Tracing exogenous surfactant in vivo in rabbits by the natural variation of 13C

BACKGROUND: Respiratory Distress Syndrome (RDS) is a prematurity-related breathing disorder caused by a quantitative deficiency of pulmonary surfactant. Surfactant replacement therapy is effective for RDS newborns, although treatment failure has been reported. The aim of this study is to trace exogenous surfactant by 13C variation and estimate the amount reaching the lungs at different doses of the drug. METHODS: Forty-four surfactant-depleted rabbits were obtained by serial bronchoalveolar lavages (BALs), that were merged into a pool (BAL pool) for each animal. Rabbits were in nasal continuous positive airway pressure and treated with 0, 25, 50, 100 or 200 mg/kg of poractant alfa by InSurE. After 90 min, rabbits were depleted again and a new pool (BAL end experiment) was collected. Disaturated-phosphatidylcholine (DSPC) was measured by gas chromatography. DSPC-Palmitic acid (PA) 13C/12C was analyzed by isotope ratio mass spectrometry. One-way non-parametric ANOVA and post-hoc Dunn's multiple comparison were used to assess differences among experimental groups. RESULTS: Based on DSPC-PA 13C/12C in BAL pool and BAL end experiment, the estimated amount of exogenous surfactant ranged from 61 to 87% in dose-dependent way (p < 0.0001) in animals treated with 25 up to 200 mg/kg. Surfactant administration stimulated endogenous surfactant secretion. The percentage of drug recovered from lungs did not depend on the administered dose and accounted for 31% [24-40] of dose. CONCLUSIONS: We reported a risk-free method to trace exogenous surfactant in vivo. It could be a valuable tool for assessing, alongside the physiological response, the delivery efficiency of surfactant administration techniques

Decreased surfactant phosphatidylcholine synthesis in neonates with congenital diaphragmatic hernia during extracorporeal membrane oxygenation

Purpose: 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). Methods: 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-13C] glucose. The13C-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. Results: Fractional surfactant PC synthesis was decreased in CDH-ECMO patients compared to controls (2.4 ± 0.33 vs. 8.0 ± 2.4%/day, p = 0.04). The control group had a higher maximal enrichment (0.18 ± 0.03 vs. 0.09 ± 0.02 APE, p = 0.04) and reached this maximal enrichment earlier (46.7 ± 3.0 vs. 69.4 ± 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. Conclusion: 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

Decreased surfactant phosphatidylcholine synthesis in neonates with congenital diaphragmatic hernia during extracorporeal membrane oxygenation

Purpose: 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). Methods: 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-13C] glucose. The13C-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. Results: Fractional surfactant PC synthesis was decreased in CDH-ECMO patients compared to controls (2.4 ± 0.33 vs. 8.0 ± 2.4%/day, p = 0.04). The control group had a higher maximal enrichment (0.18 ± 0.03 vs. 0.09 ± 0.02 APE, p = 0.04) and reached this maximal enrichment earlier (46.7 ± 3.0 vs. 69.4 ± 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. Conclusion: 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

Altered surfactant homeostasis and recurrent respiratory failure secondary to TTF-1 nuclear targeting defect

Background: Mutations of genes affecting surfactant homeostasis, such as SFTPB, SFTPC and ABCA3, lead to diffuse lung disease in neonates and children. Haploinsufficiency of NKX2.1, the gene encoding the thyroid transcription factor-1 (TTF-1) - critical for lung, thyroid and central nervous system morphogenesis and function - causes a rare form of progressive respiratory failure designated brain-lung-thyroid syndrome. Molecular mechanisms involved in this syndrome are heterogeneous and poorly explored. We report a novel TTF-1 molecular defect causing recurrent respiratory failure episodes in an infant.Methods: The subject was an infant with severe neonatal respiratory distress syndrome followed by recurrent respiratory failure episodes, hypopituitarism and neurological abnormalities. Lung histology and ultrastructure were assessed by surgical biopsy. Surfactant-related genes were studied by direct genomic DNA sequencing and array chromatine genomic hybridization (aCGH). Surfactant protein expression in lung tissue was analyzed by confocal immunofluorescence microscopy. For kinetics studies, surfactant protein B and disaturated phosphatidylcholine (DSPC) were isolated from serial tracheal aspirates after intravenous administration of stable isotope-labeled 2H2O and 13C-leucine; fractional synthetic rate was derived from gas chromatography/mass spectrometry 2H and 13C enrichment curves. Six intubated infants with no primary lung disease were used as controls.Results: Lung biopsy showed desquamative interstitial pneumonitis and lamellar body abnormalities suggestive of genetic surfactant deficiency. Genetic studies identified a heterozygous ABCA3 mutation, L941P, previously unreported. No SFTPB, SFTPC or NKX2.1 mutations or deletions were found. However, immunofluorescence studies showed TTF-1 prevalently expressed in type II cell cytoplasm instead of nucleus, indicating defective nuclear targeting. This pattern has not been reported in human and was not found in two healthy controls and in five ABCA3 mutation carriers. Kinetic studies demonstrated a marked reduction of SP-B synthesis (43.2 vs. 76.5 \ub1 24.8%/day); conversely, DSPC synthesis was higher (12.4 vs. 6.3 \ub1 0.5%/day) compared to controls, although there was a marked reduction of DSPC content in tracheal aspirates (29.8 vs. 56.1 \ub1 12.4% of total phospholipid content).Conclusion: Defective TTF-1 signaling may result in profound surfactant homeostasis disruption and neonatal/pediatric diffuse lung disease. Heterozygous ABCA3 missense mutations may act as disease modifiers in other genetic surfactant defects

Can we improve outcome of congenital diaphragmatic hernia?

This review gives an overview of the disease spectrum of congenital diaphragmatic hernia (CDH). Etiological factors, prenatal predictors of survival, new treatment strategies and long-term morbidity are described. Early recognition of problems and improvement of treatment strategies in CDH patients may increase survival and prevent secondary morbidity. Multidisciplinary healthcare is necessary to improve healthcare for CDH patients. Absence of international therapy guidelines, lack of evidence of many therapeutic modalities and the relative low number of CDH patients calls for cooperation between centers with an expertise in the treatment of CDH patients. The international CDH Euro-Consortium is an example of such a collaborative network, which enhances exchange of knowledge, future research and development of treatment protocols

Year in review in Intensive Care Medicine 2011: III. ARDS and ECMO, weaning, mechanical ventilation, noninvasive ventilation, pediatrics and miscellanea

SCOPUS: re.jinfo:eu-repo/semantics/publishe

Year in review in Intensive Care Medicine 2010: III. ARDS and ALI, mechanical ventilation, noninvasive ventilation, weaning, endotracheal intubation, lung ultrasound and paediatrics

SCOPUS: re.jinfo:eu-repo/semantics/publishe