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Original Investigation | Caring for the Critically Ill Patient

Effect of Erythropoietin and Transfusion Threshold on Neurological Recovery After Traumatic Brain Injury:  A Randomized Clinical Trial

Claudia S. Robertson, MD1; H. Julia Hannay, PhD2; José-Miguel Yamal, PhD3; Shankar Gopinath, MD1; J. Clay Goodman, MD4; Barbara C. Tilley, PhD3 ; and the Epo Severe TBI Trial Investigators
[+] Author Affiliations
1Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
2Department of Psychology, University of Houston, Houston, Texas
3Division of Biostatistics, University of Texas Health Science Center at Houston School of Public Health, Houston
4Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
JAMA. 2014;312(1):36-47. doi:10.1001/jama.2014.6490.
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Importance  There is limited information about the effect of erythropoietin or a high hemoglobin transfusion threshold after a traumatic brain injury.

Objective  To compare the effects of erythropoietin and 2 hemoglobin transfusion thresholds (7 and 10 g/dL) on neurological recovery after traumatic brain injury.

Design, Setting, and Participants  Randomized clinical trial of 200 patients (erythropoietin, n = 102; placebo, n = 98) with closed head injury who were unable to follow commands and were enrolled within 6 hours of injury at neurosurgical intensive care units in 2 US level I trauma centers between May 2006 and August 2012. The study used a factorial design to test whether erythropoietin would fail to improve favorable outcomes by 20% and whether a hemoglobin transfusion threshold of greater than 10 g/dL would increase favorable outcomes without increasing complications. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74) and then the 24- and 48-hour doses were stopped for the remainder of the patients (n = 126). There were 99 patients assigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL.

Interventions  Intravenous erythropoietin (500 IU/kg per dose) or saline. Transfusion threshold maintained with packed red blood cells.

Main Outcomes and Measures  Glasgow Outcome Scale score dichotomized as favorable (good recovery and moderate disability) or unfavorable (severe disability, vegetative, or dead) at 6 months postinjury.

Results  There was no interaction between erythropoietin and hemoglobin transfusion threshold. Compared with placebo (favorable outcome rate: 34/89 [38.2%; 95% CI, 28.1% to 49.1%]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6%; 95% CI, 31.4% to 66.0%], P = .13; second dosing regimen: 17/57 [29.8%; 95% CI, 18.4% to 43.4%], P < .001). Favorable outcome rates were 37/87 (42.5%) for the hemoglobin transfusion threshold of 7 g/dL and 31/94 (33.0%) for 10 g/dL (95% CI for the difference, −0.06 to 0.25, P = .28). There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio, 0.32 [95% CI, 0.12 to 0.79], P = .009).

Conclusions and Relevance  In patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months. The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events. These findings do not support either approach in this setting.

Trial Registration  clinicaltrials.gov Identifier: NCT00313716

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Figure 1.
Patients Screened and Enrolled in the Trial

aA patient could have more than 1 exclusion criteria.bException from informed consent was in effect during 50 months and not available for 20 months of the trial.cIncluded screened during clinical hold (n = 52), pregnant (n = 3), uncontrolled hypertension (n = 3), receiving anticoagulants (n = 1), and other reasons (n = 37).dOf the 200 randomized, prospective consent was obtained for 106 and 94 had exception from informed consent.

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Figure 2.
Glasgow Outcome Scale Scores at 6 Months for Complete Cases

For the primary outcome, good recovery and moderate disability were combined as a favorable outcome. Severe disability, vegetative, and dead were combined as an unfavorable outcome. For the first 74 patients, the initial dosage regimen was 1 dose given within 6 hours of injury followed by 2 additional doses given every 24 hours (erythropoietin 1 regimen). In 2009, the initial dosage regimen was changed for the subsequent 126 patients to 1 dose given within 6 hours of injury (erythropoietin 2 regimen).

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Figure 3.
Kaplan-Meier Survival Curves for the Erythropoietin Dosing Regimen Groups

For the first 74 patients, the initial dosage regimen was 1 dose given within 6 hours of injury followed by 2 additional doses given every 24 hours (erythropoietin 1 regimen). In 2009, the initial dosage regimen was changed for the subsequent 126 patients to 1 dose given within 6 hours of injury (erythropoietin 2 regimen).

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Figure 4.
Kaplan-Meier Survival Curves for the Hemoglobin Transfusion Threshold Groups
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