Comparative Safety of Multiple Doses of Erythropoietin for the Treatment of Traumatic Brain Injury: A Systematic Review and Network Meta-Analysis

Background: Although many studies have shown that erythropoietin plays an important role in the prognosis of traumatic brain injury (TBI) patients, the effective dose of erythropoietin has not been clearly defined. Our aim was to systematically elucidate the safety and efficacy of erythropoietin administration regimens in TBI patients. Methods: : Data search included PubMed, the Cochrane Library, EMBASE and ClinicalTrials.gov for articles published before December, 2020, updated to June 2021. Network meta-analysis was performed when sufficient comparable evidence was available, and CINeMA tool was used to evaluated the quality of our evidence. Results: : A total of 6 RCTs involving 981 patients were included in the network meta-analysis. All studies assessed the effect of erythropoietin on mortality. Erythropoietin reduced the mortality rate in patients with TBI, and the risk of death decreased with increasing dose, but the difference was not statistically significant (odd ratio of 12,000u vs Placebo=0.98, 95%CI, 0.03-40.34; odd ratio of group 30,000u vs Placebo=0.56, 95%CI, 0.06-5.88; odd ratio of 40,000u vs Placebo=0.35, 95%CI, 0.01-9.43; odd ratio of 70,000u vs Placebo=0.29, 95%CI, 0.01-9.26; odd ratio of group 80,000u vs Placebo=0.22, 95%CI, 0.00-7.45). Three studies involving 739 patients showed that erythropoietin did not increase the incidence of deep vein thrombosis in patients with TBI. However, the risk tended to rise as the dose increases. Two studies demonstrated that erythropoietin did not increase the incidence of pulmonary embolism. The evidential quality of all the results of the evidence ranged from low to medium. Conclusion: Although the efficacy of erythropoietin was not statistically demonstrated, we found a trend in the association of erythropoietin dose with reduced mortality and increased embolic events in TBI patients. We are looking forward to more high-quality original studies focusing on the dose and timing of erythropoietin for the treatment of TBI, in order to obtain stronger evidence on the optimal erythropoietin dose.Study Registration: PROSPERO (CRD42021272500).