Introduction: Necrotizing enterocolitis is an acute inflammatory disease of the intestine that can lead to necrosis and bowel perforation. It is a severe complication of preterm birth. It’s mortality rate is up to 50% and survival after necrotizing enterocolitis leads to long-term complications. The current treatment is supportive and includes bowel rest and decompression and antibiotics. Thus, new treatments are necessary to reduce mortality and morbidity. Mesenchymal stromal cells are known to have anti-inflammatory properties and might be a promising option for treatment. Here we present a protocol for a systematic review with the aim to explore the efficacy of cell therapies with mesenchymal stromal cells in animal models of necrotizing enterocolitis. The primary outcome is histological signs of necrotizing enterocolitis. Additional outcomes include survival, bowel perforation, gut permeability, gut motility, levels of inflammatory markers, cytokine levels and adverse events. Methods: We will conduct a systematic search of MEDLINE, Embase, and Web of Science databases. The retrieved records will be screened individually by two investigators. We will include all preclinical in vivo animal models of experimentally induced necrotizing enterocolitis that evaluate the efficacy of mesenchymal stromal cells or other cell therapy treatments. Outcome data will be extracted from each article and risk of bias assessment performed. Funnel plots and SYRCLE’s risk of bias tool for animal studies will be used. Data will be reported as ratios, divided in predefined subgroups where relevant. Conclusions: This systematic review aims to examine the efficacy of mesenchymal stromal cells in preclinical models of necrotizing enterocolitis and whether there is sufficient evidence to support a clinical trial of efficacy and safety of the treatment with mesenchymal stromal cells in infants with necrotizing enterocolitis.

BackgroundNecrotizing enterocolitis is an acute inflammatory disease of the intestine that can lead to necrosis and bowel perforation. It is a severe complication of preterm birth with a prevalence of 7% in infants with a birth weight less than 1500 grams. It’s mortality rate is up to 30% and survival after necrotizing enterocolitis leads to long-term gastrointestinal and neurocognitive consequences. The current treatment is supportive and includes bowel rest and decompression and antibiotics. Thus, new treatments are necessary to reduce mortality and morbidity. Mesenchymal stromal cells are known to have anti-inflammatory properties and might be a promising option for treatment. Here we present a protocol for a systematic review with the aim to explore the efficacy of cell therapies with mesenchymal stromal cells in animal models of necrotizing enterocolitis. The primary outcome is histological signs of necrotizing enterocolitis. Additional outcomes include survival, bowel perforation, gut permeability, gut motility, levels of inflammatory markers, cytokine levels and adverse events.MethodsWe will conduct a systematic search of MEDLINE, Embase, and Web of Science databases. The retrieved records will be screened individually by two investigators. We will include all preclinical in vivo animal models of experimentally induced NEC that evaluate the efficacy of mesenchymal stromal cells or other cell therapy treatments. Outcome data will be extracted from each article and risk of bias assessment performed. Funnel plots and SYRCLE’s risk of bias tool for animal studies will be used. Data will be reported as ratios, divided in predefined subgroups where relevant. DiscussionThis systematic review aims to examine the efficacy of mesenchymal stromal cells in preclinical models of necrotizing enterocolitis and whether there is sufficient evidence to support a clinical trial of efficacy and safety of the treatment with mesenchymal stromal cells in infants with necrotizing enterocolitis.Systematic review registrationThis protocol has been registered on Open Science framework: osf.io/5rc6t

Background Glucocorticoids are widely used in the pediatric population. They are associated with numerous side effects including repercussions on the cardiovascular system. The impact on heart rate is not well known, but bradycardia has been reported, mostly with high doses. Objectives We described the occurrence of bradycardias and the variation of heart rate in critically ill children receiving glucocorticoids. Design/Methods We conducted a retrospective study including 1 month old to 18 year old children admitted to the Pediatric Intensive Care Unit between 2014 and 2017, who received a glucocorticoid dose equivalent to 1 to 15 mg/kg/day of prednisone. We collected data on exposition to glucocorticoids, heart rate before, during and after the exposition, and interventions from the medical staff in response to bradycardia. The primary outcome was the occurrence of bradycardia and the secondary outcomes were the magnitude of heart rate variation and the clinical management of bradycardias. Results We included 92 admissions (85 patients). The median dose of glucocorticoid used was 2.80 mg/kg/day of prednisone (2.08—3.80). We found 70 cases (76%) with at least one bradycardia. Before treatment, all patients had a mean heart rate higher than the 5th percentile for age. During exposition to glucocorticoids, 8 patients (10%, n = 83) had a median heart rate ≤ 5th percentile. We noted 46 cases of bradycardia (50%) that led to an intervention from the medical staff, but no patient had a major event associated to bradycardia. We found a significant association between bradycardia and age (estimate -0.136, 95% CI -0.207—-0.065, p < 0.001), glucocorticoid dose (estimate 4.820, 95% CI 2.048—7.592, p < 0.001) and intravenous administration (estimate 8.709, 95% CI 1.893—15.524, p = 0.012). Conclusion In our study, most children hospitalized at the intensive care unit receiving standard doses of glucocorticoid experienced bradycardia. The majority of episodes led to an intervention from the medical staff. Presence of bradycardia was associated with younger age, higher dose and IV administration of glucocorticoids.

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