Advertisement

Efficacy and safety of erythropoietin in patients with traumatic brain injury: A systematic review and meta-analysis

Published:August 29, 2018DOI:https://doi.org/10.1016/j.ajem.2018.08.072

      Abstract

      Objective

      The purpose of this study was to evaluate the effects of erythropoietin (EPO) on mortality and neurological outcomes in patients with traumatic brain injury (TBI).

      Materials and methods

      Electronic databases of studies published up to January 5, 2017 were searched to retrieve relevant investigations comparing the outcomes of EPO-treated patients and untreated patients following TBI. We calculated the relative risk (RR) of mortality, neurologic outcomes, and deep vein thrombosis (DVT) with corresponding 95% confidence interval (CI) using meta-analysis.

      Results

      Six randomized controlled clinical trials met the eligibility criteria. In total, 1041 patients were included among the studies. EPO was found to significantly reduce the occurrence of mortality (RR 0.68 [95% CI 0.50–0.95]; P = 0.02), but did not significantly reduce poor functional outcome (RR 1.22 [95% CI 0.82–1.81]; P = 0.33). There were no significant differences in the occurrence of complications, such as DVT, between the treatment groups (RR −0.02 [95% CI −0.06–0.02]; P = 0.81).

      Conclusions

      Results of the present meta-analysis suggest that the use of EPO may prevent death following TBI without causing adverse events, such as deep vein thrombosis. However, the role of EPO in improving neurological outcome(s) remains unclear. Further well-designed, randomized controlled trials using modified protocols and involving specific patient populations are required to clarify this issue, and to verify the findings.

      Abbreviations:

      EPO (erythropoietin), TBI (traumatic brain injury), DVT (deep vein thrombosis), CI (confidence interval), RR (relative risk), RCT (randomized controlled trial), GCS (Glasgow Coma Scale), GOS (Glasgow Outcome Scale)

      Keywords

      To read this article in full you will need to make a payment
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Emergency Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hyder A.A.
        • Wunderlich C.A.
        • Puvanachandra P.
        • Gururaj G.
        • Kobusingye O.C.
        The impact of traumatic brain injuries: a global perspective.
        NeuroRehabilitation. 2017; 22: 341-353
        • Myburgh J.A.
        • Cooper D.J.
        • Finfer S.R.
        • Venkatesh B.
        • Jones D.
        • Higgins A.
        • et al.
        Epidemiology and 12-month outcomes from traumatic brain injury in Australia and New Zealand.
        J Trauma Acute Care Surg. 2008; 64: 854-862
        • Bramlett H.M.
        • Dietrich W.D.
        Pathophysiology of cerebral ischemia and brain trauma: similarities and differences.
        J Cereb Blood Flow Metab. 2004; 24: 133-150
        • Narayan R.K.
        • Maas A.I.
        • Servadei F.
        • Skolnick B.E.
        • Tillinger M.N.
        • Marshall L.F.
        Progression of traumatic intracerebral hemorrhage: a prospective observational study.
        J Neurotrauma. 2008; 25: 629-639
        • Donnelly S.
        Why is erythropoietin made in the kidney? The kidney functions as a critmeter.
        Am J Kidney Dis. 2001; 38: 415-425
        • Depping R.
        • Kawakami K.
        • Ocker H.
        • Wagner J.M.
        • Heringlake M.
        • Noetzold A.
        • et al.
        Expression of the erythropoietin receptor in human heart.
        J Thorac Cardiovasc Surg. 2005; 130: e1-e4
        • Moon C.
        • Krawczyk M.
        • Ahn D.
        • Ahmet I.
        • Paik D.
        • Lakatta E.G.
        • et al.
        Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats.
        Proc Natl Acad Sci U S A. 2003; 100: 11612-11617
        • Jelkmann W.
        Erythropoietin after a century of research: younger than ever.
        Eur J Haematol. 2007; 78: 183-205
        • Lykissas M.G.
        • Korompilias A.V.
        • Vekris M.D.
        • Mitsionis G.I.
        • Sakellariou E.
        • Beris A.E.
        The role of erythropoietin in central and peripheral nerve injury.
        Clin Neurol Neurosurg. 2007; 109: 639-644
        • Sirén A.-L.
        • Fratelli M.
        • Brines M.
        • Goemans C.
        • Casagrande S.
        • Lewczuk P.
        • et al.
        Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress.
        Proc Natl Acad Sci U S A. 2001; 98: 4044-4049
        • Villa P.
        • Bigini P.
        • Mennini T.
        • Agnello D.
        • Laragione T.
        • Cagnotto A.
        • et al.
        Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis.
        J Exp Med. 2003; 198: 971-975
        • Nichol A.
        • French C.
        • Little L.
        • Haddad S.
        • Presneill J.
        • Arabi Y.
        • et al.
        Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial.
        Lancet. 2015; 386: 2499-2506
        • Robertson C.S.
        • Hannay H.J.
        • Yamal J.-M.
        • Gopinath S.
        • Goodman J.C.
        • Tilley B.C.
        • et al.
        Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial.
        JAMA. 2014; 312: 36-47
        • Nirula R.
        • Diaz-Arrastia R.
        • Brasel K.
        • Weigelt J.A.
        • Waxman K.
        Safety and efficacy of erythropoietin in traumatic brain injury patients: a pilot randomized trial.
        Crit Care Res Pract. 2010; (PubMed PMID: 20948886; PubMed Central PMCID: PMCPMC2951080)https://doi.org/10.1155/2010/209848
        • Abrishamkar S.
        • Safavi M.R.
        • Honarmand A.
        Effect of erythropoietin on Glasgow Coma Scale and Glasgow Outcome Scale in patient with diffuse axonal injury.
        J Res Med Sci. 2012; 17: 51-56
        • Li Z.-m.
        • Y-L Xiao
        • J-X Zhu
        • F-Y Geng
        • C-J Guo
        • Z-L Chong
        • et al.
        Recombinant human erythropoietin improves functional recovery in patients with severe traumatic brain injury: a randomized, double blind and controlled clinical trial.
        Clin Neurol Neurosurg. 2016; 150: 80-83
        • Aloizos S.
        • Evodia E.
        • Gourgiotis S.
        • Isaia E.C.
        • Seretis C.
        • Baltopoulos G.J.
        Neuroprotective effects of erythropoietin in patients with severe closed brain injury.
        Turk Neurosurg. 2015; 25: 552-558
        • Talving P.
        • Lustenberger T.
        • Inaba K.
        • Lam L.
        • Mohseni S.
        • Chan L.
        • et al.
        Erythropoiesis-stimulating agent administration and survival after severe traumatic brain injury: a prospective study.
        Arch Surg. 2012; 147: 251-255
        • Liu W.C.
        • Wen L.
        • Xie T.
        • Wang H.
        • Gong J.B.
        • Yang X.F.
        Therapeutic effect of erythropoietin in patients with traumatic brain injury: a meta-analysis of randomized controlled trials.
        J Neurosurg. 2016; : 1-8
        • Higgins J.P.
        • Green S.
        Cochrane handbook for systematic reviews of interventions.
        John Wiley & Sons, West Sussex2011
        • Dersimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Contemp Clin Trials. 1986; 7: 177-188
        • Higgins J.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Coleman T.
        • Brines M.
        Science review: recombinant human erythropoietin in critical illness: a role beyond anemia?.
        Crit Care. 2004; 8: 337-341
        • Brines M.L.
        • Ghezzi P.
        • Keenan S.
        • Agnello D.
        • De Lanerolle N.C.
        • Cerami C.
        • et al.
        Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury.
        Proc Natl Acad Sci U S A. 2000; 97: 10526-10531
        • Lu D.
        • Mahmood A.
        • Qu C.
        • Goussev A.
        • Schallert T.
        • Chopp M.
        Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury.
        J Neurotrauma. 2005; 22: 1011-1017
        • Shein NaA
        • Horowitz M.
        • Alexandrovich A.G.
        • Tsenter J.
        • Shohami E.
        Heat acclimation increases hypoxia-inducible factor 1α and erythropoietin receptor expression: implication for neuroprotection after closed head injury in mice.
        J Cereb Blood Flow Metab. 2005; 25: 1456-1465
        • Sirén A.-L.
        • Radyushkin K.
        • Boretius S.
        • Kämmer D.
        • Riechers C.-C.
        • Natt O.
        • et al.
        Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin.
        Brain. 2006; 129: 480-489
        • Kumral A.
        • Uysal N.
        • Tugyan K.
        • Sonmez A.
        • Yilmaz O.
        • Gokmen N.
        • et al.
        Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia–ischemia in rats.
        Behav Brain Res. 2004; 153: 77-86
        • Genc S.
        • Akhisaroglu M.
        • Kuralay F.
        • Genc K.
        Erythropoietin restores glutathione peroxidase activity in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced neurotoxicity in C57BL mice and stimulates murine astroglial glutathione peroxidase production in vitro.
        Neurosci Lett. 2002; : 73-76
        • Sun Y.
        • Calvert J.W.
        • Zhang J.H.
        Neonatal hypoxia/ischemia is associated with decreased inflammatory mediators after erythropoietin administration.
        Stroke. 2005; 36: 1672-1678
        • Puetz V.
        • Campos C.R.
        • Eliasziw M.
        • Hill M.D.
        • Demchuk A.M.
        Assessing the benefits of hemicraniectomy: what is a favourable outcome?.
        Lancet Neurol. 2007; 6: 580