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

      review-article
      1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 1 , 3 , 4 , 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 25 , 26 , 27 , 28 , 29 , 30 , 1 , 3 , 4 , 31 , 32 , , On behalf of the Infection, Inflammation, Immunology and Immunisation (I4) section of the European Society for Paediatric Research (ESPR)
      Pediatric Research
      Nature Publishing Group US

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          Abstract

          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.

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          Most cited references127

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration

            Systematic reviews and meta-analyses are essential to summarise evidence relating to efficacy and safety of healthcare interventions accurately and reliably. The clarity and transparency of these reports, however, are not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (quality of reporting of meta-analysis) statement—a reporting guideline published in 1999—there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realising these issues, an international group that included experienced authors and methodologists developed PRISMA (preferred reporting items for systematic reviews and meta-analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this explanation and elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA statement, this document, and the associated website (www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.
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              Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network.

              Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients. Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28. The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [+/-SD], 12+/-11 vs. 10+/-11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight (P<0.001), respectively, and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water (P<0.001), respectively. In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.
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                Author and article information

                Contributors
                Eleanor.molloy@tcd.ie
                Journal
                Pediatr Res
                Pediatr Res
                Pediatric Research
                Nature Publishing Group US (New York )
                0031-3998
                1530-0447
                7 January 2022
                7 January 2022
                2022
                : 91
                : 4
                : 735-742
                Affiliations
                [1 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, Discipline of Paediatrics, Trinity College Dublin, , The University of Dublin & Children’s Hospital Ireland (CHI) at Tallaght, ; Dublin, Ireland
                [2 ]GRID grid.416409.e, ISNI 0000 0004 0617 8280, John Stearne Medical Library, Trinity College Dublin, , St. James’ Hospital, ; Dublin, Ireland
                [3 ]GRID grid.416409.e, ISNI 0000 0004 0617 8280, Trinity Translational Medicine Institute, , St. James Hospital, ; Dublin, Ireland
                [4 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, Trinity Research in Childhood Centre (TRiCC), , Trinity College Dublin, ; Dublin, Ireland
                [5 ]GRID grid.412244.5, ISNI 0000 0004 4689 5540, Department of Pediatrics and Adolescence Medicine, , University Hospital of North Norway, ; Tromsø, Norway
                [6 ]GRID grid.10919.30, ISNI 0000000122595234, Paediatric Research Group, Faculty of Health Sciences, , UiT-The Arctic University of Norway, ; Tromsø, Norway
                [7 ]GRID grid.11201.33, ISNI 0000 0001 2219 0747, School of Nursing and Midwifery, Faculty of Health, , University of Plymouth, ; Plymouth, UK
                [8 ]GRID grid.417100.3, ISNI 0000 0004 0620 3132, Division of Woman and Baby, Department of Neonatology, , Wilhelmina Children’s Hospital (part of UMC Utrecht) and University of Utrecht, ; Utrecht, The Netherlands
                [9 ]GRID grid.414659.b, ISNI 0000 0000 8828 1230, Neonatal Health and Development, , Telethon Kids Institute, ; Perth, WA Australia
                [10 ]GRID grid.415259.e, ISNI 0000 0004 0625 8678, Neonatal Directorate, , King Edward Memorial Hospital for Women, ; Perth, WA Australia
                [11 ]GRID grid.8515.9, ISNI 0000 0001 0423 4662, Clinic of Neonatology, Department Mother-Woman-Child, , Lausanne University Hospital and University of Lausanne, ; Lausanne, Switzerland
                [12 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Paediatric Critical Care Research Group, Child Health Research Centre, , University of Queensland, ; Brisbane, QLD Australia
                [13 ]GRID grid.240562.7, Paediatric Intensive Care Unit, , Queensland Children’s Hospital, ; Brisbane, QLD Australia
                [14 ]GRID grid.5734.5, ISNI 0000 0001 0726 5157, Department of Pediatrics, Bern University Hospital, , University of Bern, ; Bern, Switzerland
                [15 ]GRID grid.78028.35, ISNI 0000 0000 9559 0613, Department of Neonatology, , Pirogov Russian National Research Medical University, ; Moscow, Russia
                [16 ]GRID grid.413202.6, ISNI 0000 0004 0626 2490, Department of Paediatrics, , Tergooi Hospital, ; Blaricum, The Netherlands
                [17 ]GRID grid.7177.6, ISNI 0000000084992262, Department of Paediatrics, Amsterdam UMC, Emma Children’s Hospital, , University of Amsterdam, ; Amsterdam, The Netherlands
                [18 ]GRID grid.461578.9, Department of Neonatology, Radboud Institute for Health Sciences, Radboud University Medical Center, , Amalia Children’s Hospital, ; Nijmegen, The Netherlands
                [19 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Karolinska University Hospital and Karolinska Institutet, ; Stockholm, Sweden
                [20 ]GRID grid.15276.37, ISNI 0000 0004 1936 8091, Department of Paediatrics, , University of Florida, ; Gainesville, FL USA
                [21 ]GRID grid.15276.37, ISNI 0000 0004 1936 8091, Department of Pathology, Immunology, and Laboratory Medicine, , University of Florida, ; Gainesville, FY USA
                [22 ]GRID grid.411984.1, ISNI 0000 0001 0482 5331, Department of Neonatology, Clinic for Paediatric Cardiology, Intensive Care and Neonatology, , University Medical Centre Göttingen, ; Göttingen, Germany
                [23 ]GRID grid.412826.b, ISNI 0000 0004 0611 0905, Neonatal Unit, Department of Obstetrics and Gynecology, , Motol University Hospital and Second Faculty of Medicine, ; Prague, Czech Republic
                [24 ]GRID grid.4491.8, ISNI 0000 0004 1937 116X, Institute of Pathological Physiology, First Faculty of Medicine, , Charles University, ; Prague, Czech Republic
                [25 ]GRID grid.416135.4, ISNI 0000 0004 0649 0805, Department of Pediatrics, Division of Neonatology, , Erasmus MC-Sophia Children’s Hospital, ; Rotterdam, The Netherlands
                [26 ]GRID grid.40263.33, ISNI 0000 0004 1936 9094, Department of Pediatrics, Women & Infants Hospital of Rhode Island, , Alpert Medical School of Brown University, ; Providence, RI USA
                [27 ]GRID grid.239585.0, ISNI 0000 0001 2285 2675, Division of Neonatal-Perinatal Medicine, Department of Pediatrics, , Columbia University Medical Center, ; New York City, NY USA
                [28 ]GRID grid.262962.b, ISNI 0000 0004 1936 9342, Division of Neonatology, Edward Doisy Research Center, , Saint Louis University, ; St. Louis, MO USA
                [29 ]GRID grid.415996.6, ISNI 0000 0004 0400 683X, Institute of Translational Medicine, University of Liverpool, Centre for Women’s Health Research, , Liverpool Women’s Hospital, ; Liverpool, UK
                [30 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Department of Neonatal Medicine, School of Public Health, Faculty of Medicine, , Imperial College London, ; Chelsea and Westminster Campus, London, UK
                [31 ]GRID grid.411886.2, ISNI 0000 0004 0488 4333, Department of Paediatrics, , Coombe Women’s and Infant’s University Hospital, ; Dublin, Ireland
                [32 ]Department of Neonatology, CHI at Crumlin, Dublin, Ireland
                Article
                1883
                10.1038/s41390-021-01883-y
                9064797
                34997225
                b396b59d-049f-41da-a9aa-b32ad0aee5da
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 23 July 2021
                : 23 October 2021
                : 28 October 2021
                Categories
                Systematic Review
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                © International Pediatric Research Foundation, Inc 2022

                Pediatrics
                Pediatrics

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