%) NS O2 at 36 weeks (%) <0.05 IVH > 2 (%) <0.01 Lindner et al. Pediatrics 103:961, 1999

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

de Klerk and de Klerk. J Paedr Child Health 37:161:201
CPAP in Infants Kg CPAP Control p value n=59 n=57 Intubated (%) <0.001 Surfactant (%) <0.001 Ventilation (d) 2 6 <0.05 Oxygen suppl (d) 2 4 <0.01 O2 at 28d (%) 0 11 <0.05 O2 at 28d or death (%) 3 16 <0.05 O2 at 36w or death (%) de Klerk and de Klerk. J Paedr Child Health 37:161:201

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

Demographic Characteristics of ELBW and BPD
Without BPD With BPD Characteristic (n=50) (n=97) Gestational age (wk) * Birth weight (gm) Sex (% male) * Race (% white) 32 43 Roentgenographic score * *p<0.005 Kraybill et al., J. Pediatr 115: , 1989

Treatment Variables of ELBW infants and BPD
Without BPD With BPD Characteristic (n=29) (n=90) Pressure management PIP (cm H2O) At 48 hr At 96 hr Paw (cm H2O) At 48 hr At 96 hr Kraybill et al., J. Pediatr 115: , 1989

Treatment Variables of ELBW infants and BPD
Without BPD With BPD Characteristic (n=29) (n=90) Oxygen management FiO2 (%) At 48 hr At 96 hr PaO2 (mmHg) At 48 hr At 96 hr PA-aO2 (mmHg) At 48 hr At 96 hr Kraybill et al., J. Pediatr 115: , 1989

Relative Risk for BPD Variable N Relative risk (95% CI)
Highest PaO2 at 48 or 96 hr < 70 mm Hg 30 Reference group 70-80 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

Logistic Regression Model to Predict BPD
Independent Variable p r Sex (male) < PaCO2 at 48 hr < Roentgenographic score Gestational age Race Kraybill et al., J. Pediatr 115: , 1989

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

Infants on MV (%) Duration of MV (hours) Normocapnia
20 40 60 80 100 Permissive hypercapnia p = Log rank test Infants on MV (%) 12 24 36 48 60 72 84 96 Duration of MV (hours)

The Steroid And VEntilation (SAVE) Trial
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

Centers and Principal Investigators
SAVE Trial Centers and Principal Investigators Univ of Alabama at Birmingham Wally Carlo, MD Harvard University Ann Stark, MD Emory University Barbara Stoll, MD Case Western Reserve University Avroy Fanaroff, MB, BCh Yale University Richard Ehrenkranz, MD University of Tennessee-Memphis Sheldon Korones, MD UT Southwestern Medical Center-Dallas Jon Tyson, MD Wayne State University Seetha Shankaran, MD Brown University William Oh, MD University of Miami Charles Bauer, MD University of Cincinnati Ed Donovan, MD Stanford University David Stevenson, MD University of New Mexico Lu-Ann Papile, MD Research Triangle Institute Ken Poole, PhD NICHD Linda Wright, MD

Hypothesis A strategy of minimal ventilation support (defined as a PCO2 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.

Sample Size 1200 infants Ventilator strategy Minimal Routine
SAVE Trial Sample Size 1200 infants Ventilator strategy Minimal Routine Stress Dose Placebo Steroid strategy

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

Ventilatory Intervention (Continued)
SAVE Trial Ventilatory Intervention (Continued) 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. Ventilator strategy is maintained for ten days unless extubation occurs sooner.

Methods - Ventilatory Management
SAVE Trial Methods - Ventilatory Management Goals: Minimal ventilation group - PCO2 > 52 mmHg Routine ventilation group - PCO2 < 48 mmHg 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 < 10/min, FiO2 < 0.50, and pH > 7.25) were used

Ventilatory Intervention
SAVE Trial Ventilatory Intervention Routine ventilator support (Normocapnia) PCO2 goal: < 48 mmHg PaO2 goal: mmHg O2 sat goal: % pH goal: ³ 7.20 Minimal ventilator support (Permissive hypercapnia) PCO2 goal: > 52 mmHg PaO2 goal: mmHg O2 sat goal: % pH goal: ³ 7.20

Results - Primary Outcome Measure
SAVE Trial Results - Primary Outcome Measure Minimal Routine Ventilation Ventilation RR CI (N=109) (N=111) Mortality or CLD (%) ( ) Mortality (%) ( ) CLD (%) ( )

Results - Secondary Analyses
SAVE Trial Results - Secondary Analyses Minimal Routine Ventilation Ventilation RR CI NNT CLD or death in gm (%) ( )* 6 Ventilation at 36 wk (%) ( )* 7 O2/CPAP/Vent at 36 wk (%) ( ) — *p<0.05

PCO2 While on a Ventilator
Weighted PCO2 (mmHg) Study Day

TIMING OF SURFACTANT AND LUNG VOLUTRAUMA
6 Prophylactic Surfactant “Rescue” Surfactant 4 (cc/cmH2O•kg) Compliance Comments: Inflation of the lungs before administration of surfactant injured the lungs (reduced lung compliance). 2 60 120 180 240 Age (min) . Ingirmarsson et al. Pediatr Res 41:255A, 1997

Surfactant: which one to use?
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) 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)

Surfactant use: repeat doses
Repeat doses are given depending on the clinical status and the ventilatory settings Higher threshold (>40% FiO2 with a MAP > 7 cm H2O) for uncomplicated RDS Lower threshold (>30% FiO2) may reduce mortality in infants with RDS complicated by perinatal compromise or sepsis (Kattwinkel et al. Pediatrics 106: , 2000)

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) Multiple doses of surfactant are normally required for moderate to severe RDS, as has been shown in studies by Dunn and Speer, and reviewed by Roger Soll in his Cochrane review.

Surfactant use: how many doses?
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) Older studies on synthetic surfactants such as exosurf also reached similar conclusions, with the OSIRIS study concluding that two doses were as good as 3-4 doses, and the American Exosurf neonatal study showing that 3 doses were better than one dose.

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

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

Elective HFJV: Meta-analysis of 3 studies
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 ] Increase in PVL in the trial by Wiswell [RR (1.19, 21.04), NNH 4.0 (2.3,14.5)] where a ‘high volume strategy' was not the standard protocol Requires more investigation (Bhuta and Henderson-Smart. Cochrane Rev 4, 2001)

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 (1.06,2.96), NNH 6] Insufficient evidence for conclusions at present (HIFO Study Group. J Pediatr 1993;122: ; Bhuta and Henderson-Smart. Cochrane Rev 4, 2001) The HIFO study with 182 infants with severe RDS is the only good study for rescue HFOV in preterm babies. There is an uncontrolled rescue study by Clark in 1986.

Newer modes of ventilation
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) (Schulze et al. J Pediatr 135: ,1999) Continuous tracheal gas insufflation (CTGI) (Dassieu et al. Intensive Care Med 24: ,1998) Perflurocarbon assisted gas exchange (PAGE) (Wolfson et al. Pediatr Pulmonol 26:42-63,1998)

Surfactant use: prophylactic vs. selective use
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. Meta-analysis : For every 100 infants treated prophylactically, there will be 2 fewer pneumothoraces, and 5 fewer deaths. 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. Meta-analysis indicates that for every 100 infants treated prophylactically, there will be 2 fewer pneumothoraces, and 5 fewer deaths. These studies have been mostly conducted in infants below 30 weeks of age. One problem with prophylactic use is over-treatment, as twice as many babies will receive surfactant. Another problem is logistics. Not all deliveries of preterm babies occur in hospitals with neonatologists and surfactants immediately available 24 hours a day.

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

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

Pathways controlling airway smooth muscle tone : . Parasympathetic cholinergic : contraction, increase mucus . Beta-adrenergic : relaxation . Nonadrenergic, noncholinergic (NANC) or Peptidergic : Bronchoconstrictor : Substance P Bronchodilator : VIP (possibly deficient in Asthma)

WHY ? Sufficient bronchial smooth muscle, even in tiny premies Hyperplastic smooth muscle and metaplastic epithelium in BPD Correlation with family history of Asthma

Bronchodilators - How ? Albuterol 50 mg q 4-6 hrs for 2-3 days. If improvement noted, continue, and reassess weekly.

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. 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)

Moderately early steroids (7-14 days)
BPD or BPD/Death at 28 d and 36 w were decreased by steroids (NNT =7 for BPD28 and 4 for BPD36), and weaning from ventilator was faster. 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 )

Delayed Steroids (>3 weeks)
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. 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.

Inhaled steroids 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) Type, dosage, and delivery methods still need to be optimized

Other medications: Vitamin A
Vitamin A Control (N=405) (N=402) Birth weight (grams) 770   138 Gestational age (weeks) 27  2 27 2 Mean airway pressure (cm H2O) 7  3 7  2 FiO   0.20 Baseline retinol (µg/dL) 16  6 16  6 Tyson et al. NEJM 340:1962, 1999

Other antioxidants 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) Catalase, Glutathione peroxidase etc are under investigation.

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.

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

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 )

Bronchopulmonary Dysplasia: Prevention and Management

Similar presentations

Presentation on theme: "Bronchopulmonary Dysplasia: Prevention and Management"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Bronchopulmonary Dysplasia: Prevention and Management

Similar presentations

Presentation on theme: "Bronchopulmonary Dysplasia: Prevention and Management"— Presentation transcript:

Similar presentations

About project

Feedback