Letter to the Editor Erythropoietin in Traumatic Brain Injury: An Answer Will Come Soon LETTER: brain injury (TBI) is a major cause of morbidity and T raumatic mortality in the United States. It is estimated that each year
TBIs are associated with 1.1 million emergency department visits, 235,000 hospitalizations, and 50,000 deaths (1). Despite improvements in medical interventions, there are still no neuroprotective agents available to counteract secondary or delayed damage to the traumatically injured human brain or to promote its repair. TBI encompasses heterogeneous etiologic, anatomical, and molecular patterns of injury that exhibit different propensities to cause cerebral damage. Without careful consideration of individual injuries, the results of therapeutic trials remain difficult to interpret. In preclinical studies, erythropoietin (EPO) has shown to protect against neurologic injury in several experimental models both in vitro and in vivo (3). Human EPO is the main regulator of erythropoiesis, and its recombinant form has greatly improved the management of anemia resulting from chronic renal failure and has substantially improved quality of life in patients undergoing dialysis. The detection of EPO and its receptor in the brain and other organs has stimulated the search for other biological roles of these proteins. Now we know that EPO has cytoprotective effects on endothelial cells, glial cells, and neurons. It is antiapoptotic, antioxidative, and anti-inflammatory (5) and also has angiogenic and neurogenic effects (6).
To date, some clinical trials have been concluded, with investigators discovering the uncertain efficacy of EPO as neuroprotectant (2, 9, 10). Recently, Robertson et al. (8) conducted a randomized clinical trial of 200 patients with TBI who were enrolled within 6 hours of injury to test the effect of 2 approaches, transfusion threshold and EPO therapy, on neurologic outcome. The authors found that neither the administration of EPO nor maintaining a hemoglobin concentration of at least 10 g/dL resulted in improved neurologic outcome in patients at 6 months. It has been suggested that these inconclusive findings also would reflect a substantial lack of statistical power of the study. It should be considered, however, that most of the favorable data accumulated on EPO effects come from preclinical studies. Although experimental studies represent a basic premise for future clinical investigations, important issues still need to be addressed, for instance, the safety of recombinant human EPO administration in the setting of brain injury in humans. It must be taken into account that all the information available regarding the safety of EPO administration comes from its non-neurologic use. The logical extension of these arguments is that translating such information from anemic recombinant human EPO-treated to TBI-affected patients can be misleading, because the interaction and influence between EPO and different physiologic variables, as well as with common drugs used in patients with TBI, are unknown.
WORLD NEUROSURGERY 84 [5]: 1491e1492, NOVEMBER 2015
Also, although EPO is usually a well-tolerated drug, several lines of evidence have shown that therapy with recombinant EPO can result in hypertension, hypertensive encephalopathy, seizures, and thrombotic/vascular events. Although in pioneering clinical studies, we did not report adverse effects during treatment with EPO, these findings should be cautionary. In this regard, we have provided evidence that recombinant human EPO treatment at a dose of 1000 IU/kg, administered every 8 hours, is effective providing neuroprotection after TBI (4). The dose used in the study by Robertson et al. (8) is the lowest dose known to be effective in the experimental settings. It can be argued that the unfavorable results from this clinical trial can be related to the small dose used and frequency of administration. Furthermore, the investigators changed the dosing of the EPO regimen mid-study. This change to a less-efficacious regimen further limited the authors’ ability to detect effects. Large pragmatic, international, multicenter trials are required to resolve such uncertainty, especially when the plausible absolute difference in outcome is likely to be small. The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial is a stratified prospective, multicenter, randomized, blinded, parallel-group, placebocontrolled phase 3 trial (7). It aims to determine whether the administration of EPO compared with placebo improves neurologic outcomes in patients with moderate or severe TBI at 6 months after injury. The trial is designed to recruit 606 patients between 15 and 65 years of age with severe or moderate TBI and uses a subcutaneous EPO regimen. When completed, the trial aims to provide evidence on the efficacy and safety of EPO in TBI. Hopefully, it will clarify optimal tolerated dosages, therapeutic time window, and duration of therapy. Giovanni Grasso1, Concetta Alafaci2, Michele Buemi3 From the 1Section of Neurosurgery, Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo, Palermo, Italy; 2Department of Neurosurgery, University of Messina, Messina, Italy; and 3Department of Internal Medicine, University of Messina, Messina, Italy To whom correspondence should be addressed: Giovanni Grasso, M.D., Ph.D. [E-mail: [email protected]] Published online 5 June 2015; http://dx.doi.org/10.1016/j.wneu.2015.05.056.
REFERENCES 1. Centers for Disease Control and Prevention: Rates of hospitalization related to traumatic brain injury-nine states, 2003. MMWR Morb Mortal Wkly Rep 56: 167-170, 2007. 2. Ehrenreich H, Bartels C, Sargin D, Stawicki S, Krampe H: Recombinant human erythropoietin in the treatment of human brain disease: focus on cognition. J Renal Nutr 18:146-153, 2008. 3. Grasso G, Sfacteria A, Meli F, Passalacqua M, Fodale V, Buemi M, Giambartino F, Iacopino DG, Tomasello F: The role of erythropoietin in neuroprotection: therapeutic perspectives. Drug News Perspect 20:315-320, 2007. 4. Grasso G, Sfacteria A, Meli F, Fodale V, Buemi M, Iacopino DG: Neuroprotection by erythropoietin administration after experimental traumatic brain injury. Brain Res 1182:99-105, 2007. 5. Juul SE, Beyer RP, Bammler TK, McPherson RJ, Wilkerson J, Farin FM: Microarray analysis of high-dose recombinant erythropoietin treatment of unilateral brain injury in neonatal mouse hippocampus. Pediatr Res 65:485-492, 2009. 6. Maiese K, Chong ZZ, Hou J, Shang YC: Erythropoietin and oxidative stress. Curr Neurovasc Res 5:125-142, 2008.
www.WORLDNEUROSURGERY.org
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LETTER TO THE EDITOR
7. Nichol A, French C, Little L, Presneill J, Cooper DJ, Haddad S, Duranteau J, Huet O, Skrifvars M, Arabi Y, Bellomo R; EPO-TBI Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group: Erythropoietin in Traumatic Brain Injury: study protocol for a randomised controlled trial. Trials 16:39, 2015.
9. Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ: Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg 111:171-180, 2009.
8. Robertson CS, Hannay HJ, Yamal JM, Gopinath S, Goodman JC, Tilley BC, ; Epo Severe TBITI, Baldwin A, Rivera Lara L, Saucedo-Crespo H, Ahmed O, Sadasivan S, Ponce L, Cruz-Navarro J, Shahin H, Aisiku IP, Doshi P, Valadka A, Neipert L, Waguspack JM, Rubin ML, Benoit JS, Swank P: Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 312:36-47, 2014.
10. Wu YW, Bauer LA, Ballard RA, Ferriero DM, Glidden DV, Mayock DE, Chang T, Durand DJ, Song D, Bonifacio SL, Gonzalez FF, Glass HC, Juul SE: Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics 130:683-691, 2012.
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www.SCIENCEDIRECT.com
84 [5]: 1491e1492, NOVEMBER 2015 WORLD NEUROSURGERY
TBIs are associated with 1.1 million emergency department visits, 235,000 hospitalizations, and 50,000 deaths (1). Despite improvements in medical interventions, there are still no neuroprotective agents available to counteract secondary or delayed damage to the traumatically injured human brain or to promote its repair. TBI encompasses heterogeneous etiologic, anatomical, and molecular patterns of injury that exhibit different propensities to cause cerebral damage. Without careful consideration of individual injuries, the results of therapeutic trials remain difficult to interpret. In preclinical studies, erythropoietin (EPO) has shown to protect against neurologic injury in several experimental models both in vitro and in vivo (3). Human EPO is the main regulator of erythropoiesis, and its recombinant form has greatly improved the management of anemia resulting from chronic renal failure and has substantially improved quality of life in patients undergoing dialysis. The detection of EPO and its receptor in the brain and other organs has stimulated the search for other biological roles of these proteins. Now we know that EPO has cytoprotective effects on endothelial cells, glial cells, and neurons. It is antiapoptotic, antioxidative, and anti-inflammatory (5) and also has angiogenic and neurogenic effects (6).
To date, some clinical trials have been concluded, with investigators discovering the uncertain efficacy of EPO as neuroprotectant (2, 9, 10). Recently, Robertson et al. (8) conducted a randomized clinical trial of 200 patients with TBI who were enrolled within 6 hours of injury to test the effect of 2 approaches, transfusion threshold and EPO therapy, on neurologic outcome. The authors found that neither the administration of EPO nor maintaining a hemoglobin concentration of at least 10 g/dL resulted in improved neurologic outcome in patients at 6 months. It has been suggested that these inconclusive findings also would reflect a substantial lack of statistical power of the study. It should be considered, however, that most of the favorable data accumulated on EPO effects come from preclinical studies. Although experimental studies represent a basic premise for future clinical investigations, important issues still need to be addressed, for instance, the safety of recombinant human EPO administration in the setting of brain injury in humans. It must be taken into account that all the information available regarding the safety of EPO administration comes from its non-neurologic use. The logical extension of these arguments is that translating such information from anemic recombinant human EPO-treated to TBI-affected patients can be misleading, because the interaction and influence between EPO and different physiologic variables, as well as with common drugs used in patients with TBI, are unknown.
WORLD NEUROSURGERY 84 [5]: 1491e1492, NOVEMBER 2015
Also, although EPO is usually a well-tolerated drug, several lines of evidence have shown that therapy with recombinant EPO can result in hypertension, hypertensive encephalopathy, seizures, and thrombotic/vascular events. Although in pioneering clinical studies, we did not report adverse effects during treatment with EPO, these findings should be cautionary. In this regard, we have provided evidence that recombinant human EPO treatment at a dose of 1000 IU/kg, administered every 8 hours, is effective providing neuroprotection after TBI (4). The dose used in the study by Robertson et al. (8) is the lowest dose known to be effective in the experimental settings. It can be argued that the unfavorable results from this clinical trial can be related to the small dose used and frequency of administration. Furthermore, the investigators changed the dosing of the EPO regimen mid-study. This change to a less-efficacious regimen further limited the authors’ ability to detect effects. Large pragmatic, international, multicenter trials are required to resolve such uncertainty, especially when the plausible absolute difference in outcome is likely to be small. The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial is a stratified prospective, multicenter, randomized, blinded, parallel-group, placebocontrolled phase 3 trial (7). It aims to determine whether the administration of EPO compared with placebo improves neurologic outcomes in patients with moderate or severe TBI at 6 months after injury. The trial is designed to recruit 606 patients between 15 and 65 years of age with severe or moderate TBI and uses a subcutaneous EPO regimen. When completed, the trial aims to provide evidence on the efficacy and safety of EPO in TBI. Hopefully, it will clarify optimal tolerated dosages, therapeutic time window, and duration of therapy. Giovanni Grasso1, Concetta Alafaci2, Michele Buemi3 From the 1Section of Neurosurgery, Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo, Palermo, Italy; 2Department of Neurosurgery, University of Messina, Messina, Italy; and 3Department of Internal Medicine, University of Messina, Messina, Italy To whom correspondence should be addressed: Giovanni Grasso, M.D., Ph.D. [E-mail: [email protected]] Published online 5 June 2015; http://dx.doi.org/10.1016/j.wneu.2015.05.056.
REFERENCES 1. Centers for Disease Control and Prevention: Rates of hospitalization related to traumatic brain injury-nine states, 2003. MMWR Morb Mortal Wkly Rep 56: 167-170, 2007. 2. Ehrenreich H, Bartels C, Sargin D, Stawicki S, Krampe H: Recombinant human erythropoietin in the treatment of human brain disease: focus on cognition. J Renal Nutr 18:146-153, 2008. 3. Grasso G, Sfacteria A, Meli F, Passalacqua M, Fodale V, Buemi M, Giambartino F, Iacopino DG, Tomasello F: The role of erythropoietin in neuroprotection: therapeutic perspectives. Drug News Perspect 20:315-320, 2007. 4. Grasso G, Sfacteria A, Meli F, Fodale V, Buemi M, Iacopino DG: Neuroprotection by erythropoietin administration after experimental traumatic brain injury. Brain Res 1182:99-105, 2007. 5. Juul SE, Beyer RP, Bammler TK, McPherson RJ, Wilkerson J, Farin FM: Microarray analysis of high-dose recombinant erythropoietin treatment of unilateral brain injury in neonatal mouse hippocampus. Pediatr Res 65:485-492, 2009. 6. Maiese K, Chong ZZ, Hou J, Shang YC: Erythropoietin and oxidative stress. Curr Neurovasc Res 5:125-142, 2008.
www.WORLDNEUROSURGERY.org
1491
LETTER TO THE EDITOR
7. Nichol A, French C, Little L, Presneill J, Cooper DJ, Haddad S, Duranteau J, Huet O, Skrifvars M, Arabi Y, Bellomo R; EPO-TBI Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group: Erythropoietin in Traumatic Brain Injury: study protocol for a randomised controlled trial. Trials 16:39, 2015.
9. Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ: Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg 111:171-180, 2009.
8. Robertson CS, Hannay HJ, Yamal JM, Gopinath S, Goodman JC, Tilley BC, ; Epo Severe TBITI, Baldwin A, Rivera Lara L, Saucedo-Crespo H, Ahmed O, Sadasivan S, Ponce L, Cruz-Navarro J, Shahin H, Aisiku IP, Doshi P, Valadka A, Neipert L, Waguspack JM, Rubin ML, Benoit JS, Swank P: Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 312:36-47, 2014.
10. Wu YW, Bauer LA, Ballard RA, Ferriero DM, Glidden DV, Mayock DE, Chang T, Durand DJ, Song D, Bonifacio SL, Gonzalez FF, Glass HC, Juul SE: Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics 130:683-691, 2012.
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www.SCIENCEDIRECT.com
84 [5]: 1491e1492, NOVEMBER 2015 WORLD NEUROSURGERY
