Maternal activation of the EGFR prevents translocation of gut-residing pathogenic Escherichia coli in a model of late-onset neonatal sepsis.

Late-onset sepsis (LOS) is a highly consequential complication of preterm birth and is defined by a positive blood culture obtained after 72 h of age. The causative bacteria can be found in patients' intestinal tracts days before dissemination, and cohort studies suggest reduced LOS risk in breastfed preterm infants through unknown mechanisms. Reduced concentrations of epidermal growth factor (EGF) of maternal origin within the intestinal tract of mice correlated to the translocation of a gut-resident human pathogen Escherichia coli, which spreads systemically and caused a rapid, fatal disease in pups. Translocation of Escherichia coli was associated with the formation of colonic goblet cell-associated antigen passages (GAPs), which translocate enteric bacteria across the intestinal epithelium. Thus, maternally derived EGF, and potentially other EGFR ligands, prevents dissemination of a gut-resident pathogen by inhibiting goblet cell-mediated bacterial translocation. Through manipulation of maternally derived EGF and alteration of the earliest gut defenses, we have developed an animal model of pathogen dissemination which recapitulates gut-origin neonatal LOS.

Neutrophil extracellular trap inhibition increases inflammation, bacteraemia and mortality in murine necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease affecting primarily premature infants. The disease is characterized by intestinal inflammation and leucocyte infiltration, often progressing to necrosis, perforation, systemic inflammatory response and death. Neutrophil extracellular traps (NETs), denoting nuclear DNA, histone and antimicrobial protein release, have been suggested to play a role in NEC. This study aimed to determine the role of NETs in NEC and explore the effect of chloramidine, a NET inhibitor, on a murine NEC-like intestinal injury model. Blood and intestinal tissues were collected from infants diagnosed with ≥ Stage II NEC, and levels of nucleosomes and NETs, respectively, were compared with those of case-matched controls. In mice, NEC was induced with dithizone/Klebsiella, and mice in the treatment group received 40 mg/kg chloramidine. Bacterial load, intestinal histology, plasma myeloperoxidase and cytokine levels, and immunofluorescent staining were compared with controls. Nucleosomes were significantly elevated in both human and mouse NEC plasma, whereas NET staining was only present in NEC tissue in both species. Chloramidine treatment increased systemic inflammation, bacterial load, organ injury and mortality in murine NEC. Taken together, our findings suggest that NETs are critical in the innate immune defence during NEC in preventing systemic bacteraemia.

2019 American Heart Association Focused Update on Neonatal Resuscitation: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

This 2019 focused update to the American Heart Association neonatal resuscitation guidelines is based on 2 evidence reviews recently completed under the direction of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. The International Liaison Committee on Resuscitation Expert Systematic Reviewer and content experts performed comprehensive reviews of the scientific literature on the appropriate initial oxygen concentration for use during neonatal resuscitation in 2 groups: term and late-preterm newborns (≥35 weeks of gestation) and preterm newborns (<35 weeks of gestation). This article summarizes those evidence reviews and presents recommendations. The recommendations for neonatal resuscitation are as follows: In term and late-preterm newborns (≥35 weeks of gestation) receiving respiratory support at birth, the initial use of 21% oxygen is reasonable. One hundred percent oxygen should not be used to initiate resuscitation because it is associated with excess mortality. In preterm newborns (<35 weeks of gestation) receiving respiratory support at birth, it may be reasonable to begin with 21% to 30% oxygen and to base subsequent oxygen titration on oxygen saturation targets. These guidelines require no change in the Neonatal Resuscitation Algorithm-2015 Update.

A Hybrid Form of Telemedicine: A Unique Way to Extend Intensive Care Service to Neonates in Medically Underserved Areas.

BACKGROUND: More than 90% of neonatal intensive care units (NICUs) in the United States are in urban areas, denying rural residents' easy NICU access. Telemedicine use for patient contact and management, although studied in adults and children, is understudied in neonates. A hybrid telemedicine system, with 24/7 neonatal nurse practitioner coverage and with a neonatologist physically present 3 days per week and telemedicine coverage the remaining days, was recently implemented at Comanche County Memorial Hospital's (CCMH) Level II NICU. OBJECTIVE: To compare outcomes of moderately ill infants between 32-35 weeks gestational age (GA) managed by our hybrid telemedicine program with outcomes of similar neonates receiving standard care in a Level IV NICU at Oklahoma University Medical Center (OUMC). DESIGN/METHODS: This was a retrospective, noninferiority study comparing outcomes of neonates receiving hybrid telemedicine versus standard care. All 32-35 weeks GA infants admitted between July 2013 and June 2015 were included. OUMC infants came from areas geographically comparable with CCMH. Infants requiring prolonged mechanical ventilation or advanced subspecialty services were excluded. Outcome variables were length of stay, type and duration of respiratory support, length of antibiotic therapy, and time to full enteral feedings. RESULTS: Eighty-seven neonates at CCMH and 56 neonates at OUMC were included in the analysis. Compared with neonates at OUMC, neonates at CCMH had shorter hospitalizations, fewer days of supplemental oxygen, and fewer noninvasive ventilation support days, and reached full enteral feeds sooner. CONCLUSIONS: The hybrid telemedicine system is a safe and effective strategy for extending intensive care to neonates in medically underserved areas.

Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study.

BACKGROUND: Gut bacteria might predispose to or protect from necrotising enterocolitis, a severe illness linked to prematurity. In this observational prospective study we aimed to assess whether one or more bacterial taxa in the gut differ between infants who subsequently develop necrotising enterocolitis (cases) and those who do not (controls). METHODS: We enrolled very low birthweight (1500 g and lower) infants in the primary cohort (St Louis Children's Hospital) between July 7, 2009, and Sept 16, 2013, and in the secondary cohorts (Kosair Children's Hospital and Children's Hospital at Oklahoma University) between Sept 12, 2011 and May 25, 2013. We prospectively collected and then froze stool samples for all infants. Cases were defined as infants whose clinical courses were consistent with necrotising enterocolitis and whose radiographs fulfilled criteria for Bell's stage 2 or 3 necrotising enterocolitis. Control infants (one to four per case; not fixed ratios) with similar gestational ages, birthweight, and birth dates were selected from the population after cases were identified. Using primers specific for bacterial 16S rRNA genes, we amplified and then pyrosequenced faecal DNA from stool samples. With use of Dirichlet multinomial analysis and mixed models to account for repeated measures, we identified host factors, including development of necrotising enterocolitis, associated with gut bacterial populations. FINDINGS: We studied 2492 stool samples from 122 infants in the primary cohort, of whom 28 developed necrotising enterocolitis; 94 infants were used as controls. The microbial community structure in case stools differed significantly from those in control stools. These differences emerged only after the first month of age. In mixed models, the time-by-necrotising-enterocolitis interaction was positively associated with Gammaproteobacteria (p=0·0010) and negatively associated with strictly anaerobic bacteria, especially Negativicutes (p=0·0019). We studied 1094 stool samples from 44 infants in the secondary cohorts. 18 infants developed necrotising enterocolitis (cases) and 26 were controls. After combining data from all cohorts (166 infants, 3586 stools, 46 cases of necrotising enterocolitis), there were increased proportions of Gammaproteobacteria (p=0·0011) and lower proportions of both Negativicutes (p=0·0013) and the combined Clostridia-Negativicutes class (p=0·0051) in infants who went on to develop necrotising enterocolitis compared with controls. These associations were strongest in both the primary cohort and the overall cohort for infants born at less than 27 weeks' gestation. INTERPRETATION: A relative abundance of Gammaproteobacteria (ie, Gram-negative facultative bacilli) and relative paucity of strict anaerobic bacteria (especially Negativicutes) precede necrotising enterocolitis in very low birthweight infants. These data offer candidate targets for interventions to prevent necrotising enterocolitis, at least among infants born at less than 27 weeks' gestation. FUNDING: National Institutes of Health (NIH), Foundation for the NIH, the Children's Discovery Institute.

Clinical sequelae of gut microbiome development and disruption in hospitalized preterm infants.

Aberrant preterm infant gut microbiota assembly predisposes to early-life disorders and persistent health problems. Here, we characterize gut microbiome dynamics over the first 3 months of life in 236 preterm infants hospitalized in three neonatal intensive care units using shotgun metagenomics of 2,512 stools and metatranscriptomics of 1,381 stools. Strain tracking, taxonomic and functional profiling, and comprehensive clinical metadata identify Enterobacteriaceae, enterococci, and staphylococci as primarily exploiting available niches to populate the gut microbiome. Clostridioides difficile lineages persist between individuals in single centers, and Staphylococcus epidermidis lineages persist within and, unexpectedly, between centers. Collectively, antibiotic and non-antibiotic medications influence gut microbiome composition to greater extents than maternal or baseline variables. Finally, we identify a persistent low-diversity gut microbiome in neonates who develop necrotizing enterocolitis after day of life 40. Overall, we comprehensively describe gut microbiome dynamics in response to medical interventions in preterm, hospitalized neonates.

Gut pathogen colonization precedes bloodstream infection in the neonatal intensive care unit.

Bacterial bloodstream infections (BSIs) resulting in late-onset sepsis affect up to half of extremely preterm infants and have substantial morbidity and mortality. Bacterial species associated with BSIs in neonatal intensive care units (NICUs) commonly colonize the preterm infant gut microbiome. Accordingly, we hypothesized that the gut microbiome is a reservoir of BSI-causing pathogenic strains that increase in abundance before BSI onset. We analyzed 550 previously published fecal metagenomes from 115 hospitalized neonates and found that recent ampicillin, gentamicin, or vancomycin exposure was associated with increased abundance of Enterobacteriaceae and Enterococcaceae in infant guts. We then performed shotgun metagenomic sequencing on 462 longitudinal fecal samples from 19 preterm infants (cases) with BSI and 37 non-BSI controls, along with whole-genome sequencing of the BSI isolates. Infants with BSI caused by Enterobacteriaceae were more likely than infants with BSI caused by other organisms to have had ampicillin, gentamicin, or vancomycin exposure in the 10 days before BSI. Relative to controls, gut microbiomes of cases had increased relative abundance of the BSI-causing species and clustered by Bray-Curtis dissimilarity according to BSI pathogen. We demonstrated that 11 of 19 (58%) of gut microbiomes before BSI, and 15 of 19 (79%) of gut microbiomes at any time, harbored the BSI isolate with fewer than 20 genomic substitutions. Last, BSI strains from the Enterobacteriaceae and Enterococcaceae families were detected in multiple infants, indicating BSI-strain transmission. Our findings support future studies to evaluate BSI risk prediction strategies based on gut microbiome abundance in hospitalized preterm infants.

Transitional changes in cardiac and cerebral hemodynamics in term neonates at birth.

OBJECTIVE: To describe cardiac function, cerebral regional oxygen saturation (rSO(2)), and cerebral blood flow (CBF) that correspond to changes in arterial oxygen saturation (SaO(2)) in normal term neonates immediately after birth and after the transition. STUDY DESIGN: In this prospective observational study, cardiac function and cerebral hemodynamics were assessed by echocardiography and Doppler ultrasonography 3 times during the first 20 minutes after vaginal delivery, then again at 24-48 hours after delivery. Cerebral rSO(2) (by near-infrared spectroscopy) and preductal SaO(2) (by pulse oximetry) were assessed continuously. RESULTS: In 20 neonates, SaO(2) increased progressively from 65% at 1 minute after birth to 97% at 17 minutes after birth. Cerebral rSO(2) increased from 47% at 1 minute to 83% at 8 minutes, then decreased progressively to 73% at 20 minutes. Middle cerebral artery mean velocity decreased from 34 cm/s at 7 minutes to 25 cm/s at 14 minutes. The patent ductus arteriosus (PDA) shunt was balanced at 5 minutes but became increasingly left to right. Left ventricular stroke volume was increased. Middle cerebral artery mean velocity demonstrated an inverse relationship with the PDA shunt. Further hemodynamic changes were noted on the posttransitional assessment. CONCLUSION: After birth, ductal shunting rapidly changes from balanced to left to right, with a responsive increase in left ventricular stroke volume. Cerebral rSO(2) increases as SaO(2) rises during the first 8 minutes, subsequently, it decreases due to a drop in CBF and despite a further increase in SaO(2). The reduction in CBF is likely due to an increase in arterial O(2) content, PDA shunting, or both.

Report of an international conference on the medical and ethical management of the neonate at the edge of viability: a review of approaches from five countries.

Current United States guidelines for neonatal resuscitation note that there is no mandate to resuscitate infants in all situations. For example, the fetus that at the time of delivery is determined to be so premature as to be non-viable need not be aggressively resuscitated. The hypothetical case of an extremely premature infant was presented to neonatologists from the United States and four other European countries at a September 2006 international meeting sponsored by the World Health Organization Collaborating Center in Reproductive Health of Atlanta (currently, the Global Collaborating Center in Reproductive Health). Responses to the case varied by country, due to differences in legal, ethical and related practice parameters, rather than differences in medical technology, as similar medical technology was available within each country. Variations in approach seemed to stem from physicians' perceptions of their ability to remove the neonate from life support if this appeared non-beneficial. There appears to be a desire for greater convergence in practice options and more open discussion regarding the practical problems underlying the variability. Specifically, the conference attendees identified four areas that need to be addressed: (1) lack of international consensus guidelines in viability and therapeutic options, (2) lack of bodies capable of generating these guidelines, (3) variation in laws between countries, and (4) the frequent failure of physicians and families to confront death at the beginning of life.

2019 American Heart Association Focused Update on Neonatal Resuscitation: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

This 2019 focused update to the American Heart Association neonatal resuscitation guidelines is based on 2 evidence reviews recently completed under the direction of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. The International Liaison Committee on Resuscitation Expert Systematic Reviewer and content experts performed comprehensive reviews of the scientific literature on the appropriate initial oxygen concentration for use during neonatal resuscitation in 2 groups: term and late-preterm newborns (≥35 weeks of gestation) and preterm newborns (<35 weeks of gestation). This article summarizes those evidence reviews and presents recommendations. The recommendations for neonatal resuscitation are as follows: In term and late-preterm newborns (≥35 weeks of gestation) receiving respiratory support at birth, the initial use of 21% oxygen is reasonable. One hundred percent oxygen should not be used to initiate resuscitation because it is associated with excess mortality. In preterm newborns (<35 weeks of gestation) receiving respiratory support at birth, it may be reasonable to begin with 21% to 30% oxygen and to base subsequent oxygen titration on oxygen saturation targets. These guidelines require no change in the Neonatal Resuscitation Algorithm-2015 Update.

Recent Recommendations and Emerging Science in Neonatal Resuscitation.

The Neonatal Resuscitation Program, initially an expertise- and consensus-based approach, has evolved into an evidence-based algorithm. Ventilation remains the key component of successful resuscitation of neonates. Recent changes in recommendations include management of cord clamping, multiple methods to prevent hypothermia, rescinding of mandatory intubation and suction of the nonvigorous meconium-stained infant, electrocardiographic monitoring, and establishing an airway for ventilation before initiation of chest compressions. Emerging science, including issues such as cord milking, oxygen targeting, and laryngeal mask use, may lead to future program modifications. Technology such as video laryngoscopy and telemedicine will affect the way training and care is delivered.

Impact of electronic cardiac (ECG) monitoring on delivery room resuscitation and neonatal outcomes.

AIM: In 2016, the neonatal resuscitation guidelines suggested electronic cardiac (ECG) monitoring to assess heart rate for an infant receiving positive pressure ventilation immediately after birth. Our aim was to study the impact of ECG monitoring on delivery room resuscitation interventions and neonatal outcomes. METHODS: Observational cohort study compared maternal, perinatal and infant characteristics, before (retrospective cohort, calendar year 2015) and after (prospective cohort, calendar year 2017) implementation of ECG monitoring in the delivery room. Association of ECG monitoring with delivery room resuscitation practice interventions and neonatal outcomes was assessed using unadjusted and adjusted multivariable regression analyses. RESULTS: Of 632 newly born infants who received positive pressure ventilation in the delivery room, ECG monitoring was performed in 369 (the prospective cohort) compared with no ECG monitoring in 263 (the retrospective cohort). Compared to neonates in the retrospective cohort, neonates with ECG monitoring had a significantly lower endotracheal intubation rate (36% vs 48%, P < .005) in the delivery room and higher 5-min Apgar scores (7 [5-8] vs 6 [5-8], P < .05). There was no difference in mortality (31 [8%] vs 23 [9%]), but infants who received ECG monitoring had increased odds of receiving chest compressions with an adjusted odds ratio of 3.6 (95% confidence interval: 1.4-9.5). CONCLUSION: Introduction of ECG monitoring in the delivery room was associated with fewer endotracheal intubations, and an increase use of chest compressions with no difference in mortality.

A directory for neonatal intensive care: potential for facilitating network-based research in neonatology.

Directories of contact information have evolved over time from thick paperback times such as the "Yellow Pages" to electronic forms that are searchable and have other functionalities. In our clinical specialty, the development of a professional directory helped to promote collaboration in clinical care, education, and quality improvement. However, there are opportunities for increasing the utility of the directory by taking advantage of modern web-based tools, and expanding the use of the directory to fill a gap in the area of collaborative research.

Risk factors for advanced resuscitation in term and near-term infants: a case-control study.

OBJECTIVE: (1) To determine which antepartum and/or intrapartum factors are associated with the need for advanced neonatal resuscitation (ANR) at birth in infants with gestational age (GA) ≥34 weeks. (2) To develop a risk score for the need for ANR in neonates with GA ≥34 weeks. DESIGN: Prospective multicentre, case-control study. In total, 16 centres participated in this study: 10 in Argentina, 1 in Chile, 3 in Brazil and 2 in the USA. RESULTS: A case-control study conducted from December 2011 to April 2013. Of a total of 61 593 births, 58 429 were reported as an GA ≥34 weeks, and of these, only 219 (0.37%) received ANR. After excluding 23 cases, 196 cases and 784 consecutive birth controls were included in the analysis. The final model was generated with three antepartum and seven intrapartum factors, which correctly classified 88.9% of the observations. The area under the receiver operating characteristic (AROC) performed to evaluate discrimination was 0.88, 95% CI 0.62 to 0.91. The AROC performed for external validity testing of the model in the validation sample was 0.87 with 95% CI 0.58 to 0.92. CONCLUSIONS: We identified 10 risk factors significantly associated with the need for ANR in newborns ≥34 weeks. We developed a validated risk score that allows the identification of newborns at higher risk of need for ANR. Using this tool, the presence of specialised personnel in the delivery room may be designated more appropriately.