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Respiratory distress syndrome (RDS) care pathways evolve slowly as new evidence emerges. We report the sixth version of “European Guidelines for the Management of RDS” by a panel of experienced European neonatologists and an expert perinatal obstetrician based on available literature up to end of 2022. Optimising outcome for babies with RDS includes prediction of risk of preterm delivery, appropriate maternal transfer to a perinatal centre, and appropriate and timely use of antenatal steroids. Evidence-based lung-protective management includes initiation of non-invasive respiratory support from birth, judicious use of oxygen, early surfactant administration, caffeine therapy, and avoidance of intubation and mechanical ventilation where possible. Methods of ongoing non-invasive respiratory support have been further refined and may help reduce chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease, although minimising time spent on mechanical ventilation by targeted use of postnatal corticosteroids remains essential. The general care of infants with RDS is also reviewed, including emphasis on appropriate cardiovascular support and judicious use of antibiotics as being important determinants of best outcome. We would like to dedicate this guideline to the memory of Professor Henry Halliday who died on November 12, 2022.These updated guidelines contain evidence from recent Cochrane reviews and medical literature since 2019. Strength of evidence supporting recommendations has been evaluated using the GRADE system. There are changes to some of the previous recommendations as well as some changes to the strength of evidence supporting recommendations that have not changed. This guideline has been endorsed by the European Society for Paediatric Research (ESPR) and the Union of European Neonatal and Perinatal Societies (UENPS).

Background There is no strict correlation between early bronchopulmonary dysplasia and long-term respiratory disease. Early inhaled corticosteroids seem to reduce the incidence of bronchopulmonary dysplasia, but the long-term outcome remains unknown. Research question The aim of this study was to evaluate the effect of early inhaled corticosteroids on chronic respiratory morbidity. Methods Fifty-nine survivors from the Prague cohort included in Neonatal European Study of Inhaled Steroids underwent further follow-up comprising of respiratory morbidity monitoring during the first 2 years of life followed by objective lung function testing performed at the age of 5.9 years (range 5-7 years). Both outcomes were pursued and finalized before the unblinding of budesonide subgroups. Results Fifty randomized (budesonide vs placebo group, 56% vs 44%) survivors were included in the study. Spirometry was successfully performed in 48 children. No statistically significant differences were found in the lung function test (forced expiratory flow [FEF] - FEF75 , FEF50, FEF25 , and FEF25-75; FEV1 , forced vital capacity [FVC], FEV1 /FVC) although mild trend to the improvement of expiratory flow pattern was observed in the budesonide group (median z-score of FEV1 /FVC -0.376 vs -0.983, P = .13; median z-score of FEF25-75 -1.004 vs -1.458, P = .13; median z-score of FEF75 -0.527 vs -0.996, P = .17). Children assigned to budesonide had a significantly lower rate of symptoms of chronic lung disease (34.6% vs 68.2%; P = .04) than children assigned to placebo. Interpretation Our study suggests that early inhaled budesonide was associated with the trend to the improvement of functional lung parameters and with a lower rate of symptoms of chronic lung disease within the first 2 years of life.

Fatty acid esters of long-chain hydroxy fatty acids or (O-acyl)-hydroxy fatty acids (OAHFAs) were identified for the first time in vernix caseosa and characterized using chromatography and mass spectrometry. OAHFAs were isolated from the total lipid extract by a two-step semipreparative TLC. The general structure of OAHFAs was established using high-resolution and tandem mass spectrometry of intact lipids and their transesterification and derivatization products. Two isomeric lipid classes were identified: O-acyl esters of ω-hydroxy fatty acids (ωOAHFA) and O-acyl esters of α-hydroxy fatty acids (αOAHFAs). To the best of our knowledge, αOAHFAs have never been detected in any biological sample before. Chromatographic separation and identification of OAHFAs species were achieved using non-aqueous reversed-phase HPLC coupled to electrospray ionization hybrid linear ion trap-Orbitrap mass spectrometry. The lipid species were detected as deprotonated molecules, and their structures were elucidated using data-dependent fragmentation in the negative ion mode. More than 400 OAHFAs were identified in this way. The most abundant ωOAHFAs species were 28:0/ω-18:2, 29:0/ω-18:2, 30:0/ω-18:2, 32:0/ω-18:2, and 30:0/ω-18:3, while αOAHFAs comprised saturated species 21:0/α-24:0, 22:0/α-24:0, 23:0/α-24:0, 24:0/α-24:0, and 26:0/α-24:0. OAHFAs were estimated to account for approximately 0.04% of vernix caseosa lipids. Graphical Abstract.

Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report updated recommendations of a European Panel of expert neonatologists who developed consensus guidelines after critical examination of the most up-to-date evidence in 2007 and 2010. This second update of the guidelines is based upon published evidence up to the end of 2012. Strong evidence exists for the role of antenatal steroids in RDS prevention, but it is still not clear if the benefit of repeated courses on respiratory outcomes outweighs the risk of adverse outcomes in the short and long term. Many practices involved in preterm neonatal stabilization at birth are not evidence based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in the management of RDS but the best preparation, optimal dose and timing of administration at different gestations is not completely clear. In addition, use of very early continuous positive airway pressure (CPAP) has altered the indications for prophylactic surfactant administration. Respiratory support in the form of mechanical ventilation may be lifesaving but can cause lung injury, and protocols should be directed at avoiding mechanical ventilation where possible by using non-invasive respiratory support such as CPAP. For babies with RDS to have best outcomes, it is essential that they have optimal supportive care, including maintenance of normal body temperature, proper fluid management, good nutritional support, appropriate management of the ductus arteriosus and support of the circulation to maintain adequate tissue perfusion. Copyright (c) 2013 S. Karger AG, Basel

Aim: To compare the 5-year survival without major disability in infants born at the threshold of viability at 22–25 weeks who were actively treated in the delivery room and admitted to a NICU to that of those born at 26–27 weeks of gestation. Methods: All infants between 22+0 and 27+6 weeks of gestation admitted to a regional intensive care unit during 1999–2003 were enroled prospectively. The survival and major disability at 5 years of age were analysed by gestational age. Results: Of 242 treated infants, 202 survived (83.5%). Although the overall survival rate was significantly higher in the 25–27 weeks’ gestation infants than the 22–24 weeks’ gestation infants (p

a Department of Neonatology, University Children’s Hospital, Tubingen , Germany; b Royal Maternity Hospital, and Department of Child Health, Queen’s University, Belfast , UK; c General Faculty Hospital in Prague, Prague , Czech Republic; d Department of Pediatrics and Adolescence and Neonatal Research Laboratory, Oulu University Hospital, University of Oulu, Oulu , Finland; e Department of Neonatology, Kaplan Medical Center, Rehovot, and f Hebrew University, Jerusalem , Israel; g Assistance Publique-Hopitaux de Paris, Service de Medecine Neonatale de Port-Royal and Universite Paris Descartes, Paris , France; h Department of Paediatrics, Children’s Hospital, Azienda Ospedaliero-Universitaria, Ancona , Italy; i Children’s National Medical Center, Washington, D.C. , USA; j Department of Paediatrics, Erasmus MC Sophia Children’s Hospital, Rotterdam , The Netherlands; k Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart , and l Department of Clinical Pharmacology, University Hospital Tubingen, Tubingen , Germany

Objective. To determine whether early surfactant administration is superior to selective delayed treatment in terms of improving survival and/or reducing chronic lung disease in extremely premature neonates with respiratory distress syndrome (RDS) treated by high-frequency oscillatory ventilation (HFOV). Design. Prospective randomized clinical trial. Setting. Tertiary neonatal intensive care unit (NICU) in the Perinatology Center of Prague. Patients. Forty-three extremely premature infants who needed artificial ventilation within 3 h after delivery. Interventions. Patients were randomly assigned to either early (n=21) or delayed (n=22) administration of surfactant. All were ventilated by HFOV as the primary mode of ventilation using the high volume strategy aimed at optimizing lung volume. Curosurf at a dose of 100 mg/kg was given as a single bolus via the endotracheal tube within 1 min immediately after intubation in the early group (EARL), or during HFOV only when defined criteria were reached in the delayed (DEL) group. Measurements and results. No differences were noted in demographic data between the two groups. Fewer infants randomized to the EARL group required oxygen use or died at 36 weeks (combined outcome 29% vs 64%, p=0.021), and there was a lower incidence of any intraventricular hemorrhage in this group (43 vs 82%, p=0.008). Conclusions. When compared to delayed dosing, early administration of surfactant followed by HFOV facilitates and accelerates respiratory stabilization during the acute phase of severe RDS, may reduce the incidence of chronic lung disease or death and may positively influence the incidence of severe intracranial pathology in extremely premature infants with primary surfactant insufficiency.

The activity, amount and protein composition of pyruvate dehydrogenase (PDH) and respiratory chain complexes were studied in muscle mitochondria obtained postmortally from 6 neonates with a gestational age of 23–29 weeks. The activities of PDH and respiratory chain complex III and IV and citrate synthase were significantly lower in comparison with control children aged 0.5–2 and 2–20 years. Protein analyses revealed a parallel decrease in the content of PDH, respiratory chain complexes and their subunits in the cases analyzed. The observed immaturity of the mitochondrial energy-providing system suggests that significant development of mitochondrial energy metabolism occurs during the last 3 months of prenatal development. The metabolic disturbances of mitochondrial energy conversion associated with the low functional capacity and content of PDH and respiratory chain complexes may play an important role in the morbidity of very premature neonates.

A 17-year-old primigravid woman presented with Cushing's syndrome. Typical clinical symptoms and signs developed at the beginning of pregnancy. By week 17 of gestation, plasma cortisol diurnal rhythm was absent and there was a paradoxical increase in plasma cortisol after a 1-mg dexamethasone overnight suppression test. Basal urinary free cortisol was 10 times above the upper limit (in pregnancy) and ACTH levels were suppressed. The diagnosis of ACTH--independent Cushing's syndrome was established. MRI scans revealed normal adrenal and pituitary glands. To control hypercortisolism, the patient was treated with metyrapone. At 34 weeks of gestation, the patient developed preeclampsia and underwent caesarean section. A female infant weighing 1070 g was delivered. No apparent metyrapone-induced teratogenic effects were observed. Cushing's syndrome in the patient resolved within three weeks of delivery. No corticosteroid replacement therapy either for child or mother was needed. Eight months after delivery the patient became pregnant again and rapidly developed Cushing's syndrome with typical clinical symptoms and signs and laboratory results (urinary free cortisol 6464 nmol/24 h). This second pregnancy was unwanted and terminated by artificial abortion that was followed by rapid resolution of hypercortisolism. A third pregnancy, 12 months after delivery was also accompanied by the rapid development of hypercortisolism which recovered after artificial termination. The mechanisms by which pregnancy-induced Cushing's syndrome occurred in this patient are unclear. Aberrant responsiveness or hyperresponsiveness of adrenocortical cells to a non-ACTH and non-CRH substance produced in excess in pregnancy should be considered. Metyrapone suppression of hypercortisolism currently represents the best treatment for these rare cases.

Extremely preterm infants often develop chronic lung disease (CLD) characterized by heterogeneous aeration; poorly supported, floppy airways; and air trapping. High-frequency jet ventilation (HFJV) with high end-expiratory pressure (optimal lung volume strategy [OLVS]) may improve airway patency, lead to better gas distribution, improve gas exchange, and facilitate extubation. In a pilot trial, this study sought to explore the effect of HFJV on oxygenation, ventilation, and ease of extubation in preterm infants with evolving CLD and refractory respiratory failure (RRF). From September 2002 to October 2004, 12 episodes of RRF developed in 10 ventilated extremely immature infants with evolving CLD (10 on conventional and two on high-frequency oscillation). Chorioamnionitis was confirmed in all infants, patent ductus arteriosus was ligated in five patients, and UREAPLASMA UREALYTICUM was cultured from trachea in four patients. HFJV with OLVS was initiated when oxygenation index (OI) > 10 or exhaled tidal volume (V TE) >or= 7 mL/kg were required to maintain partial pressure of carbon dioxide, arterial (Pa CO2) < 60 mm Hg. Inspiratory time (0.02/s) and frequency (310 to 420/min) were set initially with adjustment of pressure amplitude to keep Pa CO2 between 45 and 55 mm Hg. Ventilatory stabilization and weaning from mechanical ventilation with extubation to nasal continuous positive airway pressure (CPAP) were the goals of this approach. Gas exchange data were analyzed by Analysis of variance for repeated measures. Ten patients on 11 occasions of RRF were extubated to nasal CPAP successfully in a median of 15.5 days. Nine of 10 patients survived (one died of pentalogy of Cantrell), all required supplemental O2 at 36 weeks. Pa CO2 decreased within 1 hour after the initiation of HFJV, and OI decreased by 24 hours. Both remained significantly lower until successful extubation ( P < 0.02). Compared with conventional ventilation or high-frequency oscillatory ventilation, HFJV used with OLVS appears to improve gas exchange and may facilitate weaning from mechanical ventilation (MV) in extremely immature infants with evolving CLD. These encouraging pilot data need to be confirmed in a larger clinical trial.

We sought to determine the normocapnic values of expiratory tidal volume measured by hot-wire anemometer, and to evaluate how often expiratory tidal volume exceeds estimated anatomical dead space during high-frequency oscillatory ventilation (HFOV) in preterm infants. We also sought to determine the relationship between expiratory tidal volume and other respiratory parameters. The neonatal respiration monitor SLE 2100 VPM, a hot-wire anemometer, was used to measure expired tidal volume (V(T,E)) in patients ventilated by the Sensormedics 3,100A during routine clinical use of HFOV. Two hundred and fourteen simultaneous measurements of PaCO(2), V(T,E), fraction of inspired oxygen (FiO(2)), continuous distending pressure (CDP), frequency, and amplitude were obtained from 28 patients. The median birth weight was 852 g (range, 435-3,450 g), and median gestational age was 27.2 weeks (range, 23.3-41.0 weeks). One hundred and eighteen (55%) normocapnic measurements, 42 (20%) hypocapnic measurements, and 54 (25%) hypercapnic measurements were recorded in which the median V(T,E) was 1.67 ml/kg (95% confidence interval (CI), 1.55-1.79), 1.94 ml/kg (95% CI, 1.74-2.14), and 1.54 ml/kg (95% CI, 1.42-1.66), respectively. The measured V(T,E) exceeded 2.0 ml/kg in 30 instances of normocapnic V(T,E) (14%) and 54 of all V(T,E) (25%), and 3 ml/kg only in 7 (3%) and 11 (5%) instances of normocapnic and all V(T,E). There was a significant difference in median normocapnic V(T,E) obtained when FiO(2) was between 0.21-0.35, compared to values obtained when FiO(2) was 0.36-1.0 (1.61 ml/kg (95% CI, 1.52-1.70) vs. 2.06 ml/kg (95% CI, 1.93-2.19), P0.002). The calculated values of PaCO(2) between 35-47, using the calculated regression equation for prediction of PaCO(2) (mmHg), correctly predicted normocapnic values in 60% of measurements. Values47 should predict hypercapnia in 81% of cases. In conclusion, expired tidal volume measurement by heated double-wire anemometer sensor is feasible, provides useful real-time information about tidal volume changes, and may improve the clinical management of HFOV.