Congenital diaphragmatic hernia (CDH) may result in severe respiratory insufficiency with a high morbidity. The role of a disturbed surfactant metabolism in the pathogenesis of CDH is unclear. We therefore studied endogenous surfactant metabolism in the most severe CDH patients who required extracorporeal membrane oxygenation (ECMO). Eleven neonates with CDH who required ECMO and ten ventilated neonates without significant lung disease received a 24-h infusion of the stable isotope [U-C-13] glucose. The C-13-incorporation into palmitic acid in surfactant phosphatidylcholine (PC) isolated from serial tracheal aspirates was measured. Mean PC concentration in epithelial lining fluid (ELF) was measured during the first 4 days of the study. Fractional surfactant PC synthesis was decreased in CDH-ECMO patients compared to controls (2.4 +/- A 0.33 vs. 8.0 +/- A 2.4%/day, p = 0.04). The control group had a higher maximal enrichment (0.18 +/- A 0.03 vs. 0.09 +/- A 0.02 APE, p = 0.04) and reached this maximal enrichment earlier (46.7 +/- A 3.0 vs. 69.4 +/- A 6.6 h, p = 0.004) compared to the CDH-ECMO group, which reflects higher and faster precursor incorporation in the control group. Surfactant PC concentration in ELF was similar in both groups. These results show that CDH patients who require ECMO have a decreased surfactant PC synthesis, which may be part of the pathogenesis of severe pulmonary insufficiency and has a negative impact on weaning from ECMO.