Daphne J. Janssen

Surfactant metabolism in the neonate

With the use of stable isotope-labeled intravenous precursors for surfactant phosphatidylcholine (PC) synthesis, it has been shown that the de novo synthesis rates in preterm infants with respiratory distress syndrome (RDS) are very low as are turnover rates. This is consistent with animal data. Surfactant therapy does not inhibit endogenous surfactant synthesis, and prenatal corticosteroids stimulate it. With the use of stable isotope-labeled PC given endotracheally, surfactant pool size was estimated. It turned out to be low in RDS, as expected. Similar studies were performed in term neonates with severe lung diseases. In general, patients with lung injury show a lower surfactant synthesis. The controversy around surfactant in congenital diaphragmatic hernia (CDH) persists: studies on CDH with and without extracorporeal membrane oxygenation yielded different results. In severe meconium aspiration syndrome surfactant synthesis was found to be decreased but surfactant pool size was maintained. It is possible and safe to study surfactant metabolism in human neonates with the use of stable isotopes. This can help in answering clinical questions and has the potential to bring new in vitro and animal findings about surfactant metabolism to the patient.

Treatment with exogenous surfactant stimulates endogenous surfactant synthesis in premature infants with respiratory distress syndrome

ObjectiveTreatment of preterm infants with respiratory distress syndrome (RDS) with exogenous surfactant has greatly improved clinical outcome. Some infants require multiple doses, and it has not been studied whether these large amounts of exogenous surfactant disturb endogenous surfactant metabolism in humans. We studied endogenous surfactant metabolism in relation to different amounts of exogenous surfactant, administered as rescue therapy for RDS. DesignProspective clinical study. SettingNeonatal intensive care unit in a university hospital. PatientsA total of 27 preterm infants intubated and mechanically ventilated for respiratory insufficiency. InterventionsInfants received a 24-hr infusion with the stable isotope [U-13C]glucose starting 5.3 ± 0.5 hrs after birth. The 13C-incorporation into palmitic acid in surfactant phosphatidylcholine (PC) isolated from serial tracheal aspirates was measured. Infants received either zero (n = 5), one (n = 4), two (n = 15), or three (n = 3) doses of Survanta (100 mg/kg) when clinically indicated. Measurements and Main ResultsUsing multiple regression analysis, the absolute synthesis rate (ASR) of surfactant PC from plasma glucose increased with 1.3 ± 0.4 mg/kg/day per dose of Survanta (p = .007) (mean ± sem). The ASR of surfactant PC from glucose was increased by prenatal corticosteroid treatment with 1.3 ± 0.4 mg/kg/day per dose corticosteroid (p = .004), and by the presence of a patent ductus arteriosus with 2.1 ± 0.7 mg/kg/day (p = .01). ConclusionThese data are reassuring and show for the first time in preterm infants that multiple doses of exogenous surfactant for RDS are tolerated well by the developing lung and stimulate endogenous surfactant synthesis.

Surfactant Phosphatidylcholine Half-life and Pool Size Measurements in Premature Baboons Developing Bronchopulmonary Dysplasia

Because minimal information is available about surfactant metabolism in bronchopulmonary dysplasia, we measured half-lives and pool sizes of surfactant phosphatidylcholine in very preterm baboons recovering from respiratory distress syndrome and developing bronchopulmonary dysplasia, using stable isotopes, radioactive isotopes, and direct pool size measurements. Eight ventilated premature baboons received 2H-DPPC (dipalmitoyl phosphatidylcholine) on d 5 of life, and radioactive 14C-DPPC with a treatment dose of surfactant on d 8. After 14 d, lung pool sizes of saturated phosphatidylcholine were measured. Half-life of 2H-DPPC (d 5) in tracheal aspirates was 28 ± 4 h (mean ± SEM). Half-life of radioactive DPPC (d 8) was 35 ± 4 h. Saturated phosphatidylcholine pool size measured with stable isotopes on d 5 was 129 ± 14 μmol/kg, and 123 ± 11 μmol/kg on d 14 at autopsy. Half-lives were comparable to those obtained at d 0 and d 6 in our previous baboon studies. We conclude that surfactant metabolism does not change during the early development of bronchopulmonary dysplasia, more specifically, the metabolism of exogenous surfactant on d 8 is similar to that on the day of birth. Surfactant pool size is low at birth, increases after surfactant therapy, and is kept constant during the first 2 wk of life by endogenous surfactant synthesis. Measurements with stable isotopes are comparable to measurements with radioactive tracers and measurements at autopsy.

275 Epithelial Repair in The Preterm Lung is Decreased in The Early Phase of Bronchopulmonary Dysplasia

Background: In the early phases bronchopulmonary dysplasia (BPD) is characterized by epithelial and endothelial damage and inflammation. A recent study showed an absent or decreased concentration of keratinocyte growth factor, a factor contributing to epithelial repair, in early BPD (Danan C et al, Am J Respir Crit Care Med. 2002;165:1384–7).Aim: To investigate whether bronchoalveolar lavage fluid (BALF) from preterm infants who develop BPD has a decreased capacity to stimulate epithelial repair compared to BALF from infants who recover from respiratory distress syndrome (RDS).Methods: A standardized blind bronchoalveolar lavage was performed with 2x1 ml/kg saline in ventilated preterm infants with a gestational age <30 weeks on day 2 to 4 of life. Infants who recovered from RDS were all extubated within the first week of life. BPD was defined as oxygen requirement at 28 days of life. A bronchial epithelial cell line (BEAS) was grown to confluence and a scratch of known surface area was made in the epithelium (Geiser et al, Am J Physiol Lung Cell Mol Physiol 2000;279:L1184–90). BALF (or control medium without serum) was added to the cell cultures for 18 hours and the closure of the epithelial wound was assessed (expressed as % closure above control medium).Results: BALF from infants who developed BPD (n=13) had a significantly lower capacity to stimulate epithelial wound closure than BALF from infants who recovered from RDS (n=10): 25±5% versus 48±4.5% closure above control medium (p=0.02 by t-test) (mean±SEM).Conclusion: BALF on day 2 to 4 from preterm infants who develop BPD has a decreased capacity to stimulate epithelial repair in an in vitro assay compared to BALF from infants who recover from RDS. This suggests that besides epithelial injury also decreased epithelial repair plays a role in the early phase of BPD development. Further investigations are necessary to elucidate which growth factors or other factors are important for the decreased epithelial repair in the early phase of BPD development.