European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update.

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).

A first-in-human clinical study of a new SP-B and SP-C enriched synthetic surfactant (CHF5633) in preterm babies with respiratory distress syndrome: two-year outcomes.

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 <70, or BSID-III cognitive composite score <85. In addition, a health status questionnaire was used to check for functional disability including respiratory problems and related treatments, sensory and neurodevelopment assessments, communication skills as well as the number of hospitalizations. RESULTS: 35 of 39 survivors had a neurodevelopmental assessment, 24 infants being evaluated by Bayley's Scales and 11 by health status questionnaires only. 23 children had scores within normal limits and one had BSID-III <85. The remaining 11 were judged clinically to have normal development. Health status questionnaires detected only issues that would normally be expected in preterm-born children. CONCLUSIONS: This assessment offers reassurance that treatment with CHF5633 surfactant was not associated with adverse neurodevelopmental, respiratory, or health outcomes by two years corrected age.

Decreasing cerebral palsy prevalence in multiple births in the modern era: a population cohort study of European data.

Multiple births (twins or higher order multiples) are increasing in developed countries and may present higher risk for cerebral palsy (CP). However, few studies can reliably investigate trends over time because these outcomes are relatively rare. OBJECTIVE: We pooled data from European CP registers to investigate CP birth prevalence and its trends among single and multiple births born between 1990 and 2008. DESIGN: Population cohort study. SETTING: 12 population-based registers from the Surveillance of Cerebral Palsy in Europe collaboration. PARTICIPANTS: 4 446 125 single and multiple live births, of whom 8416 (0.19%) had CP of prenatal or perinatal origin. MAIN OUTCOMES: CP diagnosis ascertained in childhood using harmonised methods; CP subtype; Motor impairment severity among CP cases. RESULTS: The rate of multiple births increased from 1990. Multiples displayed higher risk for CP (RR=4.27, 95% CI 4.00 to 4.57). For singletons and multiples alike, risk for CP was higher among births of lower gestational age (GA) or birth weight (BW). However, CP birth prevalence declined significantly among very preterm (<32 weeks) and very low BW (<1500 g) multiples. Singletons and multiples with CP displayed similar severity of motor impairment. CONCLUSIONS: Between 1990 and 2008, CP birth prevalence decreased steadily among multiples with low GA or BW. Furthermore, multiples with CP display similar profiles of severe motor impairment compared with CP singletons. Improvements in management of preterm birth since the 1990s may also have been responsible for providing better prospects for multiples.

European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019 Update.

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.

A first-in-human clinical study of a new SP-B and SP-C enriched synthetic surfactant (CHF5633) in preterm babies with respiratory distress syndrome.

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 (FiO2) ≥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 FiO2 after dosing and need for poractant-alfa rescue. RESULTS: Rapid and sustained improvements in FiO2 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 viral bronchiolitis 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.

European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2016 Update.

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.

Surfactant therapy for neonatal respiratory distress syndrome in 2013.

Surfactant whether given prophylactically in the delivery room or to babies with established respiratory distress syndrome (RDS) reduces the severity of RDS, incidence of air leaks and pneumothorax and, most importantly, neonatal death. Despite being the most intensively studied intervention in neonatal medicine, there is still debate among neonatologists regarding the best preparations, the optimal dose and mode of administration and when best to intervene with surfactant. European Consensus Guidelines on the management of RDS have been developed and updated twice since 2007 reflecting changes in practice as new evidence emerges and in this article we summarize current opinion regarding optimal surfactant use in the present era of non-invasive respiratory support.

Surfactant therapy: past, present and future.

Surfactant replacement in preterm infants with respiratory distress syndrome (RDS) has been a major therapeutic breakthrough and the most intensively studied intervention in neonatal medicine. Surfactant whether given prophylactically in the delivery room or in babies with established RDS reduces the severity of RDS, the incidence of air leaks and pneumothorax and, most importantly, neonatal death. Many randomized controlled trials have explored different strategies to optimize the effect of surfactant administration and have further improved neonatal outcome. Whenever indicated, surfactant should be administered as early as possible in the course of the RDS.

European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants--2013 update.

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.

Extremely low-dose dexamethasone to facilitate extubation in mechanically ventilated preterm babies.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major respiratory complication of extreme prematurity. Dexamethasone is effective in reducing ventilation requirements in babies with BPD, but follow-up studies have raised concerns about long-term neurological sequelae. Few studies have investigated the lowest dose effective for weaning from mechanical ventilation. OBJECTIVES: Between January 2004 and December 2008 the practice in a tertiary neonatal unit was to use extremely low doses of dexamethasone for severe BPD, commencing at 0.05 mg/kg/day and decreasing over 9 days, with a cumulative dose of 0.24 mg/kg. The objective of this observational study was to assess the effectiveness of the extremely low-dose course in facilitating extubation. METHODS: The babies who had received extremely low-dose dexamethasone to facilitate weaning from mechanical ventilation were identified. Details of treatment and respiratory support were recorded. Serial oxygenation indices (OI) during the dexamethasone course were calculated, and these were analysed to assess the effect of treatment on ventilation requirements. RESULTS: One hundred and ninety extremely preterm babies were admitted during this 5-year period. Sixteen babies received extremely low-dose dexamethasone. The median gestation was 25 weeks and the median birth weight was 644 g. Before starting dexamethasone, the median OI was 10.6, but by day 7 of treatment it had fallen to 5.4. By the end of the course, 12 of the 16 babies had been successfully extubated. CONCLUSIONS: This short dexamethasone course appears effective in facilitating extubation. Randomised trials with long-term follow-up are needed to determine the role of extremely low-dose dexamethasone in preterm babies with evolving BPD.

European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants - 2010 update.

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.

Maternal betamethasone and chorioamnionitis induce different collagenases during lung maturation in fetal sheep.

BACKGROUND: Fetal lung maturation occurs after both maternal corticosteroid administration and chorioamnionitis. The effectors of this antenatally-induced lung maturation are not understood. Matrix metalloproteinases (MMPs) 2 and 9 are type-IV collagenases that can degrade alveolar basement membranes. OBJECTIVES: We hypothesized that the structural changes of lung maturation by both antenatal corticosteroid treatment and chorioamnionitis would be associated with increases in these MMPs. METHODS: 64 pregnant ewes were randomly assigned to one of four treatment groups: intra-amniotic injection of 10 mg endotoxin, maternal intramuscular injection of 0.5 mg/kg betamethasone, both treatments combined or saline-treated controls. We quantified MMP-2 which is derived from connective tissue and MMP-9 which is predominantly derived from neutrophils in fetal lung fluid of lambs after maternal corticosteroid therapy and induction of chorioamnionitis and the combination of both therapies given at 109-111 days' gestational age with delivery 1, 5 or 15 days later. RESULTS: Betamethasone, endotoxin and the combined treatments increased both surfactant pool size, lung gas volume and reduced alveolar wall thickness at 15 days. MMP-2 concentration was increased after betamethasone. MMP-9 concentration increased after endotoxin-induced chorioamnionitis but decreased by the combined treatments. CONCLUSION: Lung maturation via different pathways may use different forms of collagenases for remodelling lung structure.

Selective fluconazole prophylaxis in high-risk babies to reduce invasive fungal infection.

OBJECTIVES: To evaluate the impact of selective fluconazole prophylaxis on incidence of invasive fungal infection and emergence of fluconazole resistance in neonatal intensive care. DESIGN: Retrospective study of very low birthweight (VLBW) babies (<1500 g birth weight) admitted to a neonatal intensive care unit (NICU) in the period 1 year before and after the implementation of an antifungal prophylaxis guideline. PATIENTS: VLBW babies with an additional risk factor: colonisation of Candida species from surface sites with a central venous catheter; third generation cephalosporin treatment; or total duration of antibiotic treatment >10 days. Fluconazole protocol: Fluconazole 6 mg/kg for 3 weeks. Dose interval is every 72 h during the first 2 weeks of life. Thereafter, dose interval is reduced to every 48 h until 3 weeks old when daily fluconazole is given. Fluconazole is administered orally when enteral feeding achieved. RESULTS: 121 and 107 VLBW babies were admitted to the NICU in the year before and after the guideline was implemented, respectively. Data were available in 110 and 102 charts. 33/110 and 31/102 babies were eligible for fluconazole prophylaxis in the period before and after guideline implementation. 6/33 babies eligible for prophylaxis developed culture proven Candida sepsis before compared with no (0/31) babies after the guideline was implemented (p = 0.03). One baby (1/31) did develop probable Candida sepsis in the post guideline implementation period. During both study periods all Candida isolates remained fully susceptible to fluconazole. CONCLUSIONS: Selective antifungal prophylaxis has reduced invasive fungal sepsis in one NICU without evidence of fluconazole resistance emerging.

Influence of maternal diabetes mellitus on fetal iron status.

OBJECTIVE: To determine the effects of maternal diabetes on fetal iron status using serum transferrin receptors (STfR) and their ratio to ferritin (TfR-F index) in cord blood. METHODS: Iron, ferritin, erythropoietin, STfR and haemoglobin concentration were measured and TfR-F index calculated in 97 maternal/cord blood pairs. Forty-nine women had type 1 diabetes (diagnosed before pregnancy) and these were compared with forty-eight non- diabetic controls. The women with type 1 diabetes were recruited consecutively from attendance at the joint antenatal endocrine clinic while the control group of women was recruited from consecutive attendance at the remaining antenatal clinics. RESULTS: The infants of the diabetic women had significantly lower levels of ferritin (47 vs 169 mug/l; p<0.01) and higher STfR (17.4 vs 12.9 mg/l; p<0.01) and TfR-F index (10.4 vs 5.8; p<0.01) than controls. They were also significantly more acidotic at birth (7.25 vs 7.30; p<0.01), were born at an earlier gestation (36.7 vs 39.7 weeks; p<0.01) and had higher z Scores for weight (0.53 vs 0.02; p = 0.016). CONCLUSIONS: Maternal diabetes causes depletion of fetal iron stores and is associated with higher fetal iron demands as indicated by higher STfR level and TfR-F index in cord blood.

Modeling and remodeling of the lung in neonatal chronic lung disease: implications for therapy.

Neonatal chronic lung disease (CLD) is the major long-term pulmonary complication of preterm birth affecting about 20% of infants who need mechanical ventilation. CLD is the result of abnormal repair processes following inflammatory lung injury that lead to remodeling of the lung. Inflammation may be initiated by a variety of stimuli including mechanical ventilation, oxygen toxicity and infection. The resultant neutrophil chemotaxis and degranulation leads to the release of enzymes such as matrix metalloproteinases that can cause proteolysis of the lung extracellular matrix. Abnormal healing with remodeling leads to poorly compliant lungs with reduced capacity for gas exchange. Drugs can influence the normal process of lung modeling or remodeling. Fetal lung development can be influenced by glucocorticosteroids and inflammation. Both can cause abnormal lung modeling with fewer, larger alveoli and accelerated lung maturation, which confers benefits in terms of reduced morbidity and mortality from respiratory distress syndrome but potentially increases the risk of subsequent lung injury. Antioxidants, such as retinol (vitamin A), administered post-natally may reduce the effects of oxidative stress leading to a modest reduction in CLD but they require repeated intramuscular injections. Postnatal glucocorticosteroid therapy can modify the lung inflammatory response and reduce CLD but it can also have detrimental effects on the developing brain and lung, thereby creating a clinical dilemma for neonatologists. Proteinase inhibitors may be a rational therapy but more research is needed before they can be accepted as a treatment for preterm neonates.'Modeling' is defined as planning or forming that follows a set pattern. The term is used to describe the normal process of lung growth and development that culminates in mature branching alveolar air spaces surrounded by a network of capillaries. Normal lung modeling occurs under a variety of genetic and hormonal influences that can be altered, leading to abnormal patterns of growth. 'Remodeling' is defined as altering the structure of or re-making and, in the case of the lung, is used to describe the abnormal patterns of lung growth that occur after lung injury. Modeling and remodeling of the lungs occur to an extent throughout life but never more rapidly than during the fetal and early neonatal periods, and factors that influence this process may lead to development of neonatal CLD. Some of the factors involved in normal and abnormal lung modeling and inflammation and glucocorticosteroid-induced remodeling in the perinatal period, in the context of neonatal CLD, are reviewed with considerations of how various drugs may influence these processes.

Chorioamnionitis and increased neonatal lung lavage fluid matrix metalloproteinase-9 levels: implications for antenatal origins of chronic lung disease.

OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) degrades type IV collagen, the major constituent of lung basement membrane. We studied the effects of chorioamnionitis and antenatal corticosteroids on bronchoalveolar lavage (BAL) fluid levels of MMP-9, and its inhibitor, TIMP-1 in preterm infants. STUDY DESIGN: A prospective study was performed on serial BAL samples from 79 ventilated preterm infants at less than 33 weeks' gestation, 18 of whom were from pregnancies complicated by chorioamnionitis. MMP-9 levels were measured by gelatin zymography and TIMP-1 by enzyme-linked immunosorbent assay, and the median value for each infant was calculated. The presence and severity of chorioamnionitis were defined histologically. RESULTS: BAL fluid MMP-9 levels were higher in preterm infants in the chorioamnionitis group (86 [29-518] vs 13 [3-43] ng/mL, P =.001), and levels increased stepwise with the increasing severity of chorioamnionitis. Antenatal corticosteroids had no effect on median MMP-9 levels. Infants in the chorioamnionitis group were more likely to have chronic lung disease (CLD) develop (55% vs 28%, P <.05). TIMP-1 levels were no different between groups. CONCLUSION: Chorioamnionitis is associated with increased lung type IV collagenase levels in the ventilated preterm infant. Antenatal lung inflammation with up-regulation of MMP-9 may be important in the pathogenesis of CLD.

Airway remodelling in chronic lung disease of prematurity.

Increasing numbers of very preterm survivors are developing chronic lung disease characterised by protracted respiratory insufficiency and a requirement for supplemental oxygen. An early inflammatory response results in the development of airways remodelling. Pulmonary inflammation can be triggered by any combination of antenatal infection, mechanical ventilation or oxygen toxicity and the end result is increased lung capillary permeability and leukocyte chemotaxis. The neutrophil plays a key role in initiating lung damage by releasing enzymes such as elastase and matrix metalloproteinases that disrupt the lung extracellular matrix. The extracellular matrix is essential for the normal alignment and differentiation of pneumocytes and pulmonary capillaries. This so called "new chronic lung disease" resulting from airways remodelling and arrested lung development is characterised pathologically by fewer, larger alveoli and less pulmonary fibrosis than previously described.