Strategies for the Prevention of Bronchopulmonary Dysplasia: Wishful Thinking or Reality?
Strategies for the Prevention ofBronchopulmonary Dysplasia: Wishful Thinking or Reality? S. David Rubenstein, MD
Bronchopulmonary Dysplasia (BPD)Chronic Pulmonary Disorder which is Consequence of Lung Injury that is Abnormally Repaired
Old Definition of BPDNeed for supplemental oxygen at> 28 days or > 36 wks gestation.
New Definition of BPD•Mild BPD: need for supplemental oxygen > 28days but not at 36 weeks gestation PMA•Moderate BPD: need for supplemental oxygen >28 days and < 30% at 36 weeks PMA•Severe BPD: need for supplemental oxygen > 28days, and > 30% at 36 weeks PMA and/orpositive pressure at 36 weeks PMA
Incidence of BPD at ColumbiaBW(g) GA(wks) O2 (36 wks) Mild Mod. Severe< 750 25.4±2.0 18.3% 31.6% 15.0% 3.3%750-1000 26.9±1.8 1.4% 16.9% 1.4% 01001-1250 29.0±1.8 1.1% 0 1.1% 0<1250 27.4±2.4 5.9% 14.1% 5.0% 0.9% Sahni R., PAS 2003
“Old” BPD• Disorder related to lung injury.•Common in term & near term infants ventilated withhigh pressures and O2 .•Chest x-ray demonstrates areas of over-inflation, cysticemphysema and fibrosis.• Histopathology demonstrates interstitial and alveolaredema, small airway disease, extensive inflammation andfibrosis.
“New” BPD• More of a disorder resulting from processes thatinterfere with lung development, not injury.•Common in VLBW infants with modest ventilatoryand oxygen needs.• Chest x-ray: diffuse haziness which progresses to afine lacy pattern.•Histopathology: decreased alveolarization, minimalsmall airway disease and less inflammation/fibrosis.
New BPD: Diminished Alveolarization• Normal alveolarization begins about 28 weeksgestation: infants at term gestation have 20-50% of the adultnumber of alveoli• A variety of processes interfere with alveolarizationincluding: poor nutrition, hypoxia, hyperoxia, inflammationand glucocorticoids
New BPD: Diminished Alveolarization88 A.H. Jobe, M. Ikegami / Early Human Development 53 (1998) 81 –94Fig. 4. Alveolar numbers for human infants at birth and for ventilated infants. The curve indicates thenormal increase in alveolar number with gestation age. Ventilation of the preterm lung results in decreasedalveolar numbers. Data from Hislop and co-workers [46,47]. Jobe et al, Early Human Development: 53 (1998) 81-94
Factors Contributing to Lung Injury Jobe: Neoreviews 2006
Intrauterine Inflammation Increases the Risk of Preterm Birth• Histopathological evidence of chorioamnionitis ispresent in 40-70% of preterm births (vs. 4-18% ofterm deliveries)•Incidence of infection (positive AF culture) is32-35% with pPROM and 10-15% (spontaneousonset of preterm labor with intact membranes)
Incidence of positive chorioamniotic cultures inwomen with intact membranes undergoing cesarean section after spontaneous preterm labor Goldenberg et al NEJM 342: 1500-07, 2000
Percent of placentas harboring a microorganismBiopsy of the chorion from 1,083 placentas (initiator of delivery: preterm labor, preeclampsia) before the 28th week (Culture/PCR)Week of pregnancy 23 24 25 26 27Initiator of Delivery RoutePreterm labor: CS 56 62 42 46 34 vaginal 87 74 68 48 58Preeclampsia: CS 33 24 21 28 22 Onderdonk and the ELGAN study group Am. J Obstet. Gynecol: July 2008
Intrauterine Infection and Preterm Labor Goldenberg, NEJM: May, 2000
There is a strong relationship between markers of inflammation and BPD• Amniotic fluid proinflammatory cytokine levels areincreased in infants who develop BPD•Cord blood IL-6 concentration is an independent riskfactor for BPD and a better predictor than amniotic fluidIL-6 levels. Ghezzi 1998 & Yoon 1997, Yoon 1999
There is a strong relationship between markers of inflammation in amniotic fluid and BPD Yoon, Am J Ob Gyn; Oct 1997, 825-830
Intrauterine Infection, MMP-8 and CLD Romero et. al., Am J Ob Gyn 2001, 185: (5)1149-1155Halliday et. al., Arch Dis Child Fetal Neonatal ed 2004; 89: F61-64 2001; 84: F168-171
Antenatal Administration of Endotoxin in Fetal sheep• Promotes lung maturation• Increases proinflammatory cytokine expression (5 hrs)• Increases influx of leucocytes• Interferes with alveolar development• Augments the inflammatory response when ventilated Newnham 2001, Newnham 2002, Kramer 2001, Kramer 2002, Moss 2002, Jobe 2001
Chorioamnionitis, Mechanical Ventilation &Postnatal Sepsis: Modulators of Chronic Lung Disease • Chorioamnionitis 0.2 (0.0-0.5) • Postnatal sepsis 1.3 (0.2-2.3) • Ventilation> 7 d 1.6 (0.9-2.9) •Ventilation > 7d and 3.2 (0.9-11) chorioamnionitis •Ventilation > 7d and 2.9 (1.1-7.4) postnatal sepsis Van Marter J Ped. 2002
Mechanical Ventilation Inflammation & Alveolarization•Mechanical ventilation in experimental animalswith or without high O2 concentrations injures thelung (and decreases alveolarization)•Infants that progress to chronic lung disease havepersistence of leukocytes in alveolar lavages withhigh concentrations of inflammatory mediators.
Mechanical Ventilation Inflammation & Alveolarization•Over distention of the lung during mechanicalventilation (volutrauma) disrupts structural elementsand leads to production of inflammatory mediators(cytokines and chemokines).•Ventilation at low lung volumes (atelectrauma) alsocauses release of cytokines and influx of white bloodcells.
Delivery Room Management“Chronic Lung disease in preterm neonates may result more from antepartum or delivery room events than postnatal management.” (Jobe, J. Peds 1998) “There is perhaps nothing more dangerous for the preterm lung than an anxious physician with an endotracheal tube and a bag” (Jobe, J Peds. 2005)
Delivery Room Management•In infants with RDS, total lung capacity isreduced by a widespread proteinaceous edema•Mechanical ventilation aggravates the edema(probably by epithelial disruption); surfactantsdecrease the edema.
Delivery Room Management•Surfactant instilled after mechanical ventilationmay be inactivated by leaking protein and mayfail to enter collapsed or fluid filled regions.•This suggests that surfactant should be given asearly as possible. However, clinical trials havenot shown a consistent benefit to prophylaxis.
Delivery Room ManagementCan lung damage occur immediately afterbirth by giving a few large breaths?If yes, will surfactant still be effective?
Neonatal Resuscitation & Lung InjuryFive pairs of lamb siblings were delivered at 127-128 dgestation and one lamb in each pair was randomlyselected to receive 6 manual inflations at a volumeequal to inspiratory capacity (35-40 ml) before the startof mechanical ventilation. All lambs then receivedsurfactant at 30 minutes of age. Bjorkland et al Ped. Res. 42: 348, 1997
Neonatal Resuscitation & Lung Injury•Blood gases and pressure volume curves werethen recorded until the lambs were sacrificed at agefour hours.• Lung histopathology was then examined Bjorkland et al Ped. Res. 42: 348, 1997
Neonatal Resuscitation & Lung Injury Control lambs Experimental group 135 min.Volume (ml/kg) 30 75 min. Volume 20 45 min. (ml/kg 45-135 min. 10 Before surfactant Before surfactant 10 5 5 15 30 15 30 Pressure (cm H2O) Bjorkland et al Ped. Res. 42: 348, 1997)
Resuscitation & Lung Injury Bjorkland et al Ped. Res. 42: 348, 1997
Neonatal Resuscitation & Lung Injury•Ventilation with large breaths in an immature lungmay cause: • Epithelial and microvascular injury • Increased production of inflammatory mediators • Flux of fluid into the air spaces
Lung Overdistension Jobe (PIP = 45-50 cm H2O) Am J Respir Crit Care Med 176: 575-581 (2007)
Lung Overdistension JobeBronchoalveolar lavage fluid: TP and cell count Increased 5-fold, 11-fold, 14-fold Increased 300-fold * p < 0.01 Am J Respir Crit Care Med 176: 575-581 (2007)
Lung Overdistension Jobe Cytokine mRNA in lung tissue Am J Respir Crit Care Med 176: 575-581 (2007)
Fluid Therapy & BPD•All newborn infants exhibit an increase in urineoutput postnatally (usually in the first day of life).•In infants with RDS, the diuretic phase is delayedand commonly occurs between 24 & 48 hours of life.• A delay in the onset of diuresis until 5-7 days isassociated with an increased risk of BPD.
Fluid Therapy & BPDStudy Source Design N OutcomeVan Marter J Ped 1990 CCS 223 Infants with BPD received amounts of crystalloid & colloidVan Marter J Ped 1992 MVA 223 Incidence of BPD strongly correlated with volume of colloid received
Randomized Trials of Postnatal Na+ Supplementation•Costarino et al: (N=17) Na+ restriction during the first3-5 days of life significantly decreased the incidence ofBPD (J Pediatr 1992)•Hartnoll et al: (N=46) Delaying Na+ supplementationuntil 6% of the body weight was lost had a beneficialeffect on the risk for continuing O2 requirement(Arch Dis Child F19 1999)
Antenatal Steroids & BPD (True or False?)• Antenatal steroids decrease the incidenceof bronchopulmonary dysplasia.
Antenatal Glucocorticoid TreatmentDoes Not Reduce Chronic Lung Disease Among Surviving Preterm InfantsStudy Design: Case-referent study of 1454 LBW infantsborn between 1991-93 at four university hospitalsOutcome: In multivariate logistic regression analysesantenatal steroid Rx did not significantly decrease the rateof CLD. OR .98 (.66-1.5) Van Marter J Ped. 2001
Surfactant & BPD True or False?• The use of surfactant has decreased the likelihoodof chronic lung disease.•Surfactants work best when given before the firstbreath.
If you do not ventilate neonates it’s hard to cause BPD!
The Significance of Grunting in Hyaline Membrane Disease•In infants with HMD, grunting is a protectivemaneuver resulting from contraction of theabdominal muscles and closure of the glottis• Grunting can be prevented by intubation•Intubation (and elimination of grunting) resultedin a fall in oxygenation Harrison et al Ped. 1968
Treatment of idiopathic respiratory distresssyndrome with continuous positive airway pressure Gregory et al. N Engl J Med 284: 1333, 1971
Treatment of idiopathic respiratory distresssyndrome with continuous positive airway pressure Weight N PaO2 (pre) PaO2 (post) 930-1500 10 37.1 116.4 1501-2000 5 38.1 114.8 2001-3830 5 48.6 96.0 Gregory et al. N Engl J Med 284: 1333, 1971
Survey of Infants Admitted to 8 Neonatal ICU’s• No significant differences in survival•Columbia had the lowest incidence of O2 use at28 days and 3 months of age in survivors•Observations: early use of CPAP, permissivehypercapnia, no muscle relaxants, “J Wung” Avery et al Pediatrics 79: 77, 1987
Do clinical markers of barotrauma and oxygentoxicity explain interhospitalvariation in rates of chronic lung disease? Van Marter et al Pediatrics: 105, 1194, 2000
Columbia vs. Boston•Case-cohort study to evaluate the relationship betweenNICU practices and the occurrence of BPD• Birth weight 500-1500g (1991-93)•Three NICUs: Babies, Beth Israel Hospital & Brighamand Women’s Hospital• Outcome: O2 at 36 weeks PMA
Babies BostonBPD 4% 22%*CPAP 63% 11%*Ventilation 29% 75%*# days MV 13 d 27 d *Surfactant 10% 45%*Indomethacin 2% 28%*Sedation 0% 46%*Mortality 9% 10%Postnatal Steroids 3% 4%No significant differences in IVH, PVL, NEC or ROP
vLong-Term Neurocognitive Development Sanocka et al PAS 2002
Long-Term Neurocognitive DevelopmentHypocarbia on day one was associated with a two-fold increase in CP [odds ratio of 2.2 (1.0-4.0)]Hypercarbia (PaCO2 > 55, < 65) had no effect on theprevalence of CP, IQ or behavioral scores Sanocka et al PAS 2002
Permissive Hypercapnia•Intentional hypoventilation to avoid volutraumaand diminish lung injury.• Limited controlled data in infants to support itsefficacy & safety.
Lung Inflammatory Markers: Effect of FiCO2• Premature lambs studied at 132 days Exogenous surfactant to all (n=14) High TV and PIP for 30 minutes (10.8ml/kg, 40cm H2O)• Group I IPPV (TV 6-8ml/kg): pCO2 of 40mm Hg for 5.5 hours• Group II Same TV, PIP and F as group I; IPPV for 5.5 hours FiCO2 increased to maintain pCO2 of 95mm Hg.• Alveolar wash after IPPV Strand et al., Peds Research 2003
Lung Inflammatory Markers: Effect of FiCO21.5 1 nl PCO20.5 hi PCO2 0 Protein Total WBC PMN H2O2 Strand et al., Peds Research 2003
Protective Effects: Hypercapnia• Hypercapnic acidosis protects the heart and brain against ischemic injury and protects the lung against ischemic-reperfusion injury in experimental animals.• Hypercapnia increases cardiac output and oxygen delivery, decreases oxygen consumption, increases mesenteric blood flow, attenuates oxygen induced retinal neovascularization.
Protective Effects: Hypercapnia• Hypercapnia upregulates pulmonary nitric oxide, decreases inflammatory processes, and attenuates production of free radicals.• Human beings can tolerate exceptionally high concentrations of CO2 and recover completely.• Hypothesis: Hypercapnia may be protective in the setting of acute organ injury.
CPAP started infants in 2 epochs, BW<1000g 1999-2002 2008-11 (n=138) (n=235)CPAP failure (%) 35 36Surfactant given on failure (%) 52 63Pneumothorax (%) 7.2 9.8Mortality (%) 14.5 13.6BPD (O2 at 36wk) (%) 10.9 8.1
Infants ≤1000g with RDS requiring intubation after a trial of CPAP Blood gases at time of failure Time of intubation pH PaCO2 PaO2/FiO2 (hrs)CPAP-failure 29.7±18 7.19±.09 63±16133±86
Why is Columbia Successful with CPAP?• Early use of NPCPAP• Use of permissive hypercapnia• Acceptance by nursing staff• Bubble CPAP• Meticulous attention to CPAP circuit• Frequent suctioning; check prong position frequently• Jen T. Wung, MD (be patient; give the baby a chance)
Lung Inflammatory Markers: Effect of CPAP• Premature lambs studied at 134 days labor induced with epostane and betamethasone vaginal delivery allows spontaneous breathing• Lambs divided into 3 groups no IPPV IPPV at F = 40, PIP (maintain pCO2 at 40), PEEP 4 bubble CPAP, 5 cm H2O• Evaluate lungs at 2 hours Jobe et al., Peds Research 2002
Lung Inflammatory Markers: Effect of CPAP 7.5 * 7.4 IPPVpH 7.3 CPAP 7.2 7.1 0 15 30 60 120 time (minutes) Jobe et al., Peds Research 2002
Lung Inflammatory Markers: Effect of CPAP 80 70pCO2 (mm Hg) 60 IPPV 50 CPAP 40 30 0 15 30 60 120 time (minutes) Jobe et al., Peds Research 2002
Nasal CPAP Set up ( 2 ) 8. Manometer (optional) 9. Expiratory tubing 10. A bottle containing a solution of 0.25% acetic acid filled up to a depth of 7 cm. Distal tubing immersed to a depth of 5 cm to create +5 cmH2O
Nasal CPAPApplication (2) 4. Choose FiO2 to keep PaO2 at 50’s or O2 saturation at 83 – 93%
Nasal CPAPApplication (3) 5. Adjust a flow rate 5-10 lpm to: a) provide adequate flow to prevent rebreathings CO2 b) compensate leakage from tubing connectors and around CPAP prongs c) generate desired CPAP pressure (usually 5 cmH2O)
Nasal CPAPApplication (5) 7. Insert the lightweight corrugated tubing (preferrably with heating wire inside) in a bottle of 0.25% acetic acid solution or sterile water filled up to a height of 7 cm. The tube is immersed to a depth of 5 cm to create 5 cmH2O CPAP as long as air bubbling out of solution
Neonatal Resuscitation & Lung InjuryNeonatal resuscitation bags can deliverhigh volumes at very high pressures.ComplianceLung = Δ Volume/Δ Pressure
Factors Contributing to Lung Injury Jobe and Ikegami 1998
Effects of High TV Ventilation Wada et al., J Appl Phys 1997
Fluid Therapy & BPD•Recovery from RDS is heralded by the onset ofdiuresis.• A delayin the onset of diuresis until 5-7 days isassociated with an increased risk of BPD.•Diuretics may facilitate extubation in infants withRDS who are not exhibiting a spontaneous diuresis.
Fluid Therapy & BPDStudy Design N BW OutcomeBell et al* RCT 170 ~1430g No differenceLorenz et al** RCT 88 ~1180g No differenceTammela@ RCT 100 ~1300g BPD (4 wks)Kavvadia # RCT 168 ~ 900g No difference *NEJM 1980, **J Ped 1982, @ Eur J Ped 1992, # Arch. Dis Child 2000
Permissive Hypercapnia•VLBW infants with RDS (n= 49) randomized to ahypercapnia group (PHC) (PCO2 45-55) or normo-capnia group (NC) (PCO2 35-45).•The total number of days on assisted ventilation was2.5 in the PHC group and 9.5 in the NC group (P=.17).• No difference in BPD, IVH, PVL or air leak Mariani et al Pediatrics 1999