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.

Treatment outcome of neonatal sepsis and associated factors among neonates admitted to neonatal intensive care unit in public hospitals, Addis Ababa, Ethiopia, 2021. Multi-center cross-sectional study.

BACKGROUND: Globally, neonatal sepsis is the leading cause of neonatal mortality and morbidity, particularly in developing countries. Despite studies that revealed the prevalence of neonatal sepsis in developing countries, the outcome of the diseases, barriers for poor outcomes were inconclusive. The aim of this study was to assess the treatment outcome of neonatal sepsis and its associated factors among neonates admitted to neonatal intensive care unit in public hospitals, Addis Ababa, Ethiopia, 2021. METHODS: A cross-sectional study was carried out from February 15 to May 10, 2021 on 308 neonates admitted to neonatal intensive care units of Addis Ababa city public hospitals. Hospitals and study participants were selected by lottery and systematic random sampling techniques, respectively. Data were collected through face-to-face interviews with a structured, pretested questionnaire and by reviewing both the maternal and newborn profile cards. Epi-data version 4.6 was used to enter the collected data, which was then exported to SPSS version 26 for analysis. The 95% CI odds ratio is used to determine the direction and strength of the association between the dependent and independent variables. RESULTS: Among the total study 308 neonates, 75(24.4%) were died. Regarding the poor treatment outcome of neonatal sepsis, neonates whose mothers <37 weeks of gestational age (AOR = 4.87, 95% CI: 1.23-19.22), Grunting (AOR 6.94: 1.48-32.54), Meconium amniotic stained (AOR = 3.03, 95% CI: 1.02-9.01), Duration of rupture of membrane >18hours (AOR = 3.66, 95% CI: (1.20-11.15), Hypertensive PIH/ Eclampsia (AOR = 3.54, 95% CI: 1.24-10.09), Meropenum (AOR = 4.16, 95% CI: 1.22-14.21) and CRP positive result (AOR = 5.87, 95% CI: 1.53-22.56) were significantly associated with poor treatment outcome of neonatal sepsis. CONCLUSION AND RECOMMENDATION: The treatment outcomes of neonates were 75.6% recovered and 24.4% died. In this setting, empirical treatment was the cornerstone for managing neonatal sepsis. Professionals who are working in labor and delivery ward screened for mothers preeclampsia and duration of rupture of membrane >18hrs /PROM/ treated with antihypertensive drug and antibiotics for the prevention of neonatal sepsis.

Analysis of risk factors for death in 59 cases of critically ill neonates receiving continuous renal replacement therapy: a two-centered retrospective study.

To investigate the risk factors for death in critically ill neonates receiving continuous renal replacement therapy (CRRT). This retrospective study analyzed the clinical data of critically ill neonates receiving CRRT at two tertiary hospitals from January 2015 to December 2021. A multi-factor logistic regression analysis was performed, and the predictive value of relevant risk factors on death was verified by receiver operating characteristic (ROC) curve. A total of 59 cases of critically ill neonates were included in this study, with a mortality of 37.3%. The most common primary disease in these cases was neonatal sepsis, followed by neonatal asphyxia, and inborn errors of metabolism (IEM). Univariate analysis showed that the risk factors related to death included primary diseases; the number of organs involved in multiple organ dysfunction syndrome (MODS), neonatal critical illness scores (NCIS), and indications of CRRT; the blood lactate, blood glucose, hemoglobin, and platelet before CRRT initiation; and the incidence of bleeding or thrombosis during CRRT. Multi-factor logistic regression analysis showed that risk factors for death in critically ill neonates receiving CRRT included the occurrence of neonatal sepsis, the number of organs involved in MODS, and the NCIS. ROC curve analysis showed that the number of organs involved in MODS and NCIS had a good predictive value for death in critically ill neonates receiving CRRT, with the areas under the curve (AUC) being 0.700 and 0.810, respectively. CONCLUSION: Neonatal sepsis, the number of organs involved in MODS, and NCIS were independent risk factors for death in critically ill neonates receiving CRRT. Moreover, the number of organs involved in MODS and NCIS could effectively predict death in critically ill neonates receiving CRRT. WHAT IS KNOWN: • The population to which CRRT is applicable is gradually expanding from critically ill children to critically ill neonates. • The mortality of critically ill neonates receiving CRRT remains high. WHAT IS NEW: • The most common primary disease in critically ill neonates receiving CRRT was neonatal sepsis, followed by neonatal asphyxia and inborn errors of metabolism (IEM). • The number of organs involved in MODS and NCIS could effectively predict death in critically ill neonates receiving CRRT.

Home-based management of neonatal sepsis: 23 years of sustained implementation and effectiveness in rural Gadchiroli, India, 1996-2019.

INTRODUCTION: Although hospitalisation remains the preferred management for neonatal sepsis, it is often not possible in resource-limited settings. The Home-Based Newborn Care (HBNC) study in Gadchiroli, India (1995-1998) was the first trial to demonstrate that neonatal sepsis can be managed in the community. HBNC continues to operate in Gadchiroli. In 2015, WHO recommended community-based management of neonatal sepsis when hospitalisation is not feasible but called for implementation research. We studied the implementation and effectiveness of home-based management of neonatal sepsis over 23 years in Gadchiroli. METHODS: In this cohort study (1996-2019), community health workers (CHWs) visited neonates at home in 39 villages in Gadchiroli, India. CHWs screened, diagnosed sepsis and offered home-based antibiotic treatment if hospitalisation was refused. We evaluated the implementation outcomes of coverage, diagnostic fidelity and adoption. We assessed the association between treatment type and odds of neonatal death using mixed effects logistic regression. Time trends were analysed using the Mann-Kendall test. RESULTS: CHWs screened 93.8% (17 700/18 874) of neonates (coverage) and correctly diagnosed 89% (1051/1177) of sepsis episodes (diagnostic fidelity). Home-based management was preferred by 88.4% (929/1051) of parents (adoption), with 5.6 percent of total neonates receiving antibioties at home. Compared with neonates treated at home, the adjusted odds of death was 5.27 (95% CI 1.91 to 14.58) times higher when parents refused all treatment, 2.17 (95% CI 1.07 to 4.41) times higher when CHWs missed the diagnosis and 5.45 (95% CI 2.74 to 10.87) times higher when parents accepted hospital referral. Implementation outcomes remained consistent over 23 years (coverage p=0.57; fidelity p=0.57; adoption p=0.26; mortality p=0.71). The rate of facility births increased (p<0.01) and the sepsis incidence decreased (p<0.05) over 23 years. CONCLUSION: Implementation of home-based management of neonatal sepsis was sustainable and effective over 23 years. During this period, the need for home-based management in Gadchiroli is declining. Home-based management is advised where sepsis remains a major cause of neonatal mortality and hospital access is limited.

Platelet transfusions in a murine model of neonatal polymicrobial sepsis: Divergent effects on inflammation and mortality.

BACKGROUND: Platelet transfusions (PTxs) are often given to septic preterm neonates at high platelet count thresholds in an attempt to reduce bleeding risk. However, the largest randomized controlled trial (RCT) of neonatal transfusion thresholds found higher mortality and/or major bleeding in infants transfused at higher thresholds. Using a murine model, we investigated the effects of adult PTx on neonatal sepsis-induced mortality, systemic inflammation, and platelet consumption. STUDY DESIGN AND METHODS: Polymicrobial sepsis was induced via intraperitoneal injection of cecal slurry preparations (CS1, 2, 3) into P10 pups. Two hours after infection, pups were transfused with washed adult Green Flourescent Protein (GFP+) platelets or control. Weights, platelet counts, and GFP% were measured before 4 and 24 h post-infection. At 24 h, blood was collected for quantification of plasma cytokines. RESULTS: The CS batches varied in 24 h mortality (11%, 73%, and 30% in CS1, 2, and 3, respectively), due to differences in bacterial composition. PTx had differential effects on sepsis-induced mortality and systemic inflammatory cytokines, increasing both in mice infected with CS1 (low mortality) and decreasing both in mice infected with CS2 and 3. In a mathematical model of platelet kinetics, the consumption of transfused adult platelets was higher than that of endogenous neonatal platelets, regardless of CS batch. DISCUSSION: Our findings support the hypothesis that transfused adult platelets are consumed faster than endogenous neonatal platelets in sepsis and demonstrate that PTx can enhance or attenuate neonatal inflammation and mortality in a model of murine polymicrobial sepsis, depending on the composition of the inoculum and/or the severity of sepsis.

Progress in Diagnosis and Treatment of Neonatal Sepsis: A Review Article.

Neonatal sepsis is a serious condition in which the pathogens infiltrate the bloodstream, multiply and produce toxins causing deleterious effects to the health of neonates. It is divided into two types on the basis of the time of onset. Early onset sepsis occurs within 72 hours of birth and late onset sepsis begins after 72 hours of delivery. Neonatal sepsis continues to be a common and significant health care burden, especially in very low birth weight infants (with birthweight less than 1500 grams). Though intrapartum antibiotic prophylaxis has decreased the incidence of early-onset group B streptococcal infection dramatically, it still remains a major cause of neonatal sepsis. As the signs and symptoms of neonatal sepsis are nonspecific, early diagnosis and prompt treatment remain a challenge. Keywords: cytokines; immunoglobulin; neonatal sepsis; procalcitonin.

Look Who's Talking: Host and Pathogen Drivers of Staphylococcus epidermidis Virulence in Neonatal Sepsis.

Preterm infants are at increased risk for invasive neonatal bacterial infections. S. epidermidis, a ubiquitous skin commensal, is a major cause of late-onset neonatal sepsis, particularly in high-resource settings. The vulnerability of preterm infants to serious bacterial infections is commonly attributed to their distinct and developing immune system. While developmentally immature immune defences play a large role in facilitating bacterial invasion, this fails to explain why only a subset of infants develop infections with low-virulence organisms when exposed to similar risk factors in the neonatal ICU. Experimental research has explored potential virulence mechanisms contributing to the pathogenic shift of commensal S. epidermidis strains. Furthermore, comparative genomics studies have yielded insights into the emergence and spread of nosocomial S. epidermidis strains, and their genetic and functional characteristics implicated in invasive disease in neonates. These studies have highlighted the multifactorial nature of S. epidermidis traits relating to pathogenicity and commensalism. In this review, we discuss the known host and pathogen drivers of S. epidermidis virulence in neonatal sepsis and provide future perspectives to close the gap in our understanding of S. epidermidis as a cause of neonatal morbidity and mortality.

Neonatal sepsis: a systematic review of core outcomes from randomised clinical trials.

BACKGROUND: The 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. METHODS: A 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. RESULTS: Among 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. CONCLUSIONS: This 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. IMPACT: This 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.

Paediatric and neonatal sepsis and inflammation.

Sepsis has a huge impact on global mortality and has been declared as a priority by the World Health organisation the WHO.1 Children have a high incidence of sepsis especially in the neonatal with an estimated 3 million babies affected worldwide and mortality ranges from 11 to 19%.2 In addition, long-term neurodevelopmental outcomes are affected but this is largely unquantified. However, challenges remain in the early recognition, diagnosis and standardised management of sepsis. This series on Sepsis and inflammation in children reviews the conundrums of diagnostic criteria, biomarkers, management and future strategies to improve outcomes.

Severe neonatal COVID-19: Challenges in management and therapeutic approach.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may manifest as a life-threatening respiratory infection with systemic complications. Clinical manifestations among children are generally less severe than those seen in adults, but critical cases have increasingly been reported in infants less than 1 year of age. We report a severe case of neonatal COVID-19 requiring intensive care and mechanical ventilation, further complicated by a multidrug-resistant Enterobacter asburiae super-infection. Chest X-rays, lung ultrasound, and chest computed tomography revealed extensive interstitial pneumonia with multiple consolidations, associated with persistent increased work of breathing and feeding difficulties. SARS-CoV-2 RNA was detected in respiratory specimens and stools, but not in other biological samples, with a rapid clearance in stools. Serological tests demonstrated a specific SARS-CoV-2 antibody response mounted by the neonate and sustained over time. The therapeutic approach included the use of enoxaparin and steroids which may have contributed to the bacterial complication, underlying the challenges in managing neonatal COVID-19, where the balance between viral replication and immunomodulation maybe even more challenging than in older ages.

Hemodynamic dysfunction in neonatal sepsis.

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. IMPACT: Cardiovascular 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.

Soft tissue infection as a rare cause of neonatal sepsis.

Umbilical venous and peripherally inserted central venous catheters are often used in preterm infants, but complications include late-onset catheter-associated infections. Conversely, other sites of infection have to be taken into account in the case of clinical deterioration. In this Image in Science and Medicine paper, we report on a preterm infant with a rare cause of neonatal sepsis.

The effect of exchange transfusion on mortality in neonatal sepsis: a meta-analysis.

Although antimicrobials are the cornerstone of neonatal sepsis management, adjunctive therapies are required to improve outcomes. The aim of our study was to evaluate the effect of exchange transfusion (ET) on mortality (primary outcome) in neonatal sepsis, as well as on immunoglobulin, complement and neutrophil levels and assess its complications (secondary outcomes). Databases searched include PubMed, NCBI, Google Scholar, CINHAL, Ovid and Scopus. Randomized controlled trials (RCTs), controlled observational studies (COSs) and uncontrolled observational studies (UOSs) reporting mortality data from using ET in neonatal sepsis were included. Studies with additional interventions, non-septic ET indications and populations aged > 28 days were excluded. Data extracted include demographics, features of study, sepsis and ET, as well as mortality rates, immunological and laboratory changes and complications. Data was meta-analysed and displayed using forest plots. The meta-analysis of 14 studies (3 RCTs, 11 COSs) revealed a mortality benefit in septic neonates who underwent ET-RR 0.72 (CI 0.61-0.86, p = 0.01) and a significant increase in pooled immunological parameters (immunoglobulin, complement levels) (SMD 1.13, [0.25, 2.02], p = 0.02) and neutrophil levels (SMD 1.07 [0.04, 2.11], p = 0.03) compared to controls. The descriptive analysis of 9 UOSs revealed thrombocytopenia as the most frequently reported complication (n = 48). Moderate-high risk of bias was largely due to inadequate sample sizes and follow-up durations.Conclusion: Currently, the use of ET in neonatal sepsis is not directly recommended due to low certainty of evidence, inadequate power and moderate-high risk of bias and heterogeneity.Trial registration: PROSPERO (CRD42020176629) ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=176629 ) What is Known: • Exchange transfusion is one of the adjunctive methods for treatment of neonatal sepsis. What is New: • The pooled analysis of all studies shows that exchange transfusion has a low certainty of evidence in the context of neonatal mortality. However, at this point, this intervention cannot be refuted or recommended due to heterogeneity of studies and inadequate power.

Recurrent neonatal sepsis and progressive white matter injury in a premature newborn culture-positive for group B Streptococcus: A case report.

RATIONALE: Group B Streptococcus (GBS) remains a principal pathogen causing neonatal sepsis and meningitis, particularly in premature infants with relatively insufficient immunity. Recurrence may occur uncommonly, largely associated with subclinical mucosal persistence or repetitive exposure to exogenous sources. White matter injury (WMI) including cystic periventricular leukomalacia (PVL) has been associated with intrauterine infection/inflammation, and neonatal infection as a more significant predictor including postnatal sepsis and recurrent infection, even without microbial neuroinvasion. Furthermore, clinical and experimental evidence of WMI by some bacteria other than GBS without central nervous system invasion has been reported. However, there is little evidence of WMI associated with neonatal GBS sepsis in the absence of meningitis in the literature. PATIENT CONCERNS: A newborn at 30+4 weeks' gestation with low birthweight presented with 2 episodes (with a 13-day interval with no antibiotic therapy) of neonatal sepsis culture-proven for GBS with early-onset presentation after clinical chorioamnionitis via vertical GBS transmission and the associated conditions including prematurity-related neonatal immunodeficiency and persistent mucosal GBS carriage after the first antibiotic treatment. The perinatal GBS infection was complicated by progressive WMI presenting with ventriculomegaly and cystic PVL without a definite evidence of meningitis, intraventricular hemorrhage, and documented cerebral hypoxia or hypoperfusion conditions including septic shock. DIAGNOSES: Recurrent group B streptococcal sepsis and cystic PVL with ventriculomegaly. INTERVENTIONS: Two episodes of GBS sepsis were treated with 15-day parenteral antibiotic therapy, respectively. OUTCOMES: Resolution of the recurrent GBS sepsis without further relapses, however, complicated by WMI and subsequent about 6 months delay in motor development at 12 months' corrected age. LESSONS: This case suggests WMI associated with GBS bacteremia without central nervous system entry by viable GBS and also shows that in premature infants, intrauterine GBS infection with no interventions may lead to extensive and persistent GBS colonization, early-onset and recurrent GBS disease, and WMI. Postnatal as well as intrauterine infection/inflammation controls with maternal prophylaxis may be pivotal for prevention and limiting the magnitude of neurologic injury.