title: Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial.
abstract: BACKGROUND
  Erythropoietin might have neurocytoprotective effects. In this trial, we studied its effect on neurological recovery, mortality, and venous thrombotic events in patients with traumatic brain injury.
  
  
  METHODS
  Erythropoietin in Traumatic Brain Injury (EPO-TBI) was a double-blind, placebo-controlled trial undertaken in 29 centres (all university-affiliated teaching hospitals) in seven countries (Australia, New Zealand, France, Germany, Finland, Ireland, and Saudi Arabia). Within 24 h of brain injury, 606 patients were randomly assigned by a concealed web-based computer-generated randomisation schedule to erythropoietin (40,000 units subcutaneously) or placebo (0·9% sodium chloride subcutaneously) once per week for a maximum of three doses. Randomisation was stratified by severity of traumatic brain injury (moderate vs severe) and participating site. With the exception of designated site pharmacists, the site dosing nurses at all sites, and the pharmacists at the central pharmacy in France, all study personnel, patients, and patients' relatives were masked to treatment assignment. The primary outcome, assessed at 6 months by modified intention-to-treat analysis, was improvement in the patients' neurological status, summarised as a reduction in the proportion of patients with an Extended Glasgow Outcome Scale (GOS-E) of 1-4 (death, vegetative state, and severe disability). Two equally spaced preplanned interim analyses were done (after 202 and 404 participants were enrolled). This study is registered with ClinicalTrials.gov, number NCT00987454.
  
  
  RESULTS
  Between May 3, 2010, and Nov 1, 2014, 606 patients were enrolled and randomly assigned to erythropoietin (n=308) or placebo (n=298). Ten of these patients (six in the erythropoietin group and four in the placebo group) were lost to follow up at 6 months; therefore, data for the primary outcome analysis was available for 596 patients (302 in the erythropoietin group and 294 in the placebo group). Compared with placebo, erythropoietin did not reduce the proportion of patients with a GOS-E level of 1-4 (134 [44%] of 302 patients in the erythropoietin group vs 132 [45%] of 294 in the placebo group; relative risk [RR] 0·99 [95% CI 0·83-1·18], p=0·90). In terms of safety, erythropoietin did not significantly affect 6-month mortality versus placebo (32 [11%] of 305 patients had died at 6 months in the erythropoietin group vs 46 [16%] of 297 [16%] in the placebo group; RR 0·68 [95% CI 0·44-1·03], p=0·07) or increase the occurrence of deep venous thrombosis of the lower limbs (48 [16%] of 305 vs 54 [18%] of 298; RR 0·87 [95% CI 0·61-1·24], p=0·44).
  
  
  CONCLUSIONS
  Following moderate or severe traumatic brain injury, erythropoietin did not reduce the number of patients with severe neurological dysfunction (GOS-E level 1-4) or increase the incidence of deep venous thrombosis of the lower limbs. The effect of erythropoietin on mortality remains uncertain.
  
  
  BACKGROUND
  The National Health and Medical Research Council and the Transport Accident Commission.
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; The Alfred, Melbourne, VIC, Australia; School of Medicine and Medical Sciences, University College Dublin, Dublin Ireland; St Vincent's University Hospital, Dublin, Ireland.
authors.forename: Alistair
authors.initials: A
authors.lastname: Nichol
authors.affiliation: University of Melbourne, Melbourne, VIC, Australia; Western Health, Melbourne, VIC, Australia. Electronic address: craig.french@wh.org.au.
authors.forename: Craig
authors.initials: C
authors.lastname: French
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Little
authors.affiliation: King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia.
authors.forename: Samir
authors.initials: S
authors.lastname: Haddad
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; University of Queensland, Brisbane, QLD, Australia; Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Presneill
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
authors.forename: Yaseen
authors.initials: Y
authors.lastname: Arabi
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Bailey
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; The Alfred, Melbourne, VIC, Australia.
authors.forename: D James
authors.initials: DJ
authors.lastname: Cooper
authors.affiliation: Département d'Anesthésie-Réanimation, Hôpital de Bicêtre, Assistance Publique des Hopitaux de Paris, Hôpitaux Universitaires Paris-Sud, Université Paris-Sud, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Duranteau
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; Department of Anaesthesiology and Intensive Care Medicine, CHU La Cavale Blanche, Brest, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Huet
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; The Alfred, Melbourne, VIC, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Mak
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; Auckland City Hospital, Auckland, New Zealand.
authors.forename: Colin
authors.initials: C
authors.lastname: McArthur
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Pettilä
authors.affiliation: University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Markus
authors.initials: M
authors.lastname: Skrifvars
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; The Alfred, Melbourne, VIC, Australia.
authors.forename: Shirley
authors.initials: S
authors.lastname: Vallance
authors.affiliation: The Alfred, Melbourne, VIC, Australia.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Varma
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; The Alfred, Melbourne, VIC, Australia.
authors.forename: Judy
authors.initials: J
authors.lastname: Wills
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia; Austin Hospital, Melbourne, VIC, Australia.
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
mesh_terms: D000328:Adult; D001315:Australia / Q000453:epidemiology; D001930:Brain Injuries / Q000188:drug therapy* / Q000401:mortality; D004311:Double-Blind Method; D004921:Erythropoietin / Q000627:therapeutic use*; D005060:Europe / Q000453:epidemiology; D005260:Female; D023261:Glasgow Outcome Scale; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009520:New Zealand / Q000453:epidemiology; D012529:Saudi Arabia / Q000453:epidemiology; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000453:epidemiology; D055815:Young Adult
chemical_list: D004921:Erythropoietin