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Sepsis remains a significant cause of neonatal mortality and morbidity, especially in low- and middle-income countries. Neonatal sepsis presents with nonspecific signs and symptoms that necessitate tests to confirm the diagnosis. Early and accurate diagnosis of infection will improve clinical outcomes and decrease the overuse of antibiotics. Current diagnostic methods rely on conventional culture methods, which is time-consuming, and may delay critical therapeutic decisions. Nonculture-based techniques including molecular methods and mass spectrometry may overcome some of the limitations seen with culture-based techniques. Biomarkers including hematological indices, cell adhesion molecules, interleukins, and acute-phase reactants have been used for the diagnosis of neonatal sepsis. In this review, we examine past and current microbiological techniques, hematological indices, and inflammatory biomarkers that may aid sepsis diagnosis. The search for an ideal biomarker that has adequate diagnostic accuracy early in sepsis is still ongoing. We discuss promising strategies for the future that are being developed and tested that may help us diagnose sepsis early and improve clinical outcomes.ImpactReviews the clinical relevance of currently available diagnostic tests for sepsis.Summarizes the diagnostic accuracy of novel biomarkers for neonatal sepsis.Outlines future strategies including the use of omics technology, personalized medicine, and point of care tests.

This systematic review and meta-analysis synthesised the post-1990 literature examining the effect of human milk on morbidity, specifically necrotising enterocolitis (NEC), late onset sepsis (LOS), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD) and neurodevelopment in infants born ≤28 weeks’ gestation and/or publications with reported infant mean birth weight of ≤1500 g. Online databases including Medline, PubMed, CINAHL, Scopus, and the Cochrane Central Register of Controlled Trials were searched, and comparisons were grouped as follows: exclusive human milk (EHM) versus exclusive preterm formula (EPTF), any human milk (HM) versus EPTF, higher versus lower dose HM, and unpasteurised versus pasteurised HM. Experimental and observational studies were pooled separately in meta-analyses. Risk of bias was assessed for each individual study and the GRADE system used to judge the certainty of the findings. Forty-nine studies (with 56 reports) were included, of which 44 could be included in meta-analyses. HM provided a clear protective effect against NEC, with an approximate 4% reduction in incidence. HM also provided a possible reduction in LOS, severe ROP and severe NEC. Particularly for NEC, any volume of HM is better than EPTF, and the higher the dose the greater the protection. Evidence regarding pasteurisation is inconclusive, but it appears to have no effect on some outcomes. Improving the intake of mother’s own milk (MOM) and/or donor HM results in small improvements in morbidity in this population.

Background Neonatal sepsis remains a leading cause of mortality in neonatal units. Neonatologist-performed echocardiography (NPE) offers the potential for early detection of sepsis-associated cardiovascular dysfunction. This review examines available echocardiographic findings in septic neonates. Methods Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically reviewed prospective observational, cross-sectional, case control, and cohort studies on septic newborns with echocardiographic assessments from PubMed, Scopus and Embase. Quality assessment employed the Newcastle–Ottawa Scale, with results analyzed descriptively. Results From an initial pool of 1663 papers, 12 studies met inclusion criteria after relevance screening and eliminating duplicates/excluded studies. The review encompassed 438 septic newborns and 232 controls. Septic neonates exhibited either increased risk of pulmonary hypertension or left ventricular diastolic dysfunction, and a warm shock physiology characterized by higher cardiac outputs. Discussion The included studies exhibited heterogeneity in sepsis definitions, sepsis severity scores, echocardiographic evaluations, and demographic data of newborns. Limited sample sizes compromised analytical interpretability. Nonetheless, this work establishes a foundation for future high-quality echocardiographic studies. Conclusion Our review confirms that septic neonates show significant hemodynamic changes that can be identified using NPE. These findings underscore the need for wider NPE use to tailor hemodynamics-based strategies within this population. Impact Our study emphasizes the value of neonatologist-performed echocardiography (NPE) as a feasible tool for identifying significant hemodynamic changes in septic neonates. Our study underscores the importance of standardized echocardiographic protocols and frequent monitoring of cardiac function in septic neonates. The impact of the study lies in its potential to increase researchers’ awareness for the need for more high-quality echocardiographic data in future studies. By promoting wider use of NPE, neonatologists can more accurately assess the hemodynamic status of septic newborns and tailor treatment approaches, potentially improving patient outcomes.

Cardiovascular disturbances are a frequent occurrence in neonatal sepsis. Preterm and term infants are particularly vulnerable due to the unique features of their cardiovascular function and reserve, compared to older children and adults. The clinical manifestations of neonatal sepsis are a product of the variable inflammatory pathways involved (warm vs. cold shock physiology), developmental state of the cardiovascular system, and hormonal responses. Targeted neonatal echocardiography has played an important role in advancing our knowledge, may help delineate specific hemodynamic phenotypes in real-time, and supports an individualized physiology-based management of sepsis-associated cardiovascular dysfunction.ImpactCardiovascular dysfunction is a common sequela of sepsis. This review aims to highlight the pathophysiological mechanisms involved in hemodynamic disturbance in neonatal sepsis, provide insights from targeted neonatal echocardiography-based clinical studies, and suggest its potential incorporation in day-to-day management.

Neonatal sepsis accounts for significant morbidity and mortality, particularly among premature infants in the Neonatal Intensive Care Unit. Abnormal vital sign patterns serve as physiomarkers of sepsis and provide early warning of illness before overt clinical decompensation. The systemic inflammatory response to pathogens signals the autonomic nervous system, leading to changes in temperature, respiratory rate, heart rate, and blood pressure. In infants with comorbidities of prematurity, vital sign abnormalities often occur in the absence of infection, which confounds sepsis diagnosis. This review will cover the mechanisms of vital sign changes in neonatal sepsis, including the cholinergic anti-inflammatory pathway mediated by the vagus nerve, which is critical to the host response to infectious and inflammatory insults. We will also review the clinical implications of vital sign changes in neonatal sepsis, including their use in early warning scores and systems to direct clinicians to the bedside of infants with physiologic changes that might be due to sepsis.ImpactThis manuscript summarizes and reviews the relevant literature on the physiological manifestations of neonatal sepsis and how we monitor and analyze these through vital signs and advanced analytics.

Background Early biomarkers are needed to improve diagnosis and support antibiotic stewardship in neonatal sepsis. Heart rate variability (HRV) is proposed as such a biomarker. However, there is a lack of studies in term newborns. Infusion of lipopolysaccharide (LPS) from Escherichia coli induces systemic inflammation comparable to sepsis in newborns. We aimed to study the effect of systemic LPS induced inflammation on HRV in term newborn piglets. Methods Baseline HRV was recorded for 1 h. This control period was compared to the hourly HRV for each piglet ( n  = 9) during 4 h of LPS infusion. For comparison, we used a mixed-effects regression model. Results Systemic inflammation induced by LPS was found to reduce HRV. Compared to baseline, most measures of HRV decreased to lower values compared to baseline at 2 h, 3 h, and 4 h after initiation of LPS infusion. Heart rate (HR) was increased at 2 h, 3 h, and 4 h. When adjusting for HR in the mixed-effects regression model all reductions in HRV were explained by the increase in HR. Conclusions Reduced HRV may be an early biomarker of neonatal sepsis. However, an increase in HR alone could be an already available, more accessible, and interpretable biomarker of sepsis in term neonates. Impact In a term newborn piglet model, systemic inflammation induced by lipopolysaccharide from Escherichia coli reduced heart rate variability measures and increased heart rate. All reductions in heart rate variability were mediated by heart rate. While heart rate variability may be a biomarker of sepsis in term newborns, changes in heart rate alone could be a more readily available biomarker.

Infection in neonates remains a substantial problem. Advances for this population are hindered by the absence of a consensus definition for sepsis. In adults, the Sequential Organ Failure Assessment (SOFA) operationalizes mortality risk with infection and defines sepsis. The generalizability of the neonatal SOFA (nSOFA) for neonatal late-onset infection-related mortality remains unknown. To determine the generalizability of the nSOFA for neonatal late-onset infection-related mortality across multiple sites. A multicenter retrospective cohort study was conducted at 7 academic neonatal intensive care units between January 1, 2010, and December 31, 2019. Participants included 653 preterm (<33 weeks) very low-birth-weight infants. Late-onset (>72 hours of life) infection including bacteremia, fungemia, or surgical peritonitis. The primary outcome was late-onset infection episode mortality. The nSOFA scores from survivors and nonsurvivors with confirmed late-onset infection were compared at 9 time points (T) preceding and following event onset. In the 653 infants who met inclusion criteria, median gestational age was 25.5 weeks (interquartile range, 24-27 weeks) and median birth weight was 780 g (interquartile range, 638-960 g). A total of 366 infants (56%) were male. Late-onset infection episode mortality occurred in 97 infants (15%). Area under the receiver operating characteristic curves for mortality in the total cohort ranged across study centers from 0.71 to 0.95 (T0 hours), 0.77 to 0.96 (T6 hours), and 0.78 to 0.96 (T12 hours), with utility noted at all centers and in aggregate. Using the maximum nSOFA score at T0 or T6, the area under the receiver operating characteristic curve for mortality was 0.88 (95% CI, 0.84-0.91). Analyses stratified by sex or Gram-stain identification of pathogen class or restricted to infants born at less than 25 weeks' completed gestation did not reduce the association of the nSOFA score with infection-related mortality. The nSOFA score was associated with late-onset infection mortality in preterm infants at the time of evaluation both in aggregate and in each center. These findings suggest that the nSOFA may serve as the foundation for a consensus definition of sepsis in this population.

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.

BackgroundBloodstream infection (BSI) among neonatal intensive care unit (NICU) infants is a frequent problem associated with poor outcomes. Monitoring for abnormal heart rate characteristics (HRCs) may decrease infant mortality by alerting clinicians to sepsis before it becomes clinically apparent.MethodsHRC scores were acquired using the HRC (HeRO) monitor system from Medical Predictive Science Corporation and entered into the electronic medical record by bedside staff. We retrospectively analysed HRC scores recorded twice daily in the medical record during a 30-month period (1 January 2010 through 30 June 2012) for infants in the NICU at the Monroe Carell Jr. Children's Hospital at Vanderbilt. We identified infants that met Centers for Disease Control criteria for late-onset BSI (>3 days of life) during the study period.ResultsDuring the study period, we recorded 127 673 HRC scores from 2384 infants. We identified 46 infants with BSI. Although 8% (9701/127 673) of the HRC scores were ≥2 and 1% (1387/127 673) were ≥5, BSI (at any time) was observed in just 5% of patients with HRC scores ≥2, and 9% of patients with HRC scores ≥5. Of infants with BSI, 5/46 (11%) had at least one HRC score ≥5 and 17/46 (37%) had at least one score ≥2 recorded in the 48 h period prior to the evaluation that resulted in the first positive blood culture of the episode.ConclusionsIn our single-centre retrospective study, elevated HRC scores had limited ability to detect BSI. BSI was infrequent at any time during hospitalisation in infants with significantly elevated HRC scores.