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We undertook a case-control study of premature infants who developed clinically significant, severe pulmonary hemorrhage (PH) in the presurfactant and surfactant eras to learn more about the cause of severe PH and whether the pathogenesis of severe PH has changed with the advent of surfactant therapy. Severe PH was defined as an acute onset of severe endotracheal bleeding with an acute drop in hematocrit and the development of multilobar infiltrates on chest radiograph. Eleven premature infants from the presurfactant era population and 17 premature infants from the surfactant era population met the criteria for severe PH, all with gestational ages <32 weeks and birth weights <1,500 g (very low birth weight infants). These were each matched by gestational age, date of birth, birth order (for twins), and birth weight to 2 controls. The incidence of severe PH in infants of gestational age <32 weeks was similar in the two eras (1.8% in the presurfactant era and 3.0% in the surfactant era). Severe PH was not associated with maternal characteristics such as drug use or prenatal care, pregnancy complications, evidence of intrauterine anoxia, hyaline membrane disease, frequency of endotracheal suctioning, or patent ductus arteriosus. Premature infants suffering from severe PH in the presurfactant era required more delivery room resuscitation and had more severe early respiratory disease during the first 12 h of life as compared with their controls. However, these differences were not present in the group from the surfactant era. Infants with severe PH were more likely to have birth weights below the third percentile for gestation (severe intrauterine growth restriction). The proportion of infants receiving surfactant, and the number of surfactant doses used, did not differ between severe-PH infants and their controls in the surfactant era group. We conclude that severe intrauterine growth restriction represents a risk factor for severe PH in very low birth weight infants. The introduction of surfactant therapy has not altered the incidence of severe PH, even though it has apparently helped remove the severity of early lung disease as a risk factor. The physiological basis of severe PH requires further investigation.

Critically ill premature infants requiring mechanical ventilation and an umbilical artery catheter usually do not receive enteral feedings during the acute phase of their illness. We studied the safety and benefit of early minimal enteral feedings during this time in a prospective, controlled, and randomized study. Twenty-nine infants were randomly assigned to receive only standard intravenous fluid and nutrition (nothing per OS, NPO group; n = 13), or in addition to receive small-volume hypocaloric continuous feedings (1 ml/kg/h), beginning at 24 h of age (early-feeding group; n = 16). Standard enteral feedings were begun in both groups at the resolution of the acute phase of the illness and advanced by protocol. The two groups were of comparable birth weight, gestational age, and Apgar scores. There were no significant differences in the episodes of feeding intolerance. Two infants in the NPO group developed clinical signs of necrotizing enterocolitis. Serum diamine oxidase and somatomedin C were measured weekly until 30-60 days of age and were not different between the two groups. The early-feeding group required fewer days to reach 120 ml/kg/day enteral intake (early-feeding group 10 +/- 3 days, NPO group 13 +/- 4 days; p < 0.05). On day 30 of life the early-feeding group was 223 +/- 125 g above birth weight, while the NPO group was 95 +/- 161 g above birth weight (p < 0.05). The average intake (kcal/kg/day) from day 6 to day 30 was not different between the two groups. We conclude that early minimal feedings in critically ill very-low-birth-weight infants requiring mechanical ventilation are well tolerated and result in reduced time to reach 120 ml/kg/day of enteral feeding and in a greater weight gain by day 30 of life.

Pregnant rats received propranolol (5 or 10 mg/kg/day) from day 10 of gestation; controls were untreated. Lung wet:dry weight ratios were increased in treated fetuses delivered by hysterotomy at day 21; no difference was seen at birth after vaginal delivery. On subsequent days, treated pups exhibited higher wet:dry weight ratios, implying impaired postnatal lung water clearance. Surfactant pools were decreased proportionately at both doses. Ongoing surfactant synthesis was unaffected at either dose. Baseline secretion was reduced for those exposed to 10 mg/kg/day. Secretory response to beta-agonist stimulation was impaired in both treatment groups. Chronic beta-blockade alters fetal lung water clearance, surfactant stores, and secretory response to beta-agonists.

In contrast to the physiologic effects of glucocorticoids on lung saturated phosphatidylcholine (SPC) production, glucocorticoids have also been shown to inhibit fetal lung growth. We have found that at the time of increasing SPC production by the fetal rabbit, rat and chick lung there is a spontaneous fall in the DNA/protein ratio of the lung tissue, suggesting decreased cell proliferation similar to that which is seen with exogenous glucocorticoid treatment. Treatment of chick embryos with glucocorticoid causes a fall in the DNA/protein ratio and a rise in the SPC content of the lung; the antiglucocorticoid 11-deoxycortisol blocks both the spontaneous fall in the DNA/protein ratio and the rise in the lung SPC content. We conclude that there is a natural slowing of lung growth in response to endogenous glucocorticoid.

The development of pulmonary surfactant production by the fetal lung is essential for normal lung function at birth. Failure to produce an adequate amount of surfactant is associated with respiratory distress syndrome of the newborn (RDS). Prediction of the risk of RDS is based on the measurement of surfactant phospholipids in amniotic fluid. We have studied on ontogeny of surfactant phospholipids in the fetal rabbit by analyzing samples obtained simultaneously from lung lavage and amniotic fluid during late gestation (days 24-30). A surge in saturated phosphatidylcholine and percent saturation is observed first in lung lavage (day 26), followed 1.5-2.5 days later by a similar increase in amniotic fluid. These findings support the assumption that amniotic fluid surfactant phospholipids reflect the production of surfactant phospholipids in the developing lung.