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      Comparative safety of multiple doses of erythropoietin for the treatment of traumatic brain injury: A systematic review and network meta-analysis


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          Over the past few decades, advances in traumatic brain injury (TBI) pathology research have dynamically enriched our knowledge. Therefore, we aimed to systematically elucidate the safety and efficacy of erythropoietin (EPO) dosing regimens in patients with TBI.


          Data search included PubMed, the Cochrane Library, Embase, Web of Science, and ClinicalTrials.gov for related research published before July 2022. The network meta-analysis was conducted using ADDIS 1.16.8, and the CINeMA tool was used to assess the quality level of evidence.


          A total of six RCTs involving 981 patients were included in the network meta-analysis. EPO did not significantly reduce mortality in patients with TBI, but its risk of death decreased with increasing dosage (odds ratio (OR) of 12,000u vs. placebo = 0.98, 95% CI: 0.03–40.34; OR of group 30,000u vs. placebo = 0.56, 95% CI: 0.06–5.88; OR of 40,000u vs. placebo = 0.35, 95% CI: 0.01–9.43; OR of 70,000u vs. placebo = 0.29, 95% CI: 0.01–9.26; OR of group 80,000u vs. placebo = 0.22, 95% CI: 0.00–7.45). A total of three studies involving 739 patients showed that EPO did not increase the incidence of deep vein thrombosis in patients with TBI. However, the risk tended to rise as the dosage increased. Another two studies demonstrated that EPO did not increase the incidence of pulmonary embolism. The quality of evidence for all outcomes was low to moderate.


          Although the efficacy of EPO was not statistically demonstrated, we found a trend toward an association between EPO dosage and reduced mortality and increased embolic events in patients with TBI. More high-quality original studies should be conducted to obtain strong evidence on the optimal dosage of EPO.

          Systematic review registration

          https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=272500. The study protocol was registered with PROSPERO (CRD42021272500).

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          Most cited references28

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          Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.

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            PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews

            The methods and results of systematic reviews should be reported in sufficient detail to allow users to assess the trustworthiness and applicability of the review findings. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement was developed to facilitate transparent and complete reporting of systematic reviews and has been updated (to PRISMA 2020) to reflect recent advances in systematic review methodology and terminology. Here, we present the explanation and elaboration paper for PRISMA 2020, where we explain why reporting of each item is recommended, present bullet points that detail the reporting recommendations, and present examples from published reviews. We hope that changes to the content and structure of PRISMA 2020 will facilitate uptake of the guideline and lead to more transparent, complete, and accurate reporting of systematic reviews.
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              GRADE guidelines: 3. Rating the quality of evidence.

              This article introduces the approach of GRADE to rating quality of evidence. GRADE specifies four categories-high, moderate, low, and very low-that are applied to a body of evidence, not to individual studies. In the context of a systematic review, quality reflects our confidence that the estimates of the effect are correct. In the context of recommendations, quality reflects our confidence that the effect estimates are adequate to support a particular recommendation. Randomized trials begin as high-quality evidence, observational studies as low quality. "Quality" as used in GRADE means more than risk of bias and so may also be compromised by imprecision, inconsistency, indirectness of study results, and publication bias. In addition, several factors can increase our confidence in an estimate of effect. GRADE provides a systematic approach for considering and reporting each of these factors. GRADE separates the process of assessing quality of evidence from the process of making recommendations. Judgments about the strength of a recommendation depend on more than just the quality of evidence. Copyright © 2011 Elsevier Inc. All rights reserved.

                Author and article information

                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                13 December 2022
                : 13
                : 998320
                [1] 1School of Public Health, Lanzhou University, Lanzhou , Gansu, China
                [2] 2Evidence-Based Nursing Center, School of Nursing, Lanzhou University, Lanzhou , Gansu, China
                [3] 3Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou , Gansu, China
                [4] 4The First Clinical Medical College of Lanzhou University, Lanzhou , Gansu, China
                [5] 5Department of Rehabilitation, The First Hospital of Lanzhou University, Lanzhou , Gansu, China
                [6] 6The Second Clinical Medical College of Lanzhou University, Lanzhou , Gansu, China
                Author notes

                Edited by: Andres M. Rubiano, El Bosque University, Colombia

                Reviewed by: Kejia Hu, Massachusetts General Hospital and Harvard Medical School, United States; Giovanni Grasso, University of Palermo, Italy

                *Correspondence: Xiaofeng Luo luoxiaof@ 123456lzu.edu.cn

                This article was submitted to Neurotrauma, a section of the journal Frontiers in Neurology

                Copyright © 2022 Zheng, Duan, Xu, Wang, Ge, Xiong, Yang, Wulayin and Luo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 19 July 2022
                : 21 November 2022
                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 28, Pages: 10, Words: 5359
                Systematic Review

                erythropoietin,traumatic brain injury,optimal dose,safety,systematic review,network meta-analysis


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