Herpes virus entry mediator signaling blockade produces mortality in neonatal sepsis through induced cardiac dysfunction.

Introduction: Sepsis remains a major source of morbidity and mortality in neonates, and characterization of immune regulation in the neonatal septic response remains limited. HVEM is a checkpoint regulator which can both stimulate or inhibit immune responses and demonstrates altered expression after sepsis. We hypothesized that signaling via HVEM would be essential for the neonatal response to sepsis, and that therefore blockade of this pathway would improve survival to septic challenge. Methods: To explore this, neonatal mice were treated with cecal slurry (CS), CS with Anti-HVEM antibody (CS-Ab) or CS with isotype (CS-IT) and followed for 7-day survival. Mice from all treatment groups had thymus, lung, kidney and peritoneal fluid harvested, weighed, and stained for histologic evaluation, and changes in cardiac function were assessed with echocardiography. Results: Mortality was significantly higher for CS-Ab mice (72.2%) than for CS-IT mice (22.2%). CS resulted in dysregulated alveolar remodeling, but CS-Ab lungs demonstrated significantly less dysfunctional alveolar remodeling than CS alone (MCL 121.0 CS vs. 87.6 CS-Ab), as well as increased renal tubular vacuolization. No morphologic differences in alveolar septation or thymic karyorrhexis were found between CS-Ab and CS-IT. CS-Ab pups exhibited a marked decrease in heart rate (390.3 Sh vs. 342.1 CS-Ab), stroke volume (13.08 CS-IT vs. 8.83 CS-Ab) and ultimately cardiac output (4.90 Sh vs. 3.02 CS-Ab) as well as a significant increase in ejection fraction (73.74 Sh vs. 83.75 CS-Ab) and cardiac strain (40.74 Sh vs. 51.16 CS-Ab) as compared to CS-IT or Sham animals. Discussion: While receptor ligation of aspects of HVEM signaling, via antibody blockade, appears to mitigate aspects of lung injury and thymic involution, stimulatory signaling via HVEM still seems to be necessary for vascular and hemodynamic resilience and overall neonatal mouse survival in response to this experimental polymicrobial septic insult. This dissonance in the activity of anti-HVEM neutralizing antibody in neonatal animals speaks to the differences in how septic cardiac dysfunction should be considered and approached in the neonatal population.

Características epidemiológicas da mortalidade neonatal e infantil em uma regional de saúde / Epidemiological characteristics of neonatal and infant mortality in a health regional area

Objetivou-se analisar o perfil epidemiológico e as causas da mortalidade neonatal e infantil, em uma Regional de Saúde, de janeiro/2018 a agosto/2020. Trata-se de pesquisa exploratória, descritiva, transversal, retrospectivo, com abordagem quantitativa. A coleta de dados ocorreu em agosto de 2020, por meio de questionário elaborado pelas pesquisadoras, com base nas declarações de óbito disponibilizadas no Sistema de Informações de Mortalidade. O instrumento abordou as variáveis, sexo, raça, cor, idade da criança, idade materna, escolaridade materna, via de parto, idade gestacional, peso ao nascer, causa do óbito. Os dados foram submetidos à análise estatística descritiva e distribuição de frequência, por meio do Statistical Package for the Social Sciences (SPSS), versão 25.0. Constatou-se o predomínio de óbitos no sexo masculino (56,5%), de raça branca (87,8%), com equivalência entre extremo baixo peso e adequado (31,3%), com a principal causa de óbito por septicemia (13,9%). Quanto aos dados maternos, prevaleceram idade entre 21 e 30 anos de idade (45,2%) com gestação única (85,21%) e parto cesariano (65,2 %). Desses, 47,87% ocorreram no ano de 2018. Analisar os aspectos da mortalidade neonatal e infantil possibilita o planejamento e a readequação de ações no atendimento à saúde da criança, durante o período mais vulnerável e mais crítico dela, contribuindo, assim, para redução do número de óbitos.

This study analyzed the epidemiological profile and the causes of neonatal and infant mortality in a Health Regional Area between January 2018 and August 2020. This is an exploratory, descriptive, cross-sectional, retrospective study with a quantitative approach. Data collection took place during August 2020 through a questionnaire prepared by the researchers, based on the death certificates available in the Mortality Information System. The instrument included the variables of sex, race, color, child's age, mother's age, maternal education, childbirth mode, gestational age, birth weight, cause of death. The data were submitted to descriptive statistical analysis and frequency distribution using the Statistical Package for the Social Sciences (SPSS) version 25.0. There was a predominance of deaths among boys (56.5%), Caucasian (87.8%), with equivalence between extreme low and adequate weight (31.3%), with the main cause of death being septicemia (13.9%). As for maternal data, age between 21 to 30 years old (45.2%) prevailed, and 85.21% had a single pregnancy, with C-section childbirth (65.2%). From these, 47.87% occurred in 2018. It can be concluded that analyzing the aspects of neonatal and child mortality enables the planning and adjustment of actions in child health care during its most vulnerable and most critical period, thus contributing to reducing the number of deaths.

Mortalidad por sepsis neonatal entre los años 2016 y 2020 en Chile: una mirada nacional / Mortality due to neonatal sepsis between 2016 and 2020 in Chile: a national perspective

Introducción: La sepsis neonatal (SN) es una infección sistémica que ocurre antes de los 90 días de vida y que representa una amenaza potencialmente mortal. Esta investigación busca describir la tendencia de defunción por SN en Chile, durante el periodo 2016-2020. Materiales y métodos: Estudio descriptivo observacional, que incluyó a niños fallecidos por SN (n=249) en el periodo 2016-2020 en Chile según datos del departamento de estadísticas e información de salud de Chile. Las variables estudiadas fueron: año de fallecimiento, grupo etario, sexo, región y agente etiológico. No se requirió comité de ética. Resultados: El 2020 tuvo la menor tasa de mortalidad por SN (0,17) y el 2017 la mayor (0,31). El grupo etario de 0-2 días de nacido tuvo la mayor tasa de mortalidad (0,07), mientras que el grupo de 27-28 días corresponde a la menor (0,00). La región de Antofagasta tuvo la mayor mortalidad (0,44) y la región de Magallanes la menor (0,11). La tasa de mortalidad promedio en hombres corresponde a 0,12 y en mujeres a 0,10. En el 89,16% de los casos no se identificó el agente etiológico. Discusión: La mayor mortalidad en 2017 podría deberse a una proporción más alta de nacimientos pretérmino en dicho año. La mayor cantidad de defunciones a menor edad cronológica estaría relacionada con su inmadurez inmunológica. La no detección del agente etiológico pudo deberse al bajo rendimiento de los hemocultivos. Sin embargo, faltan más investigaciones acerca de la incidencia y mortalidad por sepsis neonatal.

Introduction: Neonatal sepsis (NS) is a systemic infection that occurs before 90 days of life and represents a life-threatening threat. This research seeks to describe the trend of death by NS in Chile, during the period 2016-2020. Materials and methods: Observational descriptive study, which included children who died due to NS (n=249) in the period 2016-2020 in Chile, according to data from the Department of Statistics and Health Information of Chile. The variables studied were: year of death, age group, sex, region and etiological agent. No ethics committee was required. Results: 2020 had the lowest mortality rate due to NS (0.17) and 2017 the highest (0.31). The age group of 0-2 days of birth had the highest mortality rate (0.07), while the group of 27-28 days corresponds to the lowest (0.00). The Antofagasta region had the highest mortality (0.44) and the Magallanes region the lowest (0.11). The average mortality rate in men corresponds to 0.12 and in women to 0.10. In 89.16% of the cases, the etiological agent was not identified. Discussion: The higher mortality in 2017 could be due to a higher proportion of preterm births in that year. The greater number of deaths at a lower chronological age would be related to their immunological immaturity. The non-detection of the etiological agent could be due to the low yield of the blood cultures. However, more research on the incidence and mortality from neonatal sepsis is lacking.

The Emerging Role of Presepsin (P-SEP) in the Diagnosis of Sepsis in the Critically Ill Infant: A Literature Review.

Sepsis causes high rates of morbidity and mortality in NICUs. The estimated incidence varies between 5 and 170 per 1000 births, depending on the social context. In very low birth-weight neonates, the level of mortality increases with the duration of hospitalization, reaching 36% among infants aged 8-14 days and 52% among infants aged 15-28 days. Early diagnosis is the only tool to improve the poor prognosis of neonatal sepsis. Blood culture, the gold standard for diagnosis, is time-consuming and poorly sensitive. C-reactive protein and procalcitonin, currently used as sepsis biomarkers, are influenced by several maternal and fetal pro-inflammatory conditions in the perinatal age. Presepsin is the N-terminal fragment of soluble CD14 subtype (sCD14-ST): it is released in the bloodstream by monocytes and macrophages, in response to bacterial invasion. Presepsin seems to be a new, promising biomarker for the early diagnosis of sepsis in neonates as it is not modified by perinatal confounding inflammatory factors. The aim of the present review is to collect current knowledge about the role of presepsin in critically ill neonates.

Fatal Neonatal Sepsis Associated with Human Adenovirus Type 56 Infection: Genomic Analysis of Three Recent Cases Detected in the United States.

BACKGROUND: Human adenovirus (HAdV)-D56 was first described in 2011 by genomics analysis of a strain isolated in France in 2008 from a fatal case of neonatal infection. Since then, it has been reported in cases of keratoconjunctivitis and male urethritis. Three epidemiologically unrelated fatal cases of neonatal sepsis associated with infection by HAdV-D strains with a similar genetic makeup were documented in the United States between 2014 and 2020. METHODS: Whole genome sequences were obtained for the isolated strains, and genomics analyses were conducted to compare them to phylogenetically related HAdV-D genomic sequences available in GenBank. RESULTS: The three new US strains were indistinguishable by in silico restriction enzyme analysis. Their genome sequences were 99.9% identical to one another and to the prototype strain isolated in 2008 from a similar context of disease. The phylogenetic reconstruction revealed a highly supported clustering of all HAdV-D56 strains isolated in various countries since 1982. Our comparison to serologically intermediate strains 15/H9 described in the literature indicated that HAdV-D56-like viruses have circulated worldwide since the late 1950s. CONCLUSION: As with other HAdV-D genotypes with the ability to infect ocular and genital mucosae, the risk of severe prenatal or perinatal HAdV-D56 infection must be considered.

MYD88, NFKB1, and IL6 transcripts overexpression are associated with poor outcomes and short survival in neonatal sepsis.

Toll-like receptor (TLR) family signature has been implicated in sepsis etiopathology. We aimed to evaluate the genetic profile of TLR pathway-related key genes; the myeloid differentiation protein 88 (MYD88), IL1 receptor-associated kinase 1 (IRAK1), the nuclear factor kappa-B1 (NFKB1), and interleukin 6 (IL6) in the blood of neonates with sepsis at the time of admission and post-treatment for the available paired-samples. This case-control study included 124 infants with sepsis admitted to the neonatal intensive care unit and 17 controls. The relative gene expressions were quantified by TaqMan Real-Time qPCR and correlated to the clinic-laboratory data. MYD88, NFKB1, and IL6 relative expressions were significantly higher in sepsis cases than controls. Higher levels of MYD88 and IL6 were found in male neonates and contributed to the sex-based separation of the cases by the principal component analysis. ROC analysis revealed MYD88 and NFKB1 transcripts to be good biomarkers for sepsis. Furthermore, patients with high circulatory MYD88 levels were associated with poor survival, as revealed by Kaplan-Meier curves analysis. MYD88, NFKB1, and IL6 transcripts showed association with different poor-outcome manifestations. Clustering analysis split the patient cohort into three distinct groups according to their transcriptomic signature and CRP levels. In conclusion, the study TLR pathway-related transcripts have a gender-specific signature, diagnostic, and prognostic clinical utility in neonatal sepsis.

Neonatal surgical outcomes: a prospective observational study at a Tertiary Academic Hospital in Johannesburg, South Africa.

PURPOSE: The neonatal period is the most vulnerable period for a child. There is a paucity of data on the burden of neonatal surgical disease in our setting. The aim of this study was to describe the frequency with which index neonatal surgical conditions are seen within our setting and to document the 30-day outcome of these patients. METHODS: This was a single-centre prospective observational study in which all neonates with paediatric surgical pathology referred to the paediatric surgical unit with a corrected gestational age of 28 days were included. RESULTS: Necrotising enterocolitis was the most frequent reason for referral to the paediatric surgical unit (n = 68, 34.34%). Gastroschisis was the most frequent congenital anomaly referred (n = 20, 10.10%). The overall morbidity was 57.58%. Surgical complications contributed to 18.51% of morbidities. The development of gram negative nosocomial sepsis was the most frequent cause of morbidity (n = 98, 50.78%). Mortality at 30 days was 21.74% (n = 40). Sepsis contributed to mortality in 35 patients (87.5%), 16 of which had gram negative sepsis. CONCLUSION: Gram-negative sepsis was a major contributing factor in the development of morbidity and mortality in our cohort. Prevention and improvement in infection control are imperative if we are to improve outcomes in our surgical neonates.

Term newborns at risk for early-onset neonatal sepsis: Clinical surveillance versus systematic paraclinical test.

INTRODUCTION: Early-onset neonatal sepsis is a rare but potentially lethal infection that is very often suspected in daily practice. Previous national guidelines recommended the use of systematic paraclinical tests for healthy term newborns with suspected infection. These guidelines were updated in 2017 by the French Health Authority (Haute Autorité de santé), and promote initial clinical monitoring taking into account the infectious risk level for term and near-term born infants. OBJECTIVES: To assess the impact of the new recommendations on antibiotic therapy prescription and invasive tests, and on the outcomes of infants born from 36weeks' gestation. MATERIALS AND METHODS: This study compared the management and the outcome of neonates born from 36weeks' gestation at the level III University Hospital of Nancy, according to their infectious risk level during two periods, before and after the update of national recommendations: from July 1 to December 31, 2017, versus July 1 to December 31, 2018. Data were retrospectively collected from the infants' files. This study compared the number and length of antibiotic treatment and the number of invasive tests, the number of documented infections, the number and length of hospitalization, and mortality between the two periods. RESULTS: During the first period, among 1248 eligible newborns, 643 presented an infectious risk factor, versus 1152 newborns with 343 having an infectious risk factor during the second period. Antibiotic treatment was initiated for 18 newborns during the first period (1.4%) and for nine during the second (0.8%) (P=0.13). The mean (SD) duration of the antibiotic treatment was longer in the first than in the second period: 6.3±2days vs. 3.1±2.3days (P=0.003). There was no death related to neonatal infection. A total of 1052 blood samples were collected during the first period versus 51 during the second (P<0.01). There was no documented infection. In the first period, there were 18 newborns (1.4%) hospitalized for suspected infection versus nine (0.8%) in the second period (P=0.13). The duration of hospitalization was 5.7±1.7days in the first period versus 5.2±3days in the second (P=0.33). CONCLUSION: In this study, the application of the new guidelines enabled a reduction of antibiotic exposure and a reduction of invasive tests without additional risk.

Aluminum Adjuvant Improves Survival Via NLRP3 Inflammasome and Myeloid Non-Granulocytic Cells in a Murine Model of Neonatal Sepsis.

ABSTRACT: Neonatal sepsis leads to significant morbidity and mortality with the highest risk of death occurring in preterm (<37 weeks) and low birth weight (<2,500 g) infants. The neonatal immune system is developmentally immature with well-described defects in innate and adaptive immune responses. Immune adjuvants used to enhance the vaccine response have emerged as potential therapeutic options, stimulating non-specific immunity and preventing sepsis mortality. Aluminum salts ("alum") have been used as immune adjuvants for over a century, but their mechanism of action remains poorly understood. This study aims to identify potential mechanisms by which pretreatment with alum induces host protective immunity to polymicrobial sepsis in neonatal mice. Utilizing genetic and cell-depletion studies, we demonstrate here that the prophylactic administration of aluminum adjuvants in neonatal mice improves sepsis survival via activation of the nucleotide oligomerization domain-like receptor family, pyrin-domain-containing 3 inflammasome and dendritic cell activation. Furthermore, this beneficial effect is dependent on myeloid, non-granulocytic Gr1-positive cells, and MyD88-signaling pathway activation. These findings suggest a promising therapeutic role for aluminum-based vaccine adjuvants to prevent development of neonatal sepsis and improve mortality in this highly vulnerable population.

Infecciones neonatales tardías / Late neonatal infections

Introducción: La infección neonatal constituye una de las enfermedades más comunes debido a la susceptibilidad de estos pacientes. Esta infección puede llegar a la sepsis neonatal e incrementar la mortalidad. Objetivo: Determinar las características clínicas y epidemiológicas de la infección neonatal tardía. Métodos: Estudio descriptivo retrospectivo y transversal de registros de neonatos ingresados en el servicio de neonatología del Hospital William Soler Ledea entre los años 2017-2019 con diagnóstico de infección. Se excluyeron aquellos registros de neonatos infectados intervenidos quirúrgicamente. Las variables estudiadas fueron: epidemiológicas, factores de riesgo, clínicas y paraclínicas. Se emplearon técnicas de estadísticas descriptivas como porcentajes, razón, media o promedio. Resultados: La muestra estuvo conformada por 1078 registros de pacientes para una tasa de infección de 59,4 × 100 ingresos. Los factores de riesgo prenatales y connatales obtuvieron razón de prevalencia < 1. Los factores de riesgo posnatales con mayor prevalencia fueron el sexo masculino (57,6 por ciento) y el cateterismo venoso central (53,6 por ciento). De 83 a 88 por ciento de los neonatos infectados presentaron alteraciones del perfil hematopoyético. Las infecciones respiratorias, de piel y de partes blandas se presentaron en 36 por ciento de los neonatos y fueron las bacterias grampositivas los principales microorganismos aislados. Hubo 11 pacientes fallecidos para una tasa de mortalidad del 22,9 por ciento. Conclusiones: La morbilidad por infección tardía es notable, predominan los factores de riesgo posnatales y el sexo masculino; la prematuridad y el bajo peso tuvieron la mayor representación en los fallecidos(AU)

Introduction: Neonatal infection is one of the most common diseases due to the sensitivity of these patients. This infection can lead to neonatal sepsis and increase mortality. Objective: Determine the clinical and epidemiological characteristics of late neonatal infection. Methods: Retrospective and cross-sectional descriptive study of records on neonates admitted to the neonatology service of William Soler Ledea Hospital in the period 2017-2019 with a diagnosis of infection. Records of infected infants undergoing surgery were excluded. The variables studied were: epidemiological, risk factors, clinical and paraclinical. Descriptive statistical techniques such as percentages, ratio, mean or average were used. Results: The sample consisted of 1078 patient´s records, with an infection rate of 59.4 × 100 admissions. Prenatal and conatal risk factors obtained prevalence ratio < 1. The postnatal risk factors with the highest prevalence were male sex (57.6 percent) and central venous catheterization (53.6 percent). From 83 to 88 percent of infected neonates had alterations in the hematopoietic profile. Respiratory, skin and soft tissue infections occurred in 36 percent of the neonates and gram-positive bacteria were the main isolated microorganisms. There were 11 patients who died representing a mortality rate of 22.9 percent. Conclusions: Morbidity due to late infection is remarkable, postnatal risk factors predominate and male sex; prematurity and low weight had the highest representation in the deceased ones(AU)

Targeting the eCIRP/TREM-1 interaction with a small molecule inhibitor improves cardiac dysfunction in neonatal sepsis.

BACKGROUND: Neonatal sepsis and the associated myocardial dysfunction remain a leading cause of infant mortality. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a ligand of triggering receptor expressed on myeloid cells-1 (TREM-1). M3 is a small CIRP-derived peptide that inhibits the eCIRP/TREM-1 interaction. We hypothesize that the eCIRP/TREM-1 interaction in cardiomyocytes contributes to sepsis-induced cardiac dysfunction in neonatal sepsis, while M3 is cardioprotective. METHODS: Serum was collected from neonates in the Neonatal Intensive Care Unit (NICU). 5-7-day old C57BL/6 mouse pups were used in this study. Primary murine neonatal cardiomyocytes were stimulated with recombinant murine (rm) CIRP with M3. TREM-1 mRNA and supernatant cytokine levels were assayed. Mitochondrial oxidative stress, ROS, and membrane potential were assayed. Neonatal mice were injected with rmCIRP and speckle-tracking echocardiography was conducted to measure cardiac strain. Sepsis was induced by i.p. cecal slurry. Mouse pups were treated with M3 or vehicle. After 16 h, echocardiography was performed followed by euthanasia for tissue analysis. A 7-day survival study was conducted. RESULTS: Serum eCIRP levels were elevated in septic human neonates. rmCIRP stimulation of cardiomyocytes increased TREM-1 gene expression. Stimulation of cardiomyocytes with rmCIRP upregulated TNF-α and IL-6 in the supernatants, while this upregulation was inhibited by M3. Stimulation of cardiomyocytes with rmCIRP resulted in a reduction in mitochondrial membrane potential (MMP) while M3 treatment returned MMP to near baseline. rmCIRP caused mitochondrial calcium overload; this was inhibited by M3. rmCIRP injection impaired longitudinal and radial cardiac strain. Sepsis resulted in cardiac dysfunction with a reduction in cardiac output and left ventricular end diastolic diameter. Both were improved by M3 treatment. Treatment with M3 attenuated serum, cardiac, and pulmonary levels of pro-inflammatory cytokines compared to vehicle-treated septic neonates. M3 dramatically increased sepsis survival. CONCLUSIONS: Inhibition of eCIRP/TREM-1 interaction with M3 is cardioprotective, decreases inflammation, and improves survival in neonatal sepsis. Trial registration Retrospectively registered.

Differences in clinical characteristics of early- and late-onset neonatal sepsis caused by Klebsiella pneumoniae.

To identify differences in the clinical characteristics of early- and late-onset sepsis (EOS and LOS) caused by Klebsiella pneumoniae (K. pneumoniae) and to describe the risk factors for multidrug-resistant K. pneumoniae (MDR-KP) infection. Infants with K. pneumoniae-induced sepsis who were admitted to a children's Hospital between Jan 2000 and Dec 2019 were included. All infants were divided into EOS and LOS groups, as well as MDR-KP and non-MDR-KP groups. Demographics, clinical characteristics, and risk factors were compared between the two groups. One hundred eighty infants (66 with EOS and 114 with LOS) were further analyzed, accounting for 36.8% of sepsis cases caused by MDR-KP. The frequency of respiratory failure, bronchopulmonary dysplasia, and intraventricular hemorrhage were more common in the LOS group and a higher rate of acute respiratory distress syndrome was more common in infants in the EOS group (P < 0.05). K. pneumoniae showed a low sensitivity to penicillin, beta-lactams and cephalosporins, and it showed a high sensitivity to levofloxacin, ciprofloxacin, and amikacin. Prematurity, low birth weight, longer antibiotic exposure time, long duration of peripheral catheter insertion, long mechanical ventilation time, and long parenteral nutrition time were associated with an increased rate of MDR-KP infection by univariate analysis (P < 0.05). The regression analysis identified a long antibiotic exposure time (OR = 1.37, 95% CI: 1.01-1.89) and long parenteral nutrition time (OR = 1.39, 95% CI: 1.01-1.89) as independent risk factors for a MDR-KP infection, and a greater gestational age and birth weight were associated with a lower risk of MDR-KP infection (OR = 0.57, 95% CI: 0.40-0.79). LOS caused by K. pneumoniae may lead to a higher frequency of complications. The risk factors for MDR-KP infection were longer duration of antibiotic exposure and parenteral nutrition. A greater gestational age and larger birth weight may decrease the risk of MDR-KP infection.

Growth restriction increases the risk of bronchopulmonary dysplasia, death, and sepsis in twins of 30 weeks or less of gestation. / Restricción de crecimiento aumenta el riesgo de displasia broncopulmonar, muerte y sepsis en gemelos de 30 o menos semanas de gestación.

INTRODUCTION: Multiple factors influence the risk of morbidity and mortality of premature infants with intrauterine growth restriction (IUGR). The comparison of twins with different intrauterine growth allows evaluating the effect of the restriction, excluding maternal factors and prenatal mana gement. Our objective was to assess the effect of IUGR on acute and chronic morbidity, and mortality of extreme preterm twins. PATIENTS AND METHOD: Twins weighing less than 1500 grams and gesta tion equal to or less than 30 weeks, of the Neocosur Network. Separate analyses were performed on concordant twin pairs, and on mild and severe discordant twins, evaluating the effect of IUGR on morbidity and mortality. A multivariate analysis was performed in order to establish the impact of this effect. RESULTS: 459 twin pairs, 227 concordant twins, 110 of mild discordance, and 122 of severe discordance. Among the concordant ones, there was only a difference in oxygen uptake at 36 weeks. In those of mild discordance, the smaller twin presented a lower frequency of hyaline membrane disease and required fewer doses of surfactant, but had a higher risk of bronchopulmonary dysplasia (BPD) or death. In severe discordant twins, the smaller one presented higher mortality, sepsis, use and permanence in mechanical ventilation, despite the lower frequency of hyaline membrane disease. In multiple regression analysis, the combined risk of BPD or death was higher in the smaller twin and of severe discordance. CONCLUSION: In discordant twins, the acute respiratory pathology was more frequent in the larger one, although the risk of BPD or death was higher in the one with IUGR.

Restricción de crecimiento aumenta el riesgo de displasia broncopulmonar, muerte y sepsis en gemelos de 30 o menos semanas de gestación / Growth restriction increases the risk of bronchopulmonary dysplasia, death, and sepsis in twins of 30 weeks or less of gestation

INTRODUCCIÓN: Múltiples factores influyen en el riesgo de morbimortalidad del prematuro con restricción del crecimiento intrauterino (RCIU). La comparación de gemelos con crecimiento intrauterino discordante permite evaluar su efecto, excluyendo factores maternos y manejo prenatal. Nuestro objetivo fue evaluar el efecto de la RCIU sobre la morbilidad aguda, crónica y mortalidad, en parejas de recién nacidos gemelares prematuros extremos. PACIENTES Y MÉTODO: Gemelos menores de 1500 g y 30 semanas de gestación, de la Red Neocosur. Se realizaron análisis separados de pares de gemelos concordantes, discordantes leves y severos, evaluando el efecto de la RCIU sobre morbi-mortalidad. Se realizó análisis multivariado para establecer magnitud del efecto. RESULTADOS: 459 pares de gemelos, 227 concordantes, 110 discordantes leves y 122 severos. Entre los concordantes solo hubo diferencia en uso de oxígeno a las 36 semanas. En discordantes leves, el menor tuvo menos enfermedad de membrana hialina y requirió menos dosis de surfactante, pero tuvo un mayor riesgo de Displasia broncopulmonar (DBP) o muerte. En discordantes severos, el menor presentó mayor mortalidad, sepsis, utilización y permanencia en ventilación mecánica, pese a menor frecuencia de enfermedad de membrana hialina. En regresión múltiple, el riesgo combinado de DBP o muerte fue mayor en gemelo menor y discordante severo. CONCLUSIÓN: En gemelos discordantes, la patología respiratoria aguda fue más frecuente en el gemelo mayor, aunque el riesgo de DBP o muerte fue mayor en el gemelo con RCIU.

INTRODUCTION: Multiple factors influence the risk of morbidity and mortality of premature infants with intrauterine growth restriction (IUGR). The comparison of twins with different intrauterine growth allows evaluating the effect of the restriction, excluding maternal factors and prenatal mana gement. Our objective was to assess the effect of IUGR on acute and chronic morbidity, and mortality of extreme preterm twins. PATIENTS AND METHOD: Twins weighing less than 1500 grams and gesta tion equal to or less than 30 weeks, of the Neocosur Network. Separate analyses were performed on concordant twin pairs, and on mild and severe discordant twins, evaluating the effect of IUGR on morbidity and mortality. A multivariate analysis was performed in order to establish the impact of this effect. RESULTS: 459 twin pairs, 227 concordant twins, 110 of mild discordance, and 122 of severe discordance. Among the concordant ones, there was only a difference in oxygen uptake at 36 weeks. In those of mild discordance, the smaller twin presented a lower frequency of hyaline membrane disease and required fewer doses of surfactant, but had a higher risk of bronchopulmonary dysplasia (BPD) or death. In severe discordant twins, the smaller one presented higher mortality, sepsis, use and permanence in mechanical ventilation, despite the lower frequency of hyaline membrane disease. In multiple regression analysis, the combined risk of BPD or death was higher in the smaller twin and of severe discordance. CONCLUSION: In discordant twins, the acute respiratory pathology was more frequent in the larger one, although the risk of BPD or death was higher in the one with IUGR.

Tratamiento antibiótico empírico inicial prolongado y riesgo de morbimortalidad en recién nacidos de muy bajo peso al nacer / Prolonged initial empirical antibiotic treatment and the risk of morbidity and mortality in very low birthweight infants

Resumen: Introducción: El objetivo de este estudio es evaluar la asociación entre la duración del tratamien to antibiótico empírico inicial y el desarrollo posterior de sepsis tardía, enterocolitis necrotizante (NEC) y muerte en recién nacidos de muy bajo peso al nacer (RNMBP). Pacientes y Método: Estudio cuantitativo, transversal analítico, en RNMBP ingresados a UCI neonatal durante un período de 5 años. Se consideró antibioterapia empírica inicial aquella que comenzó desde el nacimiento, sin conocer resultado de hemocultivos. Antibioterapia prolongada se estimó cuando la duración del tratamiento fue > 5 días. Se analizaron variables perinatales, e incidencia de sepsis tardía, NEC confirmada y mortalidad. Resultados: Se estudiaron un total de 266 RNMBP, con edad gestacional y peso de nacimiento promedios de 28,8 ± 2,5 semanas y 1.127 ± 264 g respec tivamente. Recibieron antibioterapia empírica inicial 213 (80,0%), siendo ésta prolongada en el 67,6%. Todos recibieron antibioterapia biasociada. Se pesquisaron 136 episodios de sepsis tardía, siendo los gérmenes más frecuentes el Staphylococcus coagulasa negativo y el Staphylococcus au reus. Del total de RN con antibioterapia empírica prolongada, hubo 20 casos de NEC confirmada y 15 fallecidos (10,4%) en el grupo analizado. Al comparar el uso de antibioterapia > 5 días ver sus tratamiento menor de 5 días, se observó una asociación estadísticamente significativa entre la antibioterapia prolongada y sepsis tardía (p = 0,03) y además de NEC confirmada (p = 0,03), pero no de mortalidad (p = 0,12). Conclusión: El uso de antibioterapia empírica inicial por 5 días o más se asoció a un riesgo aumentado de sepsis tardía y de NEC, pero no de la mortalidad en RNMBPN.

Abstract: Introduction: The objective of this study is to evaluate the association between the duration of ini tial empirical antibiotic treatment and the subsequent development of late-onset sepsis, necrotizing enterocolitis (NEC) and death in very low birth weight (VLBW) infants. Patients and Methods: Quantitative, cross-sectional, analytical study of VLBW infants admitted to the neonatal ICU were included over a period of five years. Initial empirical antibiotic therapy was that which started im mediately after birth, without knowing the results of blood cultures. It was considered prolonged antibiotic therapy when the treatment duration was > 5 days. Perinatal variables, as well as the inci dence of late-onset sepsis, confirmed NEC and mortality were analyzed. Results: 266 VLBW infants were studied, with an average gestational age and birth weight of 28.8 ± 2.5 weeks and 1.127 ± 264 g respectively. 213 infants received initial empiric antibiotic therapy (80.0%), which was prolonged in 67.6% of cases. All infants received two different antibiotics. 136 episodes of late-onset sepsis were described. The most common pathogens were coagulase-negative Staphylococcus and Staphylococcus aureus. Among the newborns with prolonged antibiotic therapy, there were 20 cases of confirmed NEC and 15 of the studied infants died (10.4%). When comparing the use of antibiotic therapy during > 5 days versus treatment less than 5 days duration, a statistically significant association was observed between prolonged antibiotic therapy and late-onset sepsis (p = 0.03) and confirmed NEC (p = 0.03), but not of mortality (p = 0.12). Conclusion: The use of empirical antibiotic therapy for five days or more was associated with an increased risk of late-onset sepsis and NEC, but not of mortality in VLBW infants.

Asociación de factores obstétricos y neonatales con casos de sepsis neonatal temprana. Cartagena, Colombia / Association of obstetric and neonatal factors with cases of early neonatal sepsis. Cartagena, Colombia

Introducción: La sepsis neonatal temprana es un problema de salud pública y es la principal causa de complicaciones y fallecimientos en las unidades de cuidado intensivo neonatales. Objetivo: Asociar factores de riesgo obstétrico y neonatal con la presencia de sepsis temprana en Cartagena (2014-2015). Material y Métodos: Se realizó un estudio retrospectivo de casos y control. La muestra son 183 casos y 366 controles, incluye pacientes que cumplan simultáneamente criterios de inclusión y exclusión. Se realizó análisis bivariado y se construyó modelo multivariado de regresión logística. Resultados: Entre las variables asociadas con sepsis temprana en las que se pudo definir el riesgo se encuentran la ruptura prematura de membrana >18 horas (OR 12,78 IC 95 por ciento 4,01-36,6), el riesgo de sepsis por parto vaginal (OR 2,69 IC 95 por ciento 1,58-4,57), el sexo masculino del recién nacido (OR 2,38 IC 95 por ciento1,38-4,08), y la prematuridad (OR 3,13 IC 95 por ciento 1,24-7,86) Conclusiones: En las madres con ruptura prematura de membranas y recién nacidos prematuros nacidos por vía vaginal es evidente una asociación causal con los casos de sepsis neonatal temprana(AU)

Introduction: Early neonatal sepsis is a public health problem and the leading cause of complications and deaths in neonatal intensive care units. Objective: To associate obstetric and neonatal risk factors with the presence of early sepsis in Cartagena (2014-2015). Material and Methods: Case Study and Retrospective Controls. The sample is composed of 183 cases and 366 controls, including patients who simultaneously meet inclusion and exclusion criteria. A bivariate analysis was performed and a logistic regression multivariate model was constructed. Results: Among the variables associated with early sepsis in which the risk could be defined, the following may be listed: premature rupture of membrane > 18 hours (OR 12.78 CI 95 percent 4.01-36.6), risk of sepsis due to vaginal childbirth (OR 2.69 95 percent CI 1.58-4.57), male newborn (OR 2.38 95 percent CI 1.38-4.08), and prematurity (OR 3.13 IC 95 percent 1.24-7.86). Conclusions: In mothers with premature rupture of membranes and vaginally born premature infants, a causal association with cases of early neonatal sepsis is evident(AU)

The cut-off levels of procalcitonin and C-reactive protein and the kinetics of mean platelet volume in preterm neonates with sepsis.

BACKGROUND: Sepsis is a leading cause of morbidity and mortality among newborns. C-reactive protein (CRP) and procalcitonin (PCT) have some limitations in the diagnosis of preterm neonatal sepsis. In this study, the cut-offs of PCT and CRP, and the efficacy of mean platelet volume (MPV) were investigated. METHODS: We identified key demographic details and compared laboratory values between preterm infants with early onset and late onset neonatal sepsis (EONS/LONS) retrospectively. Blood samples were collected within the first few hours of the onset of clinical sepsis (CRP 1, PCT 1, MPV 1) and were repeated after 24 h (CRP 2, PCT 2, MPV 2). The optimal cut-offs for CRP, PCT and MPV were determined using receiver operating characteristic (ROC) analysis. Furthermore, pairwise comparisons of ROC curves were made to evaluate the performances of these tests. RESULTS: In EONS, the cut-off of CRP 1 was 2.6 mg/L, the sensitivity, specificity, PPV and NPV were 80.6, 83.0, 67.5 and 90.7%, respectively (p < 0.001). At a PCT 1 cut-off of 1.1 ng/mL, the sensitivity, specificity, PPV and NPV were 78.6, 81.2, 64.7 and 89.6%, respectively (p < 0.001). The sensitivity, specificity, PPV, and NPV of the CRP 1 cut-off of 3.6 mg/L for LONS were 78.3, 87.4, 74.8, and 89.4%, respectively. At a PCT 1 cut-off of 5.2 ng/mL, the sensitivity, specificity, PPV and NPV were 58.5, 95.5, 86.1, and 82.9% respectively. For proven sepsis, the cut-off of CRP 1 was 7.0 mg/L with a 76.5% sensitivity, 98.2% specificity, 94.9% PPV and 90.5% NPV (p < 0.001). At a PCT 1 cut-off of 1.36 ng/mL, the sensitivity, specificity, PPV and NPV were 90.8, 83.4, 70.6 and 94.4%, respectively (p < 0.001). In each subgroup, other than EONS, the performances of CRP 1 and PCT 1 measurements were found to be statistically higher than MPV 1. CRP 2 cut-off levels of LONS group and proven sepsis group were found to be lower than the initial values. CONCLUSIONS: Optimal cut-off levels of CRP 1 and PCT 1 may differ in preterm sepsis subgroups. The diagnostic performances of CRP 1 and PCT 1 didn't differ however, they were more efficacious than MPV.

Sepse neonatal: mortalidade em município do sul do brasil, 2000 a 2013 / Neonatal sepsis: mortality in a municipality in southern brazil, 2000 to 2013

RESUMO Objetivo: Descrever o coeficiente de mortalidade neonatal por sepse e outras causas, além das características maternas, gestacionais, do parto, do recém-nascido e do óbito em Londrina, Paraná. Métodos: Estudo transversal e de séries temporais. Foram estudados óbitos neonatais que continham, em qualquer campo da declaração de óbito, registro de sepse neonatal, entre 2000 e 2013. Os anos foram agrupados em biênios e realizou-se cálculo do coeficiente de mortalidade neonatal e por causas específicas, segundo 10ª revisão da Classificação Internacional de Doenças (CID-10). Para a análise bivariada, considerou-se p<0,05, com cálculo da razão de prevalência e intervalo de confiança de 95% (IC95%). Resultados: Dos 745 óbitos, em 229 (30,7%) registrou-se sepse, com coeficiente de mortalidade neonatal de 7,5 óbitos por mil nascidos vivos (NVs), estando a sepse envolvida em 2,3 óbitos por mil NVs. As causas básicas da mortalidade neonatal foram afecções originadas no período perinatal e malformações congênitas. A sepse associou-se a pré-eclâmpsia, infecção do trato urinário, Apgar no 1º e 5º minutos e ocorrência de óbito tardio. Na análise descritiva de tendência, destacou-se o aumento na proporção de mães com 35 anos ou mais e com oito ou mais anos de estudo. A cobertura de pré-natal foi elevada, porém pouco mais da metade das mães realizou sete ou mais consultas. Conclusões: Nos 14 anos estudados, destacam-se o papel do pré-natal como ação preventiva dos agravos maternos e fetais e o aumento da idade e da escolaridade materna associados com a mortalidade neonatal.

ABSTRACT: Objective: To describe the neonatal mortality coefficient attributed to sepsis and other causes, and to report the maternal, neonatal and death characteristics of newborn infants that died in the city of Londrina, Paraná, in Southern Brazil. Methods: This is a cross-sectional study with a time series analysis. Neonatal deaths that contained neonatal sepsis records in any field of the death certificate between the years 2000 and 2013 were studied. The years were grouped into biennia, and cause specific neonatal mortality coefficient was calculated, according to the International Classification of Diseases, 10th revision. Results are expressed as prevalence ratio and 95% confidence interval (95CI%). For bivariate analysis, p<0.05 was considered significant. Results: Among the 745 deaths, 229 (30.7%) had sepsis, with a neonatal mortality coefficient of 7.5 per one thousand livebirths. Sepsis was involved in 2.3 deaths per 1,000 live births. The main underlying causes were conditions originated in the perinatal period and congenital malformations. Sepsis was associated with pre-eclampsia, urinary tract infection, Apgar in the 1st and 5th minutes, and occurrence of late death. In the descriptive trend analysis, there was an increased proportion of mothers aged 35 years or older and with eight or more schooling years. Prenatal coverage was high, but a little more than half of the mothers attended seven or more medical appointments. Conclusions: In the 14 years analyzed, the prenatal care was identified as a preventive measure against maternal and fetal disorders and the advanced maternal age was associated with neonatal mortality.

Utility of serum resistin in the diagnosis of neonatal sepsis and prediction of disease severity in term and late preterm infants.

Introduction Resistin is a proinflammatory hormone recently proposed as a sepsis biomarker. Our aim was to evaluate the diagnostic and prognostic values of this marker in neonatal sepsis. Methods This is a prospective observational study that includes 60 term and late preterm neonates with proven and possible sepsis besides 30 healthy controls. Resistin and other biomarkers, like C-reactive protein (CRP), were measured within 2 h of neonatal intensive care unit (NICU) admission. Infants were monitored and the primary outcome was 30-day mortality. Results Resistin was higher among septic neonates compared with controls (P<0.001). Resistin had an area under the receiver operating characteristic (ROC) curve of 0.994 for differentiating septic infants from controls. The area under the curve (AUC) for differentiating infants with culture-proven sepsis from controls was 0.999 compared with an AUC of 1 for CRP. The other markers, like platelet count, were inferior to resistin and CRP. Resistin was positively correlated with CRP [Spearman's correlation coefficient (rs)=0.55, P<0.001]. No significant differences in resistin levels were noted between survivors and non-survivors but resistin was higher among infants with severe sepsis (P=0.015) and among those who needed mechanical ventilation (P<0.001). Conclusion Resistin is useful for the diagnosis of neonatal sepsis. Resistin failed to predict mortality but was associated with indicators of disease severity.

Risk factors and clinical outcomes for carbapenem-resistant Gram-negative late-onset sepsis in a neonatal intensive care unit.

BACKGROUND: Carbapenem-resistant (CR), Gram-negative (GN), late-onset sepsis (LOS) is a serious threat in the neonatal intensive care unit (NICU). AIM: To assess the prevalence of CR-GN-LOS in NICU patients and to identify the risk factors and outcomes associated with its acquisition. METHODS: Neonates with carbapenem-susceptible (CS)-GN-LOS were compared with those with CR-GN-LOS in a two-year observational study. FINDINGS: A total of 158 patients had GN-LOS; 100 infants had CS-GN-LOS and 58 infants had CR-GN-LOS. The incidence rate of CR-GN-LOS was 6.5 cases per 1000 patient-days. The most frequent bacterial strain in both groups was Klebsiella pneumoniae. The duration of total parenteral nutrition (TPN) (P=0.006) and prior carbapenem use (P=0.01) were independent risk factors for CR-GN-LOS acquisition. CR-GN-LOS was associated with higher mortality than CS-GN-LOS (P=0.04). Birth weight, small for gestational age, time to start enteral feeding, exclusive formula feeding, previous surgery, previous antifungal use, central venous device before onset, duration of central venous device, and infectious complications were identified as dependent risk factors for overall mortality. However, only male gender (P=0.04) and infectious complications (P < 0.001) were independent risk factors associated with mortality. Infectious complication rates, duration of mechanical ventilation, and length of hospital stay were significantly higher in infants with CR compared to CS-GN-LOS. CONCLUSION: The duration of TPN and carbapenem use were the independent predictors for CR-GN-LOS acquisition. CR-GN-LOS is associated with higher mortality, infectious complication rates, longer mechanical ventilation, and longer hospital stay. Male gender and infectious complications were the independent risk factors for mortality in neonates with GN-LOS.