Cause and timing of death and sub-group differential effects of erythropoietin in the EPO-TBI study
Skrifvars MB1, French C2, Bailey M3, Presneill J4, Nichol A5, Little L6, Duranteau J7, Huet O8, Haddad S9, Arabi Y10, McArthur C11, Cooper DJ12,13, Bellomo R14.
1 Helsinki University Hospital, Department of Anesthesia, Intensive Care and Pain Medicine , Haartmaninkatu 9 , 00029 HUS , HUS, Finland , 00029 ; firstname.lastname@example.org.
2 Department of Intensive Care, Western Health, Melbourne, Victoria, Australia, Melbourne, Victoria, Australia ; Craig.French@wh.org.au.
3 Monash University, School of Public Health and Preventive Medicine, Melbourne, Victoria, Australia ; Michael.Bailey@monash.edu.
4 Royal Melbourne Hospital, 90134, Department of Intensive Care, Melbourne, Victoria, Australia ; email@example.com.
5 Monash University School of Public Health and Preventive Medicine, 161667, ANZIC-RC, Melbourne, Victoria, Australia ; Alistair.Nichol@monash.edu.
6 Monash University School of Public Health and Preventive Medicine, 161667, ANZIC-RC, Melbourne, Victoria, Australia ; firstname.lastname@example.org.
7 Hopitaux Universitaires Paris-Sud, 378965, Department of Anesthesia and Intensive Care, Le Kremlin-Bicetre, Île-de-France, France ; email@example.com.
8 Hopital de la Cavale-Blanche, 55359, Departement d’anesthésie-réanimation, Brest, Bretagne, France ; firstname.lastname@example.org.
9 King Abdullah International Medical Research Center, 309817, Intensive Care Department, Riyadh, Saudi Arabia ; email@example.com.
10 King Saud bin Abdulaziz University for Health Sciences, 48149, Intensive Care Department, Riyadh, Saudi Arabia ; firstname.lastname@example.org.
11 Auckland City Hospital, 58991, Department of Critical Care Medicine, Auckland, New Zealand ; email@example.com.
12 The Alfred, Intensive Care , Commercial Road , Melbourne, Victoria, Australia , 3004.
13 Monash University, ANZIC-RC , Level 6 , The Alfred Centre , 99 Commercial Road , Melbourne, Victoria, Australia , 3004 ; firstname.lastname@example.org.
14 Monash University, ANZIC-RC , Level 6 , The Alfred Centre , 99 Commercial Road , Melbourne, Victoria, Australia , 3004 ; email@example.com.
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The EPO-TBI study randomised 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six-month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal or death during maximal care) and non-cerebral (death following withdrawal or during maximal care due to a non-cerebral cause). The study included 305 patients treated with EPO and 297 with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (IQR 5-16) compared to 29 days (IQR 7-56) (p=0.01) with non-cerebral COD. When assessing subgroups by admission computed tomography scan injury findings, we found no significant differential effects of EPO compared to placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to ICU admission (OR 0.29, 95% confidence interval 0.14-0.61, p=0.001, p for interaction = 0.003) and in this sub-group, fewer patients died of cerebral causes in in the EPO compared to placebo group (5% compared to 14%, p=0.03). In conclusion, most TBI deaths were due to cerebral causesthat occurred during the first two weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomisation.