Protocol for the development of a core outcome set for neonatal sepsis (NESCOS).

Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients' parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.

A physiological approach to applying CPAP in the preterm infant.

Nasal continuous positive airway pressure (CPAP) is increasingly used for respiratory support in preterm infants with respiratory distress syndrome at birth and after extubation from mechanical ventilation. Controversies with CPAP use still exists due to non-uniformity of devices and interfaces used, equivalence of testing conditions for different CPAP systems, differences in study designs, and short study periods that may be insufficient to detect important and relevant clinical outcomes. Compared with ventilator-derived constant-pressure flow-opposition CPAP, variable fluidic flow-opposition CPAP systems may be advantageous and offer some clinical benefits. The distinction between constant-flow fluid-sealed bubble CPAP and variable-flow fluidic flow-opposition systems is less clear. Appropriately designed randomized clinical trials that separately address the controversies with CPAP use in various clinical settings, are necessary to determine which CPAP system results in best outcomes.

Sequential organ failure assessment scores to predict outcomes: from adults to neonates.

PURPOSE OF REVIEW: Organ dysfunction severity scores (sequential organ failure assessment or SOFA) are commonly used in the adult and pediatric populations when assessing risk of mortality and adverse outcomes from sepsis. In contrast to sepsis definition in adults and children, clinical and laboratory criteria for defining neonatal sepsis have been inconclusive. More recently, studies have attempted to better understand the clinical progression of neonatal sepsis and associated mortality. This data has guided the development of a neonatal SOFA (nSOFA) score, based on common patterns of organ dysfunction observed in this population. RECENT FINDINGS: Although SOFA scores in the adult and pediatric populations have their limitations with moderate sensitivities and specificities depending on the clinical setting, the nSOFA score has been validated in predicting sepsis attributable mortality in very low birth weight (VLBW) infants across several patient cohorts. Furthermore, the nSOFA score has been adapted for use in neonatal disease states, other than sepsis, with similar prognostic utility. SUMMARY: Utilizing an nSOFA scoring system for prediction of sepsis attributable mortality in preterm infants allows for targeted interventions based on risk stratification, as well as better delineation of neonatal sepsis with subsequent improvements in research and patient safety outcomes.

What's new in the management of neonatal early-onset sepsis?

The expert guidelines highlighted in this review provide an evidence-based framework for approaching at-risk infants and allow for a more limited and standardised approach to antibiotic use. While these guidelines have significantly reduced antibiotic utilisation worldwide, optimally each unit would individualise their approach to early onset sepsis (EOS) based on the neonatal population they serve and available resources. As advancements in EOS research continue and limitations with sepsis prediction tools are addressed, it is inevitable that our risk stratification and management guidelines will become more precise.

Infection prevention for extremely low birth weight infants in the NICU.

Extremely preterm infants are particularly vulnerable to systemic infections secondary to their immature immune defenses, prolonged hospitalizations, delays in enteral feeding, early antibiotic exposure, and need for life-sustaining invasive interventions. There have been several evidence-based practices for infection prevention in this population, such as human milk feedings, utilization of "bundle checklists" and decolonization of pathogenic organisms. Other practices, such as the use of probiotics, human milk-derived fortifiers, and antifungal prophylaxis are more controversial and require further investigation regarding the risks and benefits of such interventions. This chapter examines the susceptibility of the preterm newborn infant to invasive infections and describes several strategies for infection prevention, along with the associated limitations of such practices. It also addresses the various gaps in our understanding of preventing infections in this population, and the need for additional large multi-center randomized controlled trials. Additionally, the role of the SARs-CoV-2 global pandemic and associated strategies for infection prevention in the NICU are discussed.

The NICU Antibiotics and Outcomes (NANO) trial: a randomized multicenter clinical trial assessing empiric antibiotics and clinical outcomes in newborn preterm infants.

BACKGROUND: Early-onset sepsis is an important cause of neonatal morbidity and mortality in the preterm population. Infants perceived to be at increased risk for early-onset sepsis are often treated empirically with broad-spectrum antibiotics while awaiting confirmatory blood cultures, despite an overall incidence of early-onset sepsis of 2-3% among extremely-low-birthweight (ELBW) infants. Recent observational studies associate perinatal antibiotic use with an increased incidence of necrotizing enterocolitis, late-onset sepsis, and mortality among ELBW infants. Given currently available data and variability in clinical practice, we designed a prospective multi-institutional randomized controlled trial to determine the safety of early antibiotic use in ELBW infants. METHODS: The NICU Antibiotics and Outcomes (NANO) trial is a multicenter, double-blinded, randomized controlled trial. A sample of 802 ELBW preterm infants will undergo web-based stratified block randomization to receive empiric antibiotics (EA; ampicillin and gentamicin) or placebo during routine evaluation for early-onset sepsis. Participating sites will use preexisting institutional protocols for antibiotic dosage and duration. Infants born at participating sites with a gestational age of 29 weeks or less are eligible for enrollment. Exclusion criteria include maternal intrauterine infection, hemodynamic or respiratory instability, delivery by caesarean section for maternal indications without labor or prolonged rupture of membranes, and prior administration of antibiotics. The primary outcome is the composite incidence of necrotizing enterocolitis, late-onset sepsis, or death during participants' index hospitalization. Maternal and infant samples will be collected longitudinally and assessed for differences in microbiome composition and diversity. DISCUSSION: The NANO trial is designed to compare the rate of adverse outcomes of EA use at birth versus placebo in ELBW preterm infants. If EA at birth worsens clinical outcomes, then the results of the trial may help providers decrease antibiotic utilization in the NICU and subsequently decrease the incidence of complications associated with early antibiotic use in ELBW infants. If we instead find that EA improve outcomes, then the trial will validate a longstanding clinical practice that has not previously been supported by high-quality data. Future studies will assess long-term clinical and microbial outcomes in infants who received empiric antibiotics following delivery. TRIAL REGISTRATION: Trial registration data: June 25, 2019  NCT03997266 .

Can we back off using antibiotics in the NICU?

Antibiotics are extensively and inconsistently prescribed in neonatal ICUs, and usage does not correlate with rates of culture positive sepsis. There is mounting data describing the short and long-term adverse effects associated with antibiotic overuse in neonates, including the increased burden of multi-drug resistant organisms. Currently there is considerable variation in antibiotic prescribing practice among neonatologists. Applying the practice of antibiotic stewardship in the NICU is crucial for standardizing antibiotic use and improving outcomes in this population. Several approaches have been proposed to identify neonatal sepsis, with the hope of reducing antibiotic utilization. These strategies all have their limitations, and often include laboratory testing and treatment of well-appearing, non-septic, infants. A conservative "watch and wait" algorithm is suggested as an alternative method for when to initiate antibiotics. This observational approach relies on availability of trained personnel able to examine infants at specified intervals, without delaying antibiotics, should signs of sepsis arise.

Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants With Late-Onset Infection.

Importance: 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. Objective: To determine the generalizability of the nSOFA for neonatal late-onset infection-related mortality across multiple sites. Design, Setting, and Participants: 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. Exposures: Late-onset (>72 hours of life) infection including bacteremia, fungemia, or surgical peritonitis. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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.

Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants.

Antibiotic use in neonates can have detrimental effects on the developing gut microbiome, increasing the risk of morbidity. A majority of preterm neonates receive antibiotics after birth without clear evidence to guide this practice. Here microbiome, metabolomic, and immune marker results from the routine early antibiotic use in symptomatic preterm Neonates (REASON) study are presented. The REASON study is the first trial to randomize symptomatic preterm neonates to receive or not receive antibiotics in the first 48 h after birth. Using 16S rRNA sequencing of stool samples collected longitudinally for 91 neonates, the effect of such antibiotic use on microbiome diversity is assessed. The results illustrate that type of nutrition shapes the early infant gut microbiome. By integrating data for the gut microbiome, stool metabolites, stool immune markers, and inferred metabolic pathways, an association was discovered between Veillonella and the neurotransmitter gamma-aminobutyric acid (GABA). These results suggest early antibiotic use may impact the gut-brain axis with the potential for consequences in early life development, a finding that needs to be validated in a larger cohort.Trial Registration This project is registered at clinicaltrials.gov under the name "Antibiotic 'Dysbiosis' in Preterm Infants" with trial number NCT02784821.

Routine Early Antibiotic Use in SymptOmatic Preterm Neonates: A Pilot Randomized Controlled Trial.

We enrolled 98 infants (gestational age <33 weeks) in a pilot randomized trial of antibiotics vs no antibiotics; 55 were randomized (lower maternal infectious risk; symptoms expected for gestation). Adverse events did not differ significantly between the randomization arms. This trial establishes a framework for a larger multicentered trial.

Antibiotics Effects on the Fecal Metabolome in Preterm Infants.

Within a randomized prospective pilot study of preterm infants born at less than 33 weeks' gestation, weekly fecal samples from 19 infants were collected and metabolomic analysis was performed. The objective was to evaluate for differences in fecal metabolites in infants exposed to antibiotics vs. not exposed to antibiotics in the first 48 h after birth. Metabolomics analysis was performed on 123 stool samples. Significant differences were seen in the antibiotics vs. no antibiotics groups, including pathways related to vitamin biosynthesis, bile acids, amino acid metabolism, and neurotransmitters. Early antibiotic exposure in preterm infants may alter metabolites in the intestinal tract of preterm infants. Broader multi-omic studies that address mechanisms will guide more prudent antibiotic use in this population.

A neonatal sequential organ failure assessment score predicts mortality to late-onset sepsis in preterm very low birth weight infants.

BACKGROUND: An operational definition of organ dysfunction applicable to neonates that predicts mortality in the setting of infection is lacking. We determined the utility of an objective, electronic health record (EHR)-automated, neonatal sequential organ failure assessment (nSOFA) score to predict mortality from late-onset sepsis (LOS) in premature, very low birth weight (VLBW) infants. METHODS: Retrospective, single-center study of bacteremic preterm VLBW newborns admitted between 2012 and 2016. nSOFA scores were derived for patients with LOS at multiple time points surrounding the sepsis evaluation. RESULTS: nSOFA scores at evaluation and at all points measured after evaluation were different between survivors and non-survivors. Among patients with an nSOFA score of >4, mortality was higher at evaluation (13% vs 67%, p < 0.001), +6 h (15% vs 64%, p = 0.002), and +12 h (7% vs 71%, p < 0.001) as compared to patients with a score of ≤4. Receiver operating characteristics area under the curve was 0.77 at evaluation (95% CI 0.62-0.92; p = 0.001), 0.78 at +6 h (0.66-0.92; p < 0.001), and 0.93 at +12 h (0.86-0.997; p < 0.001). CONCLUSIONS: The nSOFA scoring system predicted mortality in VLBW infants with LOS and this automated system was integrated into our EHR. Prediction of LOS mortality is a critical step toward improvements in neonatal sepsis outcomes.

Preventing Continuous Positive Airway Pressure Failure: Evidence-Based and Physiologically Sound Practices from Delivery Room to the Neonatal Intensive Care Unit.

Routine use of continuous positive airway pressure (CPAP) to support preterm infants with respiratory distress is an evidenced-based strategy to decrease incidence of bronchopulmonary dysplasia. However, rates of CPAP failure remain unacceptably high in very premature neonates, who are at high risk for developing bronchopulmonary dysplasia. Using the GRADE framework to assess the quality of available evidence, this article reviews strategies aimed at decreasing CPAP failure, starting with delivery room interventions and followed through to system-based efforts in the neonatal intensive care unit. Despite best efforts, some very premature neonates fail CPAP. Also reviewed are predictors of CPAP failure in this vulnerable population.

What's the harm? Risks and benefits of evolving rule-out sepsis practices.

Asymptomatic term and late-preterm newborns with risk factors for early onset sepsis commonly undergo laboratory evaluation and receive empiric antibiotic therapy. Some have challenged the rationale for current "rule-out sepsis" practices, arguing that they lead to unnecessary overtreatment and healthcare costs. A series of recent clinical studies has explored scheduled serial observations as an alternative to laboratory testing and empiric antibiotics for asymptomatic newborns with historical risk factors for sepsis. These studies have shared the conclusion that serial observation is safe and cost-effective for well-appearing term and late-preterm babies, but they are also somewhat speculative because culture-proven early onset sepsis is an extremely low prevalence diagnosis. Here, we review the evolving consensus of optimal rule-out sepsis practices. We examine chorioamnionitis as an example of a problematic risk factor that has contributed to the controversy surrounding this topic. We also discuss how introduction of online sepsis risk calculators has allowed more precise delineation of a patient's chances of developing culture-proven infection. Finally, we analyze existing data from published studies to estimate the number needed to harm (NNH) when an observation-based strategy is used instead of a risk-based approach. We conclude that, if harm is defined as death or serious sepsis complications such as hemodynamic instability or neurologic injury, the NNH is 1610, compared to an NNH of 7 and 2.9 for IV infiltrates and delayed breastfeeding, respectively-two common and potentially consequential complications of NICU admission for a rule-out sepsis. We believe that the differential between risk of serious harm from observing a well-appearing term or late-preterm newborn with risk factors for sepsis and the risk of less significant but common NICU complications argues in favor of the ongoing trend toward less aggressive management of newborns with sepsis risks.