Alan H. Jobe

Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.

Objective. A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants <32 weeks’ gestational age (GA). Mild BPD was defined as a need for supplemental oxygen (O2) for ≥28 days but not at 36 weeks’ postmenstrual age (PMA) or discharge, moderate BPD as O2 for ≥28 days plus treatment with <30% O2 at 36 weeks’ PMA, and severe BPD as O2 for ≥28 days plus ≥30% O2 and/or positive pressure at 36 weeks’ PMA. The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD. Methods. Data from 4866 infants (birth weight ≤1000 g, GA <32 weeks, alive at 36 weeks’ PMA) who were entered into the National Institute of Child Health and Human Development Neonatal Research Network Very Low Birth weight (VLBW) Infant Registry between January 1, 1995 and December 31, 1999, were linked to data from the Network Extremely Low Birth Weight (ELBW) Follow-up Program, in which surviving ELBW infants have a neurodevelopmental and health assessment at 18 to 22 months’ corrected age. Linked VLBW Registry and Follow-up data were available for 3848 (79%) infants. Selected follow-up outcomes (use of pulmonary medications, rehospitalization for pulmonary causes, receipt of respiratory syncytial virus prophylaxis, and neurodevelopmental abnormalities) were compared among infants who were identified with BPD defined as O2 for 28 days (28 days definition), as O2 at 36 weeks’ PMA (36 weeks’ definition), and with the consensus definition of BPD. Results. A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months’ corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up. Conclusion. The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions.

The New Bronchopulmonary Dysplasia

Purpose of review Bronchopulmonary dysplasia (BPD) remains the most common severe complication of preterm birth. A number of recent animal models and clinical studies provide new information about pathophysiology and treatment. Recent findings The epidemiology of BPD continues to demonstrate that birth weight and gestational age are most predictive of BPD. Correlations of BPD with chorioamnionitis are clouded by the complexity of the fetal exposures to inflammation. Excessive oxygen use in preterm infants can increase the risk of BPD but low saturation targets may increase death. Numerous recent trials demonstrate that many preterm infants can be initially stabilized after delivery with continuous positive airway response (CPAP) and then be selectively treated with surfactant for respiratory distress syndrome. The growth of the lungs of the infant with BPD through childhood remains poorly characterized. Summary Recent experiences in neonatology suggest that combining less invasive care strategies that avoid excessive oxygen and ventilation, decrease postnatal infections, and optimize nutrition may decrease the incidence and severity of BPD.

Antenatal endotoxin and glucocorticoid effects on lung morphometry in preterm lambs.

In utero inflammation may accelerate fetal lung maturation but may also play a role in the pathogenesis of chronic lung disease. We examined the impact of endotoxin, a potent proinflammatory stimulus, on structural and functional maturation of preterm sheep lungs. Date bred ewes received 20 mg Escherichia coli endotoxin or saline by ultrasound guided intra-amniotic injection at 119 d gestation. A comparison group of animals received 0.5 mg/kg betamethasone, a known maturational agent, at 118 d gestation. Lambs were delivered by cesarean section at 125 d (term = 150 d) and ventilated for 40 min. Lung function data are reported elsewhere. Total and differential white cell counts were performed on amniotic fluid and fetal lung fluid samples. Morphometric analyses were performed on inflation fixed right upper lobes. Total cell count increased slightly but not significantly in both amniotic fluid and fetal lung fluid. Both endotoxin and betamethasone had similar effects on alveolarization: average alveolar volume increased by approximately 20% and total alveolar number decreased by almost 30%. Both treatments led to thinning of alveolar walls, although this was statistically significant in the betamethasone-treated group only. Although antenatal endotoxin leads to striking improvements in postnatal lung function, this may be at the expense of normal alveolar development.

Beneficial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants.

OBJECTIVE Our objective was to test the hypothesis that prenatal maternal corticosteroids would improve the subsequent response of infants to surfactant treatments. STUDY DESIGN We used the data bases of two recently published large multicenter trials of multidose surfactant treatments to retrospectively evaluate the possible interactions between maternal corticosteroids and randomized surfactant treatments on short-term ventilatory effects, complications of respiratory distress syndrome and prematurity, and 28-day death rates. RESULTS The combined use of corticosteroids and surfactant significantly decreased overall death and death caused by respiratory distress syndrome relative to either treatment alone. Ventilatory variables at 72 hours were improved in those infants receiving both treatments, and other major complications of prematurity also tended to have decreased incidences. CONCLUSION The combined use of prenatal corticosteroids, when indicated, and postnatal surfactant improves neonatal outcome.

Prenatal inflammation and lung development

Prenatal exposure of very low birth weight infants to chronic indolent chorioamnionitis with organisms such as mycoplasma and ureaplasma is frequent. Chorioamnionitis is inconsistently associated with changed risks of respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (BPD), probably because the diagnosis of chorioamnionitis does not quantify the extent or duration of the fetal exposures to infection and inflammation. The correlations between prenatal exposures and postnatal lung disease also are confounded by the imprecision of the diagnoses of RDS and BPD. In animal models, chorioamnionitis caused by pro-inflammatory mediators or live ureaplasma induces lung maturation, but also causes alveolar simplification and vascular injury. Intra-amniotic endotoxin administration also modulates the fetal innate immune system, resulting in maturation of monocytes to alveolar macrophages and the induction or paralysis of inflammatory responses depending on exposure history. Prenatal inflammation can have profound effects on the fetal lung and subsequent immune responses.

Decreased Indicators of Lung Injury with Continuous Positive Expiratory Pressure in Preterm Lambs

Continuous positive airway pressure (CPAP) is being used clinically to avoid mechanical ventilation of preterm infants as a strategy to minimize lung injury. There is little experimental information about how CPAP might minimize lung injury after preterm birth. We induced preterm labor in antenatal glucocorticoid-treated sheep carrying twins at 133 d gestation with an inhibitor of progesterone synthesis. The lambs delivered spontaneously approximately 2 d later and were randomized to three groups: no ventilation (n = 4), conventional mechanical ventilation to a target Pco2 of 40 mm Hg (n = 5), or CPAP using a bubble CPAP device set to deliver 5 cm H2O pressure (n = 6). The CPAP lambs breathed without distress and maintained Pco2 values of approximately 60 mm Hg. At 2 h of age, the lungs of the CPAP lambs held 74 ± 4 mL/kg air at 40 cm H2O pressure, which was more than the 60 ± 3 mL/kg for the ventilated lambs (p < 0.05). Lymphocyte and monocyte numbers in alveolar washes were equivalent in the unventilated, ventilated, and CPAP lambs. However, no neutrophils were found in the unventilated lambs, and the ventilated lambs had 6.6 times more neutrophils in alveolar washes than did the CPAP lambs (p < 0.05). The cells in alveolar wash from CPAP lambs contained less hydrogen peroxide than did the cells from ventilated lambs (p < 0.05). In this model in preterm lambs CPAP results in lower indicators of acute lung injury than does mechanical ventilation during the first 2 h of life.

Antenatal factors and the development of bronchopulmonary dysplasia

The lung of the preterm fetus is often exposed to antenatal glucocorticoids, and histologic chorioamnionitis is frequent. Clinically and experimentally, antenatal glucocorticoids and/or chorioamnionitis are associated with early lung maturation, but in experimental models, both glucocorticoids and intra-uterine inflammation decrease alveolarization. Experimental chorioamnionitis also can amplify the inflammatory response of the preterm lung to mechanical ventilation. In this article, the hypothesis developed is that bronchopulmonary dysplasia occurs because of repetitive adverse lung exposures, or hits, and that the initial hits may be antenatal glucocorticoid exposure and/or antenatal inflammation.

Injury and Inflammation from Resuscitation of the Preterm Infant

We review information about how the preterm lung can be injured with the initiation of mechanical ventilation at birth. Although multiple variables such as pressure, tidal volume, positive end expiratory pressure, and the gas used for ventilation may contribute to the injury, the relative contribution of each is not known. Recent studies demonstrate that injury caused by initial high tidal volume is amplified by subsequent mechanical ventilation. A model for gas inflation of the fluid-filled lung may explain why even low tidal volumes may injure the preterm lung, and why the injury may initially occur to the small airways. Ventilation strategies that minimize injury need to be developed.

Duration and characteristics of treatment of premature lambs with natural surfactant.

Premature lambs were treated with 50 mg/kg of natural surfactant lipid by tracheal instillation either at birth or shortly thereafter when respiratory failure was documented. All lambs were delivered by cesarean section and supported on infant ventilators with 100% oxygen under conditions to mimic the care of human infants with the respiratory distress syndrome. The natural surfactant used for therapy was recovered by lavage from sheep lung. Six 120-d gestational age lambs treated at birth had an initial mean oxygen pressure (pO2) value of 270 +/- 35 mm Hg; this fell within 3 h to less than 100 mm Hg. By 8.3 +/- 0.3 h after birth the lambs were in severe respiratory failure with a mean pH less than 7.1 and a mean pCO2 greater than 70 mm Hg. Six untreated lambs had pH values below 7.0 within 40 min of life despite more intensive respiratory support than was given the treated animals. Treatment with natural surfactant of 17 lambs of 120 and 130 d gestational age after early respiratory failure resulted in a prompt increase in pO2 values from about 35 mm Hg to values over 200 mm Hg and a fall in pCO2 values to normal levels in the majority of animals. This response lasted only approximately 3 h, and a second treatment was less predictably effective.

Physiology of Transition from Intrauterine to Extrauterine Life

The transition from fetus to newborn is the most complex adaptation that occurs in human experience. Lung adaptation requires coordinated clearance of fetal lung fluid, surfactant secretion, and onset of consistent breathing. The cardiovascular response requires striking changes in blood flow, pressures, and pulmonary vasodilation. Energy metabolism and thermoregulation must be quickly controlled. The primary mediators that prepare the fetus for birth and support the multiorgan transition are cortisol and catecholamine. Abnormalities in adaptation are frequently found following preterm birth or cesarean delivery at term, and many of these infants need delivery room resuscitation to assist in this transition.