Presentation on theme: "Bronchopulmonary Dysplasia: Prevention and Management"— Presentation transcript:
1Bronchopulmonary Dysplasia: Prevention and Management Namasivayam Ambalavanan M.D.Assistant Professor,Division of Neonatology,Department of Pediatrics,University of Alabama at BirminghamFeb 2003
2Overview of presentation Bronchopulmonary dysplasia: a moving target?PathogenesisStrategies for prevention of BPDStrategies for management of BPDOutcomeAppendix
3BPD 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
4IntroductionNorthway, 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
5Introduction 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
6Physiologic 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 NetworkWhat is O2 requirement (failure in test)?Saturation <88% for 5 continuous minutesAny saturation <80% on an accurate pulse oximeter reading
7Study Design Baseline phase x 5 min Oxygen reduction phase as per protocol every 10 min with continuous monitoringRapid Pass (15 min in RA>96%)No BPDBPDSome BPDSome No BPDRapid Fail (80-88% for 5 min(or) <80% immediate failO2 reduction phaseIntermediate: 88-96% in first 15 min.Monitor for total 60 min.
8Incidence Varies by definition, selection bias, survival Developed countries: NICHD Neonatal Network for 2001BPD-36 UAB All centersg 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)
9Incidence 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 BPDGA232425262728293031323334n52506263828785100168158160Survival(%)3548958997949998BPD1914421
12Conservative Indication For CV and BPD Poets and SensGitterman, et alLindner, et alde Klerk and de KlerkIntubationBPDPercent (%)Adapted from Poets and Sens*, Gitterman et al., and Lindner et al, de Klerk and de Klerk*.*and/or mortality
13Ventilatory strategies for BPD prevention Conservative indications for assisted ventilationSmallest possible tidal volumeSufficient inspiratory and expiratory timesModerate PEEP to prevent end expiratory alveolar collapse and maintain adequate lung volumeEarly/prophylactic use of surfactantAcceptance of hypercapnic acidosisAggressive weaning from assisted ventilationRescue with high frequency if air leak syndromes
14Non-ventilatory strategies for BPD prevention Antenatal steroidsVitamin A supplementation (Tyson et al. NEJM 340:1962, 1999)Avoidance of infectionsClosure 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)
15BPD Management Treatment is directed towards major pathophysiology: Pulmonary edema => DiureticsBronchoconstriction and airway hyperreactivity => BronchodilatorsAirway inflammation => SteroidsCor pulmonale => VasodilatorsChronic lung injury and repair =>Antioxidants, nutrition, prevention of infections
16Management - Diuretics DIURETICS: Furosemide + ThiazidesWhen to consider :Babies >1-2 wks w/ mod-severe lung disease on ventilatorBPD w/ volume overload“Stalled” BPDBPD w/ inadequate nutrition due to fluid restriction
17Management - 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)
18Management - Bronchodilators Types of Bronchodilators:Methylxanthines ( Theophylline, caffeine )Bronchodilator, diuretic, resp stimulantweak bronchodilator, increased side effectsb-adrenergic agonists ( mainly b2, less b1 )mainly smooth muscle relaxation, also enhance mucociliary transport, redistribute pulmonary blood flowAnticholinergics - Atropine, Ipratropium
19Management - Bronchodilators Results:Bronchodilators improve pulmonary function in the short-term.No studies on long-term efficacyInhaled 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 unitsMay maintain airway wall rigidity
20Management - 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)
21Management - Steroids STEROIDS - Widespread use, different regimens HIGH RISK: Use is not recommendedWHY ?Anti-inflammatory properties (early)Modulate lung repair (late)HOW ?Early vs Late useShort-term vs Long-term coursePO/IV vs Inhaled route
22AAP/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).”
23Summary of systemic dexamethasone for BPD BPD and BPD/Death are decreased by steroidsHowever, short-term risks are significantNo improvement in survivalLong-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 ?
24RCT OF VITAMIN A IN ELBW INFANTS Decreased Risk Increased RiskCLD or DeathCLD in SurvivorsHospital-acquired sepsisGrade 3/4 IVHDeath, 3/4 IVH, or PVLRR with 95% ClTyson et al. NEJM 340:1962, 1999
25Prevention of infections Routine antisepsis and hand-washing precautionsRoutine infection control measuresSpecific prophylaxis (when available, depending on country):Palivizumab (Synagis): humanized monoclonal antibody to RSVPneumococcal conjugate vaccine (7-valent, Prevnar)Influenza vaccine
26Treatment 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)
27Summary of BPD management Prevention is better than treatmentOxygen 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 nutritionBronchodilators and diuretics may lead to short-term improvements. Long-term effects unknown.Avoid steroids as far as possibleExperimental management: Enzyme, Gene, Cytokine, Antioxidant, Antiprotease administration, Lung transplant
28Outcome 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 delayGradual improvement in pulmonary function and cor pulmonale usual, with adequate nutrition, growth and control of infection.
29Outcome (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.
30Appendix Introduction Indications for mechanical ventilation Ventilator variables for controlling mechanical ventilationBPD PathogenesisBPD Management
31Introduction 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
32Introduction Factors influencing incidence: Survival statistics in patient populationDeveloping nations have very low CLD since most ELBWs die within 28 daysSurfactant improves survival of smaller babies, but overall incidence of BPD same[“Shift of survival and BPD curves downward”]
33Introduction (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.
34Introduction (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.
35Introduction (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.
36Goals of mechanical ventilation To achieve adequate gas exchange with minimal lung injury and other adverse effectsThe definitions of “adequate gas exchange” and “minimal lung injury” will depend on the underlying pathophysiology and the clinical condition of the neonate
37Adequate Gas ExchangeThe definition of adequate gas exchange will determine:the indications for the initiation of mechanical ventilationthe desired blood gas valuesthe ventilator adjustments to maintain the blood gas values within the desired ranges
38Indications 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 areClinical criteria:respiratory distress, as manifested by retractions (intercostal, subcostal, suprasternal) and tachypnea (respiratory rate of more than 60-70/min)Andcentral 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 %Orpersistent apnea unresponsive to medical management such as theophylline, caffeine, or CPAP
39Indications 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 7.20Severe hypoxemia: arterial oxygen tension (PaO2) < mm Hg on oxygen by hood (head box) or CPAP at FiO2 > 60-70%II: Laboratory criteria includeSevere 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.OrSevere hypoxemia: arterial oxygen tension < mm Hg on oxygen by hood (head box) or CPAP at a FiO2 of more than 60-70%
40Prophylactic mechanical ventilation is not beneficial Prophylactic mechanical ventilation not beneficial, even for extremely premature neonatesA 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.
41Prophylactic 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
42Ventilator controlsThe 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 rateThe 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 rateIn 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.
43Positive end expiratory pressure (PEEP) PEEP maintains or improves lung volume (functional residual capacity or FRC), prevents alveolar collapse, and improves V/Q matchingPEEP, rather than PIP or TI, is the main determinant of FRCLow PEEP: atelectasis, low FRC, and low PaO2High PEEP: low VT, high FRC, and high PaCO2Optimal PEEP: between cm H2O pressurePEEP maintains or improves lung volume (functional residual capacity or FRC), prevents alveolar collapse, and improves ventilation perfusion or VQ matchingPEEP, rather than peak inspiratory pressure or inspiratory pressure, is the main determinant of FRCAt 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 syndromesIn 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.
44Peak 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 volumePIP increases normally increase PaO2 and decrease PaCO2Changes 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 volumePIP increases normally increase PaO2 and decrease PaCO2
45Peak 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 PaO2High levels of PIP also increase the risk of “volutrauma”, air leak syndromes, and lung injuryPIP 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 PaO2High levels of PIP also increase the risk of “volutrauma”, air leak syndromes, and lung injuryPIP required depends mainly on the compliance of the respiratory system.
46Peak 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.
47Factors to be considered in selecting PIP Yes NoLung compliance WeightBlood gas derangement ResistanceChest rise Time constantBreath sounds PEEPOthers Others
48Ventilator rateThe ventilator rate (frequency) determines alveolar minute ventilation and thereby PaCO2alveolar 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 usedThe ventilator rate (frequency) determines alveolar minute ventilation and thereby PaCO2alveolar 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 levelsThe 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).
49TI , TE , and I:EThe TI and TE are normally adjusted based on the time constantChanges in I:E change MAP, and thus PaO2When 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)
50Gas exchangeMAP increases with increasing PIP, PEEP, TI to TE ratio, rate, and flowPIPPressureFlowRateTIPIPPEEPPEEPTimeTITE
51Inspired oxygen concentration (FiO2) Changes in FiO2 alter PaO2 directly by changing the A-a DO2Insufficient data to compare the roles of O2- induced versus pressure-associated (or volume- associated) lung injury in the neonateGenerally 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
52Inspired oxygen concentration (FiO2) During early RDS, FiO2 first increased to 0.6 to 0.7 before additional increases in MAPDuring weaning, first decrease PIP to relatively safe levels, then decrease FiO2 below 0.4 to 0.5Maintenance of an adequate MAP and V/Q matching may permit a reduction in FiO2Reduce MAP before a very low FiO2 (<0.3) is reached, to reduce the risk of air leaks.
53Flow rateAs long as a sufficient flow is used, there is minimal effect on the pressure waveform or on gas exchangeHigher flow leads to a more “square wave” pressure waveform, which increases MAP, turbulence, and risk of air leaksA minimum flow rate of about 3 times the infant’s minute ventilation is usually required, and L/min is usually sufficient
54Ventilator settingsIn view of the low compliance, short time constant, low FRC, and risk for air leaks, it is usually preferred to userapid rates (>60/min)moderate PEEP (4-5 cm H2O)low PIP (10-20 cm H2O)TI of sVT is generally mL/kg body weight
55Ventilator settingsRandomized 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)
56Clinical estimation of optimal TI and TE Short TI Optimal TI Long TIInadeq VT Short insp. plateau Long plateauChestWallMotionTimeShort TE Optimal TE Long TEAir trapping Short exp. plateau Long exp. plateauChestWallMotion
57Weaning off ventilator When good spontaneous ventilatory attempts are present and mechanical ventilation contributes only minimally to total ventilationNormally 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)
58BPD PathogenesisFeatures of the immature lung increasing susceptibility:Barotrauma : Poorly compliant airspaces, but highly compliant airwaysHyperoxia : Poorly developed antioxidant defensesInfection : Altered airway clearance, immature macrophages & WBCInflammation : Poorly developed anti-oxidant, antiproteolytic and antielastolytic systemsIncreased permeability of the alveolo-capillary membrane with decreasing gestational age.
59BPD Pathogenesis Complications of Hyperoxia: Cytotoxicity epithelium & endothelium Pulmonary edema and hemorrhageCytotoxicity on airway lining & macrophages Poor airway clearance and increased infectionPulmonary edema + inhibition of surfactant synthesis leads to worsening complianceInhibition of pulmonary vascular response to hypoxia leads to shunting , V/Q mismatchInhibition of normal lung repair, healing by fibroblast proliferationInhibition of normal lung development, decreased alveolarizationLoss of pulmonary endothelial functions
60Lung 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)
61Changes in intubation rates in relation to outcome in VLBW infants p valuen=665 n=664 n=672Intubated (%) <0.05O2 at 28d (%) <0.05Death or O2 at 28d (%) NSDeath or O2 in < 1.0 kg (%) <0.05Death or O2 in kg (%) <0.05CPAP (%) NSPoets 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
62Ventilator-Associated Lung Injury (VALI) Likely mechanismsVolume rather than pressuresEnd expiratory volume rather than VT or FRCTransalveolar pressure and reopening of alveoliRepeated collapse and reopening of alveoliVery low positive end expiratory pressureOxidant injury
63Which Volumes Cause Lung Injury? Volutrauma ZoneVolumeABA High VTB Normal VT,high PEEPTime
64EFFECT OF TIDAL VOLUME ON LUNG COMPLIANCE 1 2 3 8 cc/kg (cc/cmH2O•kg) 1238 cc/kg(cc/cmH2O•kg)ComplianceComments:In this study, only a handful of large breaths were sufficient to cause persistent lung injury, manifested as decreased lung compliance.16cc/kg32 cc/kg60120180240Age (min)Bjorklund et al. Pediatr Res 39:326A, 1996
65Early 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 intubationMay decrease the need for mechanical ventilation and improve respiratory failure and reduce mortalityMay 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
66Permissive 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
67Relative Risk for BPD Variable N Relative risk (95% CI) Highest PaCO2 at 48 or 96 hr> 50 mm Hg 21 Reference group40-49 mm Hg (0.95, 1.90)< 40 mm Hg (1.04, 2.01)Kraybill et al., J Pediatr 115: , 1989
68Risk for BPD in Neonates with RDS: Variables in Logistic Regression Odds ConfidenceRatio IntervalVE Index <a/A Ratio <Low PaCO2 (< 29 vs 40)(30-39 vs >40)Birthweight < 1000 gramsC/S Due to Fetal DistressGarland et al. Arch Pediatr Adolesc Med , 1995
69Volume vs. Pressure in Lung Injury Pulm. Epith. Hyaline Lymph Filtr.Volume Pressure Edema Injury Memb. Flow Coef.IPPV High High Yes Yes Yes Yes YesIron Lung High Low Yes Yes Yes N/A N/AStrapping Low High No No No No NoDreyfus et al, 1988; Bshouty et al, 1988; Hernandez et al, 1989; Corbridge et al, 1990; Carlton et al 1990
70CPAP at Birth in VLBW Infants CPAP Controln=70 n=57 p valueIntubated (%) <0.05Dur. intubation (d) 6(3-9) 4.5(3-7) NSO2 at 28 days (%) NSNosocomial infection (%) <0.05Gitterman et al. Eur J Pediatrics. 156:384, 1997
71CPAP at Birth in VLBW Infants 2Percent (%)Gitterman et al. Eur J Pediatrics. 156:384, 1997
72CV vs CPAP at Birth in ELBW Infants CPAP Routine Intubation p valueN=67 N=56DR intubation (%) <0.01Intubated (%) <0.01Mortality (%) NSO2 at 36 weeks (%) <0.05IVH > 2 (%) <0.01Lindner et al. Pediatrics 103:961, 1999
73CV VS CPAP at Birth in ELBW Infants 2Percent (%)Lindner et al. Pediatrics 103:961, 1999
74de Klerk and de Klerk. J Paedr Child Health 37:161:201 CPAP in Infants KgCPAP Control p valuen=59 n=57Intubated (%) <0.001Surfactant (%) <0.001Ventilation (d) 2 6 <0.05Oxygen suppl (d) 2 4 <0.01O2 at 28d (%) 0 11 <0.05O2 at 28d or death (%) 3 16 <0.05O2 at 36w or death (%)de Klerk and de Klerk. J Paedr Child Health 37:161:201
75de Klerk and de Klerk. J Paedr Child Health 37:161:201 CPAP in Infants Kg2Percent (%)de Klerk and de Klerk. J Paedr Child Health 37:161:201
76Demographic Characteristics of ELBW and BPD Without BPD With BPDCharacteristic (n=50) (n=97)Gestational age (wk) *Birth weight (gm)Sex (% male) *Race (% white) 32 43Roentgenographic score **p<0.005Kraybill et al., J. Pediatr 115: , 1989
77Treatment Variables of ELBW infants and BPD Without BPD With BPDCharacteristic (n=29) (n=90)Pressure managementPIP (cm H2O)At 48 hrAt 96 hrPaw (cm H2O) At 48 hrAt 96 hrKraybill et al., J. Pediatr 115: , 1989
78Treatment Variables of ELBW infants and BPD Without BPD With BPDCharacteristic (n=29) (n=90)Oxygen managementFiO2 (%)At 48 hrAt 96 hrPaO2 (mmHg) At 48 hrAt 96 hrPA-aO2 (mmHg)At 48 hrAt 96 hrKraybill et al., J. Pediatr 115: , 1989
79Relative Risk for BPD Variable N Relative risk (95% CI) Highest PaO2 at 48 or 96 hr< 70 mm Hg 30 Reference group70-80 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
80Logistic Regression Model to Predict BPD Independent Variable p rSex (male) <PaCO2 at 48 hr <Roentgenographic scoreGestational ageRaceKraybill et al., J. Pediatr 115: , 1989
81RANDOMIZED TRIAL OF PERMISSIVE HYPERCAPNIA IN PRETERM INFANTS G Mariani, J Cifuentes, WA CarloDepartment of Pediatrics, University of Alabama at BirminghamPediatrics 104: , 1999
82Infants on MV (%) Duration of MV (hours) Normocapnia 20406080100Permissive hypercapniap = Log rank testInfants on MV (%)1224364860728496Duration of MV (hours)
83The 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 INFANTSThe Steroid And VEntilation (SAVE) TrialNICHD Neonatal Research NetworkCarlo et al. J Pediatr 141: 370-4, Sept 2002
84Centers and Principal Investigators SAVETrialCenters and Principal InvestigatorsUniv of Alabama at Birmingham Wally Carlo, MDHarvard University Ann Stark, MDEmory University Barbara Stoll, MDCase Western Reserve University Avroy Fanaroff, MB, BChYale University Richard Ehrenkranz, MDUniversity of Tennessee-Memphis Sheldon Korones, MDUT Southwestern Medical Center-Dallas Jon Tyson, MDWayne State University Seetha Shankaran, MDBrown University William Oh, MDUniversity of Miami Charles Bauer, MDUniversity of Cincinnati Ed Donovan, MDStanford University David Stevenson, MDUniversity of New Mexico Lu-Ann Papile, MDResearch Triangle Institute Ken Poole, PhDNICHD Linda Wright, MD
85HypothesisA 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.
87Study Design Corticosteroid/Placebo Minimal/Routine ventilation SAVETrialStudy DesignMulticenterRandomized-stratified by center and birth weight group2 x 2 Factorial designInterventionsCorticosteroid/PlaceboMinimal/Routine ventilation
88Ventilatory Intervention (Continued) SAVETrialVentilatory 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.
89Methods - Ventilatory Management SAVETrialMethods - Ventilatory ManagementGoals: Minimal ventilation group - PCO2 > 52 mmHgRoutine ventilation group - PCO2 < 48 mmHgIn both groups:Priority was given to decrease tidal volume by decreasing peak inspiratory pressure (PIP) or increasing rateTidal volume was measured dailyThe same extubation criteria (rate < 10/min, FiO2 < 0.50, and pH > 7.25) were used
93PCO2 While on a Ventilator Weighted PCO2 (mmHg)Study Day
94TIMING OF SURFACTANT AND LUNG VOLUTRAUMA 6Prophylactic Surfactant“Rescue” Surfactant4(cc/cmH2O•kg)ComplianceComments:Inflation of the lungs before administration of surfactant injured the lungs (reduced lung compliance).260120180240Age (min).Ingirmarsson et al. Pediatr Res 41:255A, 1997
95Surfactant: 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)
96Surfactant use: repeat doses Repeat doses are given depending on the clinical status and the ventilatory settingsHigher threshold (>40% FiO2 with a MAP > 7 cm H2O) for uncomplicated RDSLower threshold (>30% FiO2) may reduce mortality in infants with RDS complicated by perinatal compromise or sepsis(Kattwinkel et al. Pediatrics 106: , 2000)
97Surfactant 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 oxygenationreduce ventilator requirementsreduce 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.
98Surfactant 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.
99BPD Management - difficulties in study Definition ; objective assessment of severity ; variable statusconfounding effect of multiple risk factorslimited number of patients per center ; difference between centers in patient populationhistorical controls / retrospective studies of little use since rapid changes in management techniquesTechnical limitation of PFTs ; data dropout due to death, discharge or extubation
100Elective HFOV: Meta-analysis of 8 studies (Henderson-Smart: Cochrane Rev 4, 2001) No difference in mortalityTrends toward decreases in BPD in survivors at weeks (RR 0.73 (0.57, 0.93) and death or CLD at weeksSignificant increase in severe (grades 3 & 4) IVH and in any air leak [RR 1.19 (1.03, 1.38)] in the HFOV group2 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 PVLNot currently recommended
101Elective HFJV: Meta-analysis of 3 studies Carlo 90, Wiswell 96, Keszler 97HFJV 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 protocolRequires more investigation(Bhuta and Henderson-Smart. Cochrane Rev 4, 2001)
102Rescue HFOVOnly 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.
103Newer 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)
104Surfactant 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, 2001Prophylaxis 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.
105Management - Diuretics WHY ?Clinical, XRay & Histologic evidence of interstitial & peribronchiolar pulmonary edemaAbnormal regulation of water balance ; hypervolemiaAcute and short term diuretics improve pulmonary function and occasionally gas exchangeBenefit unrelated to urine output
106Management - Diuretics Types: Loop diuretics: FurosemideThiazides : Chloro/HydrochlorothiazideSpironolactoneResults with Thiazides and Spironolactone conflicting, though blinded studies did show some improvementFurosemide also increases vasodilator PG synthesis, causes systemic and pulmonary vasodilation, increases surfactant synthesis and decreases Cl- transport in the airway epithelium
108Management - Bronchodilators WHY ?Sufficient bronchial smooth muscle, even in tiny premiesHyperplastic smooth muscle and metaplastic epithelium in BPDCorrelation with family history of Asthma
109Management - Bronchodilators Bronchodilators - How ?Albuterol 50 mg q 4-6 hrs for 2-3 days. If improvement noted, continue, and reassess weekly.
110Early 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)
111Moderately 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 )
112Delayed 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.
113Inhaled steroidsBeclomethasone and Flunisolide have been tried by nebulization. May decreaseneed for systemic steroidsside effectsBeclomethasone 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
115Other antioxidantsNo 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.
116Outcome (contd.) Long-term outcome (contd) Cor pulmonale - usually resolvesReactive Airway disease - 50% will have exercise induced bronchospasmSIDS ? - BPD spells ?- acute obstructive episodes. Some reports of increased SIDS incidence.
117Outcome (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
118Outcome (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 )