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Late-onset neonatal sepsis (LONS) remains an important threat to the health of preterm neonates in the neonatal intensive care unit. Strategies to optimize care for preterm neonates with LONS are likely to improve survival and long-term neurocognitive outcomes. However, many important questions on how to improve the prevention, early detection, and therapy for LONS in preterm neonates remain unanswered. This review identifies important knowledge gaps in the management of LONS and describe possible methods and technologies that can be used to resolve these knowledge gaps. The availability of computational medicine and hypothesis-free-omics approaches give way to building bedside feedback tools to guide clinicians in personalized management of LONS. Despite advances in technology, implementation in clinical practice is largely lacking although such tools would help clinicians to optimize many aspects of the management of LONS. We outline which steps are needed to get possible research findings implemented on the neonatal intensive care unit and provide a roadmap for future research initiatives.ImpactThis review identifies knowledge gaps in prevention, early detection, antibiotic, and additional therapy of late-onset neonatal sepsis in preterm neonates and provides a roadmap for future research efforts.Research opportunities are addressed, which could provide the means to fill knowledge gaps and the steps that need to be made before possible clinical use.Methods to personalize medicine and technologies feasible for bedside clinical use are described.

Background The assessment of the newborn after birth is fundamental for identifying those requiring resuscitation. Certain components of the Apgar score are used to assess neonatal condition, but their value is insufficiently validated. We aimed to identify the components of the Apgar score that predict neonatal resuscitation. Methods Individual patient data from two multicenter trials were analyzed. Preterm newborns under 32 weeks of gestation and term newborns with perinatal acidosis and/or resuscitation were included. The extent of resuscitation was quantified by a standardized scoring system, and the clinical condition was quantified by a specified Apgar score. Correlation, linear regression and ROC analyses were used to address the study question. Results A total of 2093 newborns were included. Newborns in poor clinical condition at 1 min received more interventions at 5 and 10 min. Heart rate, muscle tone, reflexes and breathing quality, but not skin color, were moderately strong correlated with the extent of resuscitation at 5 ( r  = 0.44 to 0.52) and 10 min ( r  = 0.38 to 0.42). Heart rate, reflexes and chest movement at 1 min best predicted the subsequent need for resuscitation (R 2  = 0.31). The rare interventions of intubation, chest compressions and epinephrine administration can be predicted by the newborn’s condition at one minute, with a high sensitivity of 84% (cutoff ≤ 4 Apgar points) or a high specificity of 86% (cutoff ≤ 7 Apgar points). Conclusions The clinical impression at 1 min can help to predict the need for medical interventions. Contrary to recent guidelines, heart rate, reflexes and chest movement seem to have the highest values. Trial registration The Test APGAR study was registered at clinicaltrials.gov (NCT00623038, 14/08/2008).

Isolation precautions required for neonatal intensive care units are part of a bundle with the aim to prevent transmission, colonization, and infection with multidrug-resistant gram-negative pathogens as neonates face an increased risk of mortality and morbidity in case of infection. The following short report describes a transmission of 3MDRGN Klebsiella pneumoniae on a neonatal intensive care unit in a university hospital in Germany. This transmission occurred even though intensified infection control measures were in place, which impressively shows the importance of surveillance, outbreak management, and awareness of contributing factors regarding outbreak situations.

ObjectivesAs quality of care in the delivery room has major impact on outcome of preterm infants, multiple guidelines have been established in recent years. There is, however, little evidence on how to proceed during postdelivery room care, the time of transfer and admission to the neonatal intensive care unit (NICU). The aim of this study was to identify processes taking place during this period with potential impact on outcome.Study designProspective observational study.SettingSingle-centre German tertiary NICU.Patients40 inborn preterm infants undergoing postdelivery room care.Main outcomePrevalence of prolonged duration of postdelivery room care, disconnections from the ventilator and positioning of preterm infants.ResultsTotal duration of postdelivery room care and NICU admission procedures were shorter in infants transferred in a transport incubator compared with using a NICU care station from birth. Extremely low birth weight (ELBW) infants spend 8% of the time in prone position in contrast to 39% in non-ELBW. Total duration of disconnection from the ventilator was 50 s and was ten times longer in infants who had nasal CPAP compared with infants intratracheally intubated. Infants with nCPAP had longer duration of disconnection from the ventilator if body weight was >1000 g or if they were transferred in a transport incubator.ConclusionsMultiple parameters like birth weight or type of transport affect neonatal care during the postdelivery room period. Prospective studies are needed to identify and optimise parameters within this period that affect long-term outcome.

Background The mitochondrial m.1555A>G mutation is associated with a high rate of permanent hearing loss, if aminoglycosides are given. Preterm infants have an increased risk of permanent hearing loss and are frequently treated with aminoglycoside antibiotics. Methods We genotyped preterm infants with a birth weight below 1500 grams who were prospectively enrolled in a large cohort study for the m.1555A>G mutation. Treatment with aminoglycoside antibiotics in combination with mitochondrial m.1555A>G mutation was tested as a predictor for failed hearing screening at discharge in a multivariate logistic regression analysis. Results 7056 infants were genotyped and analysed. Low birth weight was the most significant predictor of failed hearing screening (p = 7.3 × 10 -10 ). 12 infants (0.2%) had the m.1555A>G-mutation. In a multivariable logistic regression analysis, the combination of aminoglycoside treatment with m.1555A>G-carrier status was associated with failed hearing screening (p = 0.0058). However, only 3 out of 10 preterm m.1555A>G-carriers who were exposed to aminoglycosides failed hearing screening. The m.1555A>G-mutation was detected in all mothers of m.1555A>G-positive children, but in none of 2993 maternal DNA-samples of m.1555A>G-negative infants. Conclusion Antenatal screening for the m.1555A>G mutation by maternal genotyping of pregnant women with preterm labour might be a reasonable approach to identify infants who are at increased risk for permanent hearing loss. Additional studies are needed to estimate the relevance of cofactors like aminoglycoside plasma levels and birth weight and the amount of preterm m.1555A>G-carriers with permanent hearing loss.

We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009-2010. Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care.

The FTO gene, located on chromosome 16q12.2, and the MAF gene, located on chromosome 16q22-23, were identified as genes harboring common variants with an impact on obesity predisposition. We studied the association of common variants with birth weight, gain of body weight, body mass index (BMI), Ponderal index and relevant neonatal outcomes in a large German cohort of infants with a birth weight below 1500 grams. The single nucleotide polymorphisms rs9939609 (FTO gene) and rs1424233 (MAF gene) were genotyped using allelic discrimination assays in a prospective multicenter cohort study conducted in 15 neonatal intensive care units in Germany from September 2003 until January 2008. DNA samples were extracted from buccal swabs according to standard protocols. 1946 infants were successfully genotyped at FTO and 2149 infants at MAF. Allele frequencies were not significantly different from other European cohorts. The polymorphisms were in Hardy-Weinberg equilibrium. The polymorphisms did not show associations with birth weight, BMI and Ponderal Index at discharge, and weight gain, neither testing for a dominant, additive nor for a recessive model. Since an association of the polymorphisms with weight gain has been demonstrated in multiple populations, the lack of association in a population of preterm infants with regular tube feeding after birth and highly controlled feeding volumes provides evidence for the hypothesis that these polymorphisms affect food intake behavior and hunger rather than metabolism and energy consumption.

BackgroundThe lack of a consensus definition of neonatal sepsis and a core outcome set (COS) proves a substantial impediment to research that influences policy and practice relevant to key stakeholders, patients and parents.MethodsA systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the included studies, the described outcomes were extracted in accordance with the provisions of the Core Outcome Measures in Effectiveness Trials (COMET) handbook and registered.ResultsAmong 884 abstracts identified, 90 randomised controlled trials (RCTs) were included in this review. Only 30 manuscripts explicitly stated the primary and/or secondary outcomes. A total of 88 distinct outcomes were recorded across all 90 studies included. These were then assigned to seven different domains in line with the taxonomy for classification proposed by the COMET initiative. The most frequently reported outcome was survival with 74% (n = 67) of the studies reporting an outcome within this domain.ConclusionsThis systematic review constitutes one of the initial phases in the protocol for developing a COS in neonatal sepsis. The paucity of standardised outcome reporting in neonatal sepsis hinders comparison and synthesis of data. The final phase will involve a Delphi Survey to generate a COS in neonatal sepsis by consensus recommendation.ImpactThis systematic review identified a wide variation of outcomes reported among published RCTs on the management of neonatal sepsis.The paucity of standardised outcome reporting hinders comparison and synthesis of data and future meta-analyses with conclusive recommendations on the management of neonatal sepsis are unlikely.The final phase will involve a Delphi Survey to determine a COS by consensus recommendation with input from all relevant stakeholders.

BackgroundGuidelines advise for more than 20 years to use occlusive plastic wraps for temperature management during delivery room care but data on efficacy of different types of wrap are still scarce.MethodsA random sample of seven different types of plastic wrap was tested using prewarmed aluminium blocks.ResultsThe most effective wrap increased the time to cool by 2°C by one-third for the core and by 100% for the surface whereas the least effective wrap led to even faster heat loss compared with no wrap at all. The least effective wrap concerning all capacities tested was made from polyurethane that contains potentially toxic and narcotic monomers. Heat and water retention did not correlate to wrap thickness.DiscussionLarge differences in heat and water retention capacity warrant a careful choice of the type of wrap as some might be counterproductive. Wraps containing polyurethane should not be used.

Assessment of an infant’s condition in the delivery room represents a prerequisite to adequately initiate medical support. In her seminal paper, Virginia Apgar described five parameters to be used for such an assessment. However, since that time maternal and neonatal care has changed; interventions were improved and infants are even more premature. Nevertheless, the Apgar score is assigned to infants worldwide but there are concerns about low interobserver reliability, especially in preterm infants. Also, resuscitative interventions may preclude the interpretation of the score, which is of concern when used as an outcome parameter in delivery room intervention studies. Within the context of these changes, we performed a critical appraisal on how to assess postnatal condition of the newborn including the clinical parameters of the Apgar score, as well as selected additional parameters and a proposed new scoring system. The development of a new scoring system that guide clinicians in assessing infants and help to decide how to support postnatal adaptation is discussed. Impact This critical paper discusses the reliability of the Apgar score, as well as additional parameters, in order to improve assessment of a newborn’s postnatal condition. A revised neonatal scoring system should account for infant maturity and the interventions administered. Delivery room assessment should be directed toward determining how much medical support is needed and how the infant responds to these interventions.