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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).

Objective: To assess at 24 months corrected age (CA) the neurological, respiratory, and general health status of children born prematurely from 27 +0 to 33 +6 weeks’ gestation who were treated in a first-in-human study with a new fully synthetic surfactant (CHF5633) enriched with SP-B and SP-C proteins. Outcome measures: Children were assessed using Bayley Scales of Infant Development (BSID), with a score below normal defined as BSID-II Mental Development Index score

Applying a face mask could provoke a trigeminocardiac reflex. We compared the effect of applying bi-nasal prongs with a face mask on breathing and heart rate of preterm infants at birth.In a retrospective matched-pairs study of infants32 weeks of gestation, the use of bi-nasal prongs for respiratory support at birth was compared to the use of a face mask. Infants who were initially breathing at birth and subsequently received respiratory support were matched for gestational age (±4 days), birth weight (±300 g), general anaesthesia and gender. Breathing, heart rate and other parameters were collected before and after interface application and in the first 5 min thereafter.In total, 130 infants were included (n = 65 bi-nasal prongs, n = 65 face mask) with a median (IQR) gestational age of 27Apnoea and bradycardia occurred often after applying either bi-nasal prongs or a face mask on the face for respiratory support in preterm infants at birth.

To investigate the efficacy and safety of nebulized poractant alfa (at 200 and 400 mg/kg doses) delivered in combination with nasal continuous positive airway pressure compared with nasal continuous positive airway pressure alone in premature infants with diagnosed respiratory distress syndrome.This randomized, controlled, multinational study was conducted in infants at 28In total, 129 infants were randomized. No significant differences were observed for the primary outcome: 24 (57%), 20 (49%), and 25 (58%) infants received endotracheal surfactant and/or mechanical ventilation within 72 hours in the poractant alfa 200 mg/kg, poractant alfa 400 mg/kg, and nasal continuous positive airway pressure groups, respectively. Similarly, secondary respiratory outcomes did not differ among groups. Enrollment was halted early owing to a change in the benefit-risk balance of the intervention. Nebulized poractant alfa was well-tolerated and safe, and no serious adverse events were related to the study treatment.The intervention did not decrease the likelihood of respiratory failure within the first 72 hours of life.ClinicalTrials.gov: NCT03235986.

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.

Background The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. Methods We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of

As management of respiratory distress syndrome (RDS) advances, clinicians must continually revise their current practice. We report the fourth update of "European Guidelines for the Management of RDS" by a European panel of experienced neonatologists and an expert perinatal obstetrician based on available literature up to the end of 2018. Optimising outcome for babies with RDS includes prediction of risk of preterm delivery, need for appropriate maternal transfer to a perinatal centre and timely use of antenatal steroids. Delivery room management has become more evidence-based, and protocols for lung protection including initiation of CPAP and titration of oxygen should be implemented immediately after birth. Surfactant replacement therapy is a crucial part of management of RDS, and newer protocols for its use recommend early administration and avoidance of mechanical ventilation. Methods of maintaining babies on non-invasive respiratory support have been further developed and may cause less distress and 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 using caffeine and, if necessary, postnatal steroids are also important considerations. Protocols for optimising general care of infants with RDS are also essential with good temperature control, careful fluid and nutritional management, maintenance of perfusion and judicious use of antibiotics all being important determinants of best outcome. (c) 2019 S. Karger AG, Basel

Objective Applying a mask on the face for respiratory support could induce a trigeminocardiac reflex leading to apnoea and bradycardia. We have examined the effect of applying a face mask on breathing and heart rate in preterm infants at birth. Methods Resuscitation videos of infants ≤ 32 weeks gestation recorded from 2010 until 2018 at the Leiden University Medical Centre and the General University Hospital in Prague were reviewed. All infants received respiratory support via face mask. Breathing and heart rate were noted before and after application of the face mask and over the first 5 min. Results Recordings of 429 infants were included (median (IQR) gestational age of 28+6 (27+1-30+4) weeks). In 368/429 (86%) infants breathing was observed before application of the face mask and 197/368 (54%) of these infants stopped breathing following application of the face mask. Apnoea occurred at a median of 5 (3–17) seconds after application of the face mask with a duration of 28 (22–34) seconds of the first minute. In a logistic regression model, the occurrence of apnoea after face mask application was inversely associated with gestational age (OR = 1.424 (1.281–1.583), p Conclusion Applying a face mask for respiratory support affects breathing in a large proportion (54%) of preterm infants and this effect is gestational age dependent.

Although phototherapy (PT) is a standard treatment for neonatal jaundice, no validated clinical methods for determination of bilirubin phototherapy products are available. Thus, the aim of our study was to establish a such method for clinical use. To achieve this aim, a LC-MS/MS assay for simultaneous determination of Z-lumirubin (LR) and unconjugated bilirubin (UCB) was conducted. LR was purified after irradiation of UCB at 460 nm. The assay was tested on human sera from PT-treated neonates. Samples were separated on a HPLC system with a triple quadrupole mass spectrometer detector. The instrument response was linear up to 5.8 and 23.4 mg/dL for LR and UCB, respectively, with submicromolar limits of detection and validity parameters relevant for use in clinical medicine. Exposure of newborns to PT raised serum LR concentrations three-fold (p vs. 10.3 ± 3.3 mg/dL, p

Advances in the management of respiratory distress syndrome (RDS) ensure that clinicians must continue to revise current practice. We report the third update of the European Guidelines for the Management of RDS by a European panel of expert neonatologists including input from an expert perinatal obstetrician based on available literature up to the beginning of 2016. Optimizing the outcome for babies with RDS includes consideration of when to use antenatal steroids, and good obstetric practice includes methods of predicting the risk of preterm delivery and also consideration of whether transfer to a perinatal centre is necessary and safe. Methods for optimal delivery room management have become more evidence based, and protocols for lung protection, including initiation of continuous positive airway pressure and titration of oxygen, should be implemented from soon after birth. Surfactant replacement therapy is a crucial part of the management of RDS, and newer protocols for surfactant administration are aimed at avoiding exposure to mechanical ventilation, and there is more evidence of differences among various surfactants in clinical use. Newer methods of maintaining babies on non-invasive respiratory support have been developed and offer potential for greater comfort and less chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease although minimizing the time spent on mechanical ventilation using caffeine and if necessary postnatal steroids are also important considerations. Protocols for optimizing the general care of infants with RDS are also essential with good temperature control, careful fluid and nutritional management, maintenance of perfusion and judicious use of antibiotics all being important determinants of best outcome. (C) 2016 S. Karger AG, Basel

Objective CHF5633 (Chiesi Farmaceutici S.p.A., Parma, Italy) is the first fully synthetic surfactant enriched by peptide analogues of two human surfactant proteins. We planned to assess safety and tolerability of CHF5633 and explore preliminary efficacy. Design Multicentre cohort study. Patients Forty infants from 27 +0 to 33 +6 weeks gestation with respiratory distress syndrome requiring fraction of inspired oxygen (FiO 2 ) ≥0.35 were treated with a single dose of CHF5633 within 48 hours after birth. The first 20 received 100 mg/kg and the second 20 received 200 mg/kg. Outcome measures Adverse events (AEs) and adverse drug reactions (ADRs) were monitored with complications of prematurity considered AEs if occurring after dosing. Systemic absorption and immunogenicity were assessed. Efficacy was assessed by change in FiO 2 after dosing and need for poractant-alfa rescue. Results Rapid and sustained improvements in FiO 2 were observed in 39 (98%) infants. One responded neither to CHF5633 nor two poractant-alfa doses. A total of 79 AEs were experienced by 19 infants in the 100 mg/kg cohort and 53 AEs by 20 infants in the 200 mg/kg cohort. Most AEs were expected complications of prematurity. Two unrelated serious AEs occurred in the second cohort. One infant died of necrotising enterocolitis and another developed viralbronchiolitis after discharge. The single ADR was an episode of transient endotracheal tube obstruction following a 200 mg/kg dose. Neither systemic absorption, nor antibody development to either peptide was detected. Conclusions Both CHF5633 doses were well tolerated and showed promising clinical efficacy profile. These encouraging data provide a basis for ongoing randomised controlled trials. Trial registration number ClinicalTrials.gov NCT01651637.

Aim Minimally aggressive and easily performed techniques that facilitate spontaneous respiratory stabilisation are required to reduce rescue intubation in extremely premature infants. This study evaluated the feasibility and safety of administering surfactant into the pharynx of infants born at less than 25 weeks immediately after birth. Methods This study of 19 infants was conducted from January 2013 to July 2014 in a tertiary perinatal centre in Prague. We administered 1.5ml of Curosurf as a bolus into the pharynx and simultaneously performed a sustained inflation manoeuvre (SIM). The extent of the interventions, death and severe neonatal morbidity in the study group were compared with 20 controls born before the study period and 20 born after it. Results All infants received oropharyngeal surfactant within the median (inter-quartile range) time of 40 seconds (25-75) after cord camping. The surfactant had to be suctioned in one infant because of upper airway obstruction. Although more subsequent surfactant was administered in the study group, significantly fewer study period infants required intubation than the before and after controls (16% versus 75% and 58%, respectively, p

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

Objective: The aim of this single-center study was to identify factors that affect the short-term outcome of newborns delivered around the limits of viability. Methods: A group of 137 pregnant women who gave birth between 22+0/7 and 25+6/7 weeks of gestation was retrospectively studied. The center supports a proactive approach to infants around the limits of viability. Perinatal and neonatal characteristics were obtained and statistically evaluated. Results: A total of 166 live-born infants were enrolled during a 6-year period; 162 (97.6%) of them were admitted to the neonatal intensive care unit (ICU) and 119 (73.5%) survived until discharge. The decrease in neonatal mortality was associated with an advanced gestational age (P Conclusion: The short-term outcome of newborns delivered around the limits of viability is mostly affected by gestational age and antenatal corticosteroid treatment. A consistently proactive approach improves the survival of infants at the limits of viability. This is most pronounced in cases where the delivery is delayed beyond 24 completed gestational weeks.

Objective To determine the incidence of hypo- and hyper-capnia in a European cohort of ventilated newborn infants. Design and setting Two-point cross-sectional prospective study in 173 European neonatal intensive care units. Patients and methods Patient characteristics, ventilator settings and measurements, and blood gas analyses were collected for endotracheally ventilated newborn infants on two separate dates. Results A total of 1569 blood gas analyses were performed in 508 included patients with a mean±SD Pco 2 of 48±12 mm Hg or 6.4±1.6 kPa (range 17–104 mm Hg or 2.3–13.9 kPa). Hypocapnia (Pco 2 2 >52 mm Hg or 7 kPa) was present in, respectively, 69 (4%) and 492 (31%) of the blood gases. Hypocapnia was most common in the first 3 days of life (7.3%) and hypercapnia after the first week of life (42.6%). Pco 2 was significantly higher in preterm infants (49 mm Hg or 6.5 kPa) than term infants (43 mm Hg or 5.7 kPa) and significantly lower during pressure-limited ventilation (47 mm Hg or 6.3±1.6 kPa) compared with volume-targeted ventilation (51 mm Hg or 6.8±1.7 kPa) and high-frequency ventilation (50 mm Hg or 6.7±1.7 kPa). Conclusions This study shows that hypocapnia is a relatively uncommon finding during neonatal ventilation. The higher incidence of hypercapnia may suggest that permissive hypercapnia has found its way into daily clinical practice.

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

Prematurity is associated with delayed postnatal activation of mitochondrial oxidative phosphorylation and impaired switch from glycolytic to oxidative metabolism. Fatty acids (FA), which represent a major energy substrate in mature muscle cells, are engaged in the postnatal activation of genes of energy metabolism and lipid oxidation. To understand the mechanism activating mitochondria in human newborns, expression of the genes for mitochondrial uncoupling proteins (UCP) was characterized in autopsy samples of skeletal (n = 28) and cardiac (n = 13) muscles of preterm neonates, who mostly died during the first postnatal month, and two aborted fetuses. Transcripts levels for UCP2, UCP3, and also for genes engaged in the transport of FA between cytoplasm and mitochondria were measured using real-time reverse transcriptase PCR. In accordance with studies in mice, our results document postnatal induction of UCP3 gene expression in skeletal muscle, involvement of nutritional FA in the induction, and a role of UCP3 in mitochondrial FA oxidation. They suggest impaired postnatal activation of UCP3 gene in neonates delivered before approximately 26 wk of gestation. Mean levels of the UCP3 transcript in skeletal muscle were by two orders of magnitude higher than in the heart. In contrast to UCP3, the UCP2 gene was active in fetuses, and its expression was not affected by nutrition. Our results support a role of UCP3 in postnatal activation of lipid oxidation in skeletal muscle and suggest the involvement of UCP3 in the delayed activation of mitochondrial energy conversion in very immature preterm neonates.

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.

Fatty acid diesters of long-chain 1,2-diols (1,2-DDE), or type II wax diesters, were analyzed in the vernix caseosa of a newborn girl. 1,2-DDE were isolated from the total lipid extract by the semipreparative TLC using plates coated with silica gel. Chromatographic separation of the 1,2-DDE molecular species was achieved on the non-aqueous reversed-phase HPLC with two Nova-Pak C18 columns connected in series (a total length of 45cm) and using an acetonitrile-ethyl acetate gradient. 1,2-DDE eluted from the column in the order of their equivalent chain number. The analytes were detected as ammonium adducts by an ion-trap mass spectrometer equipped with an atmospheric pressure chemical ionization source. Their structures were elucidated using tandem mass spectrometry with MS, MS(2) and MS(3) steps in a data-dependent mode. More than two thousand molecular species of 1,2-DDE were identified in 141 chromatographic peaks. The most abundant 1,2-DDE were monounsaturated lipids consisting of a C22 diol and a C18:1 fatty acid together with C16:0, C14:0 or C15:0 fatty acids. The positions of double bonds were characterized by the fragmentation of [M+C3H5N](+) formed in the ion source.

Standard resuscitation guidelines are based on data from a range of gestational ages. We sought to evaluate the effectiveness of our delivery room resuscitation protocol across a range of gestational ages in preterm infants born at29 weeks.We performed an observational study of prospectively collected video recordings of 73 preterm infants. The percentage of bradycardic patients, time to reach target oxygen saturation and the extent of all interventions were compared between three gestational age groups: 22-24 weeks (n = 22), 25-26 weeks (n = 27) and 27-28 weeks (n = 24).Although the same resuscitation protocol was followed for all infants, bradycardic infants born25 weeks responded poorly and required significantly longer to reach oxygen saturation targets of70%,80% and90% (p0.03). They required significantly more interventions and had higher rate of death (p0.05) and severe intraventricular haemorrhage (p0.03). Significantly lower heart rate and oxygen saturation values were found in infants with intraventricular haemorrhage.Current recommendations for resuscitation may fail to achieve timely lung aeration in infants born at the borderline of viability, leading to higher mortality and morbidity. Sustained inflation and delayed cord clamping may be effective alternatives.

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.

With increasing survival rate of extremely premature neonates, their long-term outcomes including growth and risk factors for later disorders need to be considered. We prospectively evaluated anthropometric parameters in children born as extremely premature neonates.Anthropometric parameters were measured at the ages of 2 and 5 years in 72 extremely premature children born between the 22nd and 25 + 6th weeks of gestation (group I) and 85 children born between the 26th and 27 + 6th weeks of gestation (group II).Although catch-up in the postnatal growth was observed in both groups of children, resulting in growth improvement, the height of the extremely premature children at the ages of 2 and 5 years remains lower (P0.01) compared with the control population. A decline in head growth was observed in both groups between the ages of 2 and 5 years, resulting in decrease of standard deviation score (SDS) for head circumference (HC) in comparison with that of the control population, accompanied by an increased number of children with microcephaly, defined as HC-2 SD. At the age of five, microcephaly was found in 18% of children from group I and 11.7% of children from group II. At the age of 5 years, the waist and hip circumferences and ten skinfolds were not different between both groups of children.Long-term follow-up of extremely premature neonates is important not only to establish their growth patterns but also for risk factors assessment including adiposity for later development of adult-onset diseases.

Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report the updated recommendations of a European panel of expert neonatologists who had developed consensus guidelines after critical examination of the most up-to-date evidence in 2007. These updated guidelines are based upon published evidence up to the end of 2009. Strong evidence exists for the role of a single course of antenatal steroids in RDS prevention, but the potential benefit and long-term safety of repeated courses are unclear. Many practices involved in preterm neonatal stabilisation 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 always clear. Respiratory support in the form of mechanical ventilation may also be lifesaving, but can cause lung injury, and protocols should be directed at avoiding mechanical ventilation where possible by using nasal continuous positive airways pressure or nasal ventilation. For babies with RDS to have best outcomes, it is essential that they have optimal supportive care, including maintenance of a normal body temperature, proper fluid management, good nutritional support, management of the ductus arteriosus and support of the circulation to maintain adequate tissue perfusion.

OBJECTIVE: Early surfactant followed by extubation to nasal continuous positive airway pressure (nCPAP) compared with later surfactant and mechanical ventilation (MV) reduce the need for MV, air leaks, and bronchopulmonary dysplasia. This randomized, controlled trial investigated whether prophylactic surfactant followed by nCPAP compared with early nCPAP application with early selective surfactant would reduce the need for MV in the first 5 days of life. METHODS: A total of 208 inborn infants who were born at 25 to 28 weeks' gestation and were not intubated at birth were randomly assigned to prophylactic surfactant or nCPAP within 30 minutes of birth. Outcomes were assessed within the first 5 days of life and until death or discharge of the infants from hospital. RESULTS: Thirty-three (31.4%) infants in the prophylactic surfactant group needed MV in the first 5 days of life compared with 34 (33.0%) in the nCPAP group (risk ratio: 0.95 [95% confidence interval: 0.64–1.41]; P = .80). Death and type of survival at 28 days of life and 36 weeks' postmenstrual age and incidence of main morbidities of prematurity (secondary outcomes) were similar in the 2 groups. A total of 78.1% of infants in the prophylactic surfactant group and 78.6% in the nCPAP group survived in room air at 36 weeks' postmenstrual age. CONCLUSIONS: Prophylactic surfactant was not superior to nCPAP and early selective surfactant in decreasing the need for MV in the first 5 days of life and the incidence of main morbidities of prematurity in spontaneously breathing very preterm infants on nCPAP.

Objective To assess current ventilation practices in newborn infants. Study design We conducted a 2-point cross-sectional study in 173 European neonatal intensive care units, including 535 infants (mean gestational age 28 weeks and birth weight 1024 g). Patient characteristics, ventilator settings, and measurements were collected bedside from endotracheally ventilated infants. Results A total of 457 (85%) patients were conventionally ventilated. Time cycled pressure-limited ventilation was used in 59% of these patients, most often combined with synchronized intermittent mandatory ventilation (51%). Newer conventional ventilation modes like volume targeted and pressure support ventilation were used in, respectively, 9% and 7% of the patients. The mean tidal volume, measured in 84% of the conventionally ventilated patients, was 5.7 +/- 2.3 ml/kg. The mean positive end-expiratory pressure was 4.5 +/- 1.1 cmH(2)O and rarely exceeded 7 cmH(2)O. Conclusions Time cycled pressure-limited ventilation is the most commonly used mode in neonatal ventilation. Tidal volumes are usually targeted between 4 to 7 mL/kg and positive end-expiratory pressure between 4 to 6 cmH(2)O. Newer ventilation modes are only used in a minority of patients. (J Pediatr 2010; 157:767-71)

To assess whether vaginal labor after a previous caesarean section in a low gestational week performed by means of a high placed U-section technique could be recommended by obstetricians as a sufficiently safe method of choice for pregnant women.Of 309 pregnant women with a history of a high placed U-section, 166 (53.7%) met the criteria for the subsequent vaginal delivery and agreed with it. In 78%, vaginal labor started spontaneously and in 22% it was induced due to postterm pregnancy or preterm rupture of membranes.Vaginal labor was successful in 72.3% of women. Deliveries after spontaneous onset of uterine contractions (80%) were considerably more successful. In the group of women with induced labor, the success rate was below 50%. Uterine rupture was not encountered in the study group.Vaginal labor after a previous high placed U-section is a sufficiently safe method of choice for selected groups of pregnant women, but it has to be mentioned that selecting criteria can only minimize and not entirely exclude the risk of uterine rupture.

Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report the recommendations of a European panel of expert neonatologists who developed consensus guidelines after critical examination of the most up-to-date evidence in 2007. Strong evidence exists for the role of antenatal steroids in RDS prevention, but it is not clear if repeated courses are safe. 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 management of RDS but the best preparation, optimal dose and timing of administration at different gestations is not always clear. Respiratory support in the form of mechanical ventilation may also be life saving but can cause lung injury, and protocols should be directed to avoiding mechanical ventilation where possible by using nasal continuous positive airways pressure. For babies with RDS to have the best outcome, it is essential that they have optimal supportive care, including maintenance of a normal body temperature, proper fluid management, good nutritional support, management of the ductus arteriosus and support of the circulation to maintain adequate blood pressure.

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.

Background and aims: Most diseases in premature neonates are secondary to immaturity of various organ systems. Also the inadequate capacity of mitochondrial energy production may play an important role in the neonatal morbidity. Subjects and methods: The activities and amount of respiratory chain (RC) complexes, pyruvate dehydrogenase (PDH) and citrate synthase (CS) were analysed in isolated muscle mitochondria obtained at autopsy in 19 premature neonates using spectrophotometric and radioenzymatic methods and blue-native electrophoresis and Western blotting. Two groups of children recommended for muscle biopsy at the age of 0.5–2 and 3–18 years served as controls. Results: In premature neonates, the activities of RC complexes III, IV, PDH and CS were markedly lower in comparison with older children. On the contrary, the activity of complex I was higher in premature neonates than in older children. The ratios between RC complexes I, II and III and CS were significantly higher in premature neonates in comparison with older children. In addition, the protein amount of RC complexes and PDH subunits were lower in premature neonates in comparison with older children. Conclusion: The results of our study document the age-dependent differences in activities of PDH and respiratory chain complexes in early childhood. Lower functional capacity of mitochondrial energy-providing system in critically ill neonates may be explained by combination of various factors including the delay in maturation of PDH and respiratory chain complexes in very premature neonates and increased degradation of mitochondrial proteins in connection with sepsis, tissue hypoperfusion or hypoxemia.

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.

The interaction between exogenous surfactant and various modes of ventilatory support in terms of timing, quality and quantity can influence both short- and long-term outcomes of immature infants. Alterations to the pulmonary surfactant system can occur with all forms of mechanical ventilation. Experimental data suggest possible interaction between ventilatory support and exogenous surfactant even during the first breaths in the delivery room. The adverse effect on surfactant function at this time can increase the need for and duration of ventilatory support. The logical approach to ventilatory support is to be minimally aggressive with optimal recruitment of the lungs to avoid ventilator-induced lung injury. Nasal continuous positive airway pressure (CPAP) in combination with early prophylactic surfactant administration may be an effective and less damaging method capable of reducing the need of artificial ventilation, but its benefit has not been proven in extremely preterm infants less than 28 weeks’ gestation. Because of unproven efficacy of nasal CPAP in extremely premature infants, the population most at risk for adverse pulmonary and neurologic outcome, this paper focuses on the comparison of conventional and high-frequency oscillatory ventilation (HFOV) with respect to alteration of surfactant function, and short- and long-term outcomes, in both human and experimental trials. Though the two most recent large clinical trials provide reassurance with respect to the safety of first-intention high-frequency ventilation, the reduction in the risk of chronic lung disease appears to be only modest or absent. Recent laboratory investigations suggest that the key element of HFOV, namely optimization of volume, can, under some circumstances, be replicated with low tidal volume conventional ventilation and high positive end-expiratory pressure. Recent introduction of patient-triggered volume-targeted conventional ventilation into clinical practice offers the promise of a practical means of providing gentle conventional ventilation capable of minimizing ventilator-induced lung injury. Ultimately, well-designed comparative clinical trials with long-term outcomes are essential to accurately quantify risks and benefits of any new approach to mechanical ventilation. Without such data, these experimental results should not be extrapolated into clinical practice, because of the multifactorial pathophysiology of the development of chronic pulmonary disease in extremely premature infants and the risk of unanticipated adverse effects.

Background Survival of extremely low birth weight (ELBW) infants has improved in recent decades but bronchopulmonary dysplasia (BPD) remains a major problem. The effect of early inhalation of corticosteroids on survival without BPD in these infants is unclear. Objective To determine the effect of early use of inhaled budesonide in infants with gestational ages of 23 0/7–27 6/7 weeks requiring any form of positive pressure support on survival without BPD at 36 weeks’ gestational age. Methods Randomised controlled trial. Budesonide or placebo were continued until infants were either off supplementary oxygen and positive pressure support or had reached a gestational age of 32 0/7 weeks regardless of their ventilator status. The primary outcome was death before 36 weeks of gestational age or survival with BPD, defined according to the physiological definition. Results We randomly assigned 863 infants during the first 12 h of life in 40 centres in 9 countries to inhaled budesonide or placebo. In 7 infants consent was withdrawn. Of the 437 infants assigned to inhaled budesonide, 175 died or survived with BPD (40.0%), as compared with 194 of 419 infants assigned to placebo (46.3%). Further results are shown in the table. Conclusions The reduction of the primary outcome (death before 36 weeks or BPD) by inhaled budesonide in ELBW infants was of borderline statistical significance. Inhaled budesonide significantly reduced BPD, which is a component of our primary outcome and was a predefined secondary outcome.