David G. Sweet

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.

European consensus guidelines on the management of neonatal respiratory distress syndrome

Abstract 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.

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.

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.

Study of maternal influences on fetal iron status at term using cord blood transferrin receptors

AIMS To determine effects of maternal iron depletion and smoking on iron status of term babies using serum transferrin receptors (STfR) and their ratio to ferritin (TfR-F index) in cord blood. METHODS Iron, ferritin, STfR, and haemoglobin (Hb) concentration were measured and TfR-F index calculated in 67 cord /maternal blood pairs. Twenty six mothers were iron depleted (ferritin <10 μg/l) and 28 were smokers. RESULTS Maternal iron depletion was associated with decreased cord ferritin (113v 171 μg/l) and Hb (156v 168 g/l) but no change in STfR or TfR-F index. Smoking was associated with increased cord Hb (168v 157 g/l) and TfR-F index (4.1v 3.4), and decreased ferritin (123v 190 μg/l). Cord TfR-F index and Hb were positively correlated (r = 0.48). CONCLUSIONS Maternal iron depletion is associated with reduced fetal iron stores but no change in free iron availability. Smoking is associated with increased fetal iron requirements for erythropoiesis.

Oxidative stress and increased type-IV collagenase levels in bronchoalveolar lavage fluid from newborn babies

Oxidative stress may increase lung permeability by up-regulation of matrix-metalloproteinase-9 (MMP-9), a type-IV collagenase that can disrupt alveolar basement membranes. We have compared a marker of oxidative stress (protein carbonyl residues) with levels of MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in bronchoalveolar lavage samples from newborn babies. Bronchoalveolar lavage samples (n = 87, two from each time point) were taken in the first 6 postnatal days from 41 ventilated babies: 18 of <29 wk gestation, 10 of 29–36 wk, 9 term with persistent fetal circulation, and 4 term without lung disease. Respiratory disease severity at the time of bronchoalveolar lavage was assessed using the arterial–alveolar oxygen tension ratio. One sample from each time point was used for the measurement of MMP-9 by zymography and TIMP-1 by ELISA. The second sample was used to measure carbonyl group concentrations, also using an ELISA. Correlations were calculated between protein carbonyls, arterial–alveolar oxygen tension ratio, and MMP-9 and TIMP-1 concentrations. Significant correlations were found between carbonyl concentrations and arterial–alveolar oxygen tension ratio (r = −0.325, p = 0.0031, n = 81), MMP-9 (r = 0.331, p < 0.0029, n = 79), and TIMP-1 (r = 0.436, p < 0.0001, n = 87). Worsening respiratory disease in newborn babies is associated with increased carbonyl concentrations in neonatal bronchoalveolar lavage fluid, and these correlated with MMP-9 and TIMP-1 levels. Increased oxidative stress may damage the lung by increasing type-IV collagenase activity, causing disruption of the extracellular matrix.

Type I collagenases in bronchoalveolar lavage fluid from preterm babies at risk of developing chronic lung disease

OBJECTIVE To assess whether increased collagenolysis precedes severe chronic lung disease (CLD). METHODS Matrix metalloproteinase-1 (MMP-1) and MMP-8 (enzymes that degrade type I collagen, the main structural protein of lung extracellular matrix) were measured by enzyme linked immunosorbent assay in 100 bronchoalveolar lavage samples taken during the first 6 postnatal days from 45 ventilated preterm babies < 33 weeks gestation. The median value for each baby was calculated. CLD was defined as an oxygen requirement after the 36th week after conception. RESULTS MMP-8 levels in bronchoalveolar lavage fluid were higher (median 13 ng/ml) in 20 babies who developed CLD than in 25 without CLD (median 2 ng/ml). No MMP-1 was detected in any sample. CONCLUSIONS MMP-8 can be detected in bronchoalveolar lavage fluid from preterm babies, and higher levels are found in those who later develop CLD. MMP-8 may contribute to lung injury that occurs as a prelude to CLD.

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.

The role of matrix metalloproteinases -9 and -2 in development of neonatal chronic lung disease

Aim: Matrix metalloproteinases (MMPs) ‐9 and ‐2 degrade type‐IV collagen, a major constituent of lung basement membrane, and may have a role in the pathogenesis of neonatal chronic lung disease (CLD). We determined factors influencing MMP levels in neonatal bronchoalveolar lavage (BAL) fluid to establish whether an imbalance between MMP and its inhibitor could be implicated in CLD. Methods: We measured MMP‐9 and ‐2 and tissue inhibitor of metalloproteinase‐1 (TIMP‐1) levels in 316 BAL fluid samples from 121 babies of gestational ages 23 to 42 wk over the first 14 d of life to determine effects of gestation and postnatal age. Median MMP‐9, ‐2, TIMP‐1 and MMP‐9/TIMP‐1 ratio in BAL were further studied in a subgroup of 85 babies >33 wk gestation to determine their ability to predict CLD and to establish effects of antenatal corticosteroid therapy (ANCS). Results: MMP‐9, ‐2 and TIMP levels did not vary with postnatal age over the first week. Median MMP‐9 levels and MMP‐9/TIMP‐1 ratio increased with decreasing gestation in preterm babies. The MMP‐9/TIMP‐1 ratio was higher in babies who developed CLD, implying a proteinase/antiproteinase imbalance, but this association disappeared when controlled for gestational age. ANCS had no effect on BAL fluid MMP or TIMP levels.

Delayed versus Immediate Cord Clamping in Preterm Infants

Background The preferred timing of umbilical‐cord clamping in preterm infants is unclear. Methods We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late‐onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention‐to‐treat basis, accounting for multiple births. Results Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed‐clamping group and 9.0% in the immediate‐clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. Conclusions Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088.)