Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: A randomized clinical trial

Claudia S. Robertson, H. Julia Hannay, José Miguel Yamal, Shankar Gopinath, J. Clay Goodman, Barbara C. Tilley, Athena Baldwin, Lucia Rivera Lara, Hector Saucedo-Crespo, Osama Ahmed, Santhosh Sadasivan, Luciano Ponce, Jovanny Cruz-Navarro, Hazem Shahin, Imoigele P. Aisiku, Pratik Doshi, Alex Valadka, Leslie Neipert, Jace M. Waguspack, M. Laura RubinJulia S. Benoit, Paul Swank

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)36-47
Number of pages12
JournalJAMA - Journal of the American Medical Association
Volume312
Issue number1
DOIs
StatePublished - 2014
Externally publishedYes

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Erythropoietin
Randomized Controlled Trials
Hemoglobins
Closed Head Injuries
Placebos
Glasgow Outcome Scale
Traumatic Brain Injury
Trauma Centers
Incidence
Intensive Care Units
Erythrocytes
Odds Ratio
Wounds and Injuries

ASJC Scopus subject areas

  • Medicine(all)

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Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury : A randomized clinical trial. / Robertson, Claudia S.; Hannay, H. Julia; Yamal, José Miguel; Gopinath, Shankar; Goodman, J. Clay; Tilley, Barbara C.; Baldwin, Athena; Rivera Lara, Lucia; Saucedo-Crespo, Hector; Ahmed, Osama; Sadasivan, Santhosh; Ponce, Luciano; Cruz-Navarro, Jovanny; Shahin, Hazem; Aisiku, Imoigele P.; Doshi, Pratik; Valadka, Alex; Neipert, Leslie; Waguspack, Jace M.; Rubin, M. Laura; Benoit, Julia S.; Swank, Paul.

In: JAMA - Journal of the American Medical Association, Vol. 312, No. 1, 2014, p. 36-47.

Research output: Contribution to journalArticle

Robertson, CS, Hannay, HJ, Yamal, JM, Gopinath, S, Goodman, JC, Tilley, BC, 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 2014, 'Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: A randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 312, no. 1, pp. 36-47. https://doi.org/10.1001/jama.2014.6490
Robertson, Claudia S. ; Hannay, H. Julia ; Yamal, José Miguel ; Gopinath, Shankar ; Goodman, J. Clay ; Tilley, Barbara C. ; Baldwin, Athena ; Rivera Lara, Lucia ; Saucedo-Crespo, Hector ; Ahmed, Osama ; Sadasivan, Santhosh ; Ponce, Luciano ; Cruz-Navarro, Jovanny ; Shahin, Hazem ; Aisiku, Imoigele P. ; Doshi, Pratik ; Valadka, Alex ; Neipert, Leslie ; Waguspack, Jace M. ; Rubin, M. Laura ; Benoit, Julia S. ; Swank, Paul. / Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury : A randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2014 ; Vol. 312, No. 1. pp. 36-47.
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abstract = "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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TY - JOUR

T1 - Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury

T2 - A randomized clinical trial

AU - Robertson, Claudia S.

AU - Hannay, H. Julia

AU - Yamal, José Miguel

AU - Gopinath, Shankar

AU - Goodman, J. Clay

AU - Tilley, Barbara C.

AU - Baldwin, Athena

AU - Rivera Lara, Lucia

AU - Saucedo-Crespo, Hector

AU - Ahmed, Osama

AU - Sadasivan, Santhosh

AU - Ponce, Luciano

AU - Cruz-Navarro, Jovanny

AU - Shahin, Hazem

AU - Aisiku, Imoigele P.

AU - Doshi, Pratik

AU - Valadka, Alex

AU - Neipert, Leslie

AU - Waguspack, Jace M.

AU - Rubin, M. Laura

AU - Benoit, Julia S.

AU - Swank, Paul

PY - 2014

Y1 - 2014

N2 - 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

AB - 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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