Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial

Nichol, Alistair; French, Craig; Little, Lorraine; Haddad, Samir H.; Presneill, Jeffrey; Arabi, Yaseen M.; Bailey, Michael; Cooper, Jamie; Duranteau, Jacques; Huet, Olivier; Mak, Anne; McArthur, Colin; Pettilä, Ville; Skrifvars, Markus B.; Vallance, Shirley; Varma, Dinesh; Wills, Judy; Bellomo, Rinaldo

doi:10.1016/s0140-6736(15)00386-4

Cited by 226 publications

(179 citation statements)

References 25 publications

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“…In addition, EPO-TBI treatment resulted in side-effects which were not reported in some other trials (8,9,15) which may be due to EPO-TBI's higher EPO dose requirements (40,000 IU/mL for up to three doses) in comparison to 10,000 IU/mL for seven days in Aloizos et al's study and 1,000 IU/mL in six doses over two weeks in Abrishamkar et al's study. There were side effects in the placebo group of the EPO-TBI trial as well, which challenge these findings.…”

Section: Discussionmentioning

confidence: 92%

“…The primary search results for this topic consisted of a review of in-vitro and in-vivo studies up until 2009 (13), one retrospective case-control study (14), and four prospective RCTs (8)(9)(10)15). Two of these RCTs were reports of the same phase-III multi-centric placebo-control trial known as EPO-TBI; Nichol et al's report was more complete than Presneil et al's, (9,10).…”

Section: Resultsmentioning

confidence: 99%

“…Two of these RCTs were reports of the same phase-III multi-centric placebo-control trial known as EPO-TBI; Nichol et al's report was more complete than Presneil et al's, (9,10).…”

Section: Resultsmentioning

confidence: 99%

“…The entire study population analyzed was extracted from the studies of Aloizos et al and Nichol et al, including 645 patients (9,15). Both studies followed-up patients for up to six months, and an analysis of the total better outcomes of the patients showed no significant difference between the study groups ((P = 0.30; MD 1.22, 95% CI -1.09 to 3.53; participants = 638; studies = 2; I 2 = 99%) Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…We aimed to assess the efficacy of EPO use for acute TBI management according to the most recent results of a phase-III randomized clinical trial (RCT) in this field (9,10) and previous studies to provide recommendations for current clinical practice and further research.…”

Section: Objectivesmentioning

confidence: 99%

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Erythropoietin for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Meshkini¹,

Meshkini²,

Sadeghi‐Bazargani³

2016

Trauma Mon

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Context: Traumatic brain injury (TBI) is a leading cause of mortality and morbidity; despite the use of neuroprotective agents for TBI management, no evidence-based recommendation for any particular neuroprotective agent with favorable outcomes and less adverse effects has been made in TBI management. Objectives: We aimed to assess the efficacy of erythropoietin (EPO) use for TBI management. Data Sources: This study is part of a review on neuroprotective agents used for traumatic brain injury: A systematic review and meta-analyses was done, based on a wide search strategy incorporating information from Cochrane CENTRAL, MedLine/PubMed, SCOPUS, Thomson Reuters Web of Science, SID.ir, Barekat Foundation, and clinicaltrials.gov databases up to September 06, 2015. Study Selection: The present study limited the retrieved search results only to those using EPO for TBI management. Data Extraction: The retrieved randomized clinical trials (RCTs) were assessed for their quality of reporting according to the consolidated standards of reporting trials (CONSORT) checklist prior to extracting the data for meta-analysis. The meta-analyses in this review was conducted using the extended Glasgow outcome scale (GOS-E) for acute TBI patients, mortalities, and adverse-effects. Results: Four RCTs were retrieved on EPO use for acute TBI, and two of them were kept for the final analysis. The analysis of the enrolled 645 participants in these studies showed insignificant but slightly better outcomes in the placebo group, while a significant reduction in mortality rates among EPO users was observed. Slightly better outcomes in vascular and non-vascular side-effects were also observed in the intervention group. Conclusions: EPO may be considered as effective in reducing TBI mortality and vascular side-effects, while there is no evidence to support any benefits in other outcomes or for the elimination of non-vascular side-effects. Further studies, especially well-designed phase-III dose-controlled trials, are needed for building a stronger body of evidence for recommending the use of EPO for acute TBI.Keywords: Head Injury, Traumatic Brain Injury, Neuroprotective Agent, Erythropoietin, Review ContextTraumatic brain injury (TBI), which is also known as head injury (1-3), is a leading cause of mortality and morbidity (1, 4-6), especially among those of young ages (1).Epidemiological studies have demonstrated the following facts about TBI in the U.S. (1, 4): -There is an incidence rate of 558 cases per 100,000 people each year.-TBI-related disability cases are estimated as rising by 33 new cases per 100,000 people each year.-They cause more than 50,000 deaths each year.-Motor vehicle collisions (MVC) are responsible for 50% of TBI cases.TBI costs more than $48 billion a year, and between 2.5 and 6.5 million Americans alive today have been victims of a TBI-related assault. Survivors of TBI are often left with significant cognitive, behavioral, and communicative disabilities (7).Erythropoietin (EPO) is a glycoprotein hormone of the cy...

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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

“…Two of these RCTs were reports of the same phase-III multi-centric placebo-control trial known as EPO-TBI; Nichol et al's report was more complete than Presneil et al's, (9,10).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Objectivesmentioning

confidence: 99%

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Erythropoietin for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Meshkini¹,

Meshkini²,

Sadeghi‐Bazargani³

2016

Trauma Mon

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Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury

Cooper

Nichol

Bailey

et al. 2018

JAMA

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249

167

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IMPORTANCE After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes. OBJECTIVE To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTS The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018. INTERVENTIONS There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale-Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury. RESULTS Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI,-9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively. CONCLUSIONS AND RELEVANCE Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury.

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Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury

Roquilly

Moyer

Huet

et al. 2021

JAMA

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for the Atlanrea Study Group and the Société Française d'Anesthésie Réanimation (SFAR) Research Network IMPORTANCE Fluid therapy is an important component of care for patients with traumatic brain injury, but whether it modulates clinical outcomes remains unclear.OBJECTIVE To determine whether continuous infusion of hypertonic saline solution improves neurological outcome at 6 months in patients with traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTSMulticenter randomized clinical trial conducted in 9 intensive care units in France, including 370 patients with moderate to severe traumatic brain injury who were recruited from October 2017 to August 2019. Follow-up was completed in February 2020.INTERVENTIONS Adult patients with moderate to severe traumatic brain injury were randomly assigned to receive continuous infusion of 20% hypertonic saline solution plus standard care (n = 185) or standard care alone (controls; n = 185). The 20% hypertonic saline solution was administered for 48 hours or longer if patients remained at risk of intracranial hypertension. MAIN OUTCOMES AND MEASURESThe primary outcome was Extended Glasgow Outcome Scale (GOS-E) score (range, 1-8, with lower scores indicating worse functional outcome) at 6 months, obtained centrally by blinded assessors and analyzed with ordinal logistic regression adjusted for prespecified prognostic factors (with a common odds ratio [OR] >1.0 favoring intervention). There were 12 secondary outcomes measured at multiple time points, including development of intracranial hypertension and 6-month mortality. RESULTS Among 370 patients who were randomized (median age, 44 [interquartile range, 27-59] years; 77 [20.2%] women), 359 (97%) completed the trial. The adjusted common OR for the GOS-E score at 6 months was 1.02 (95% CI, 0.71-1.47; P = .92). Of the 12 secondary outcomes, 10 were not significantly different. Intracranial hypertension developed in 62 (33.7%) patients in the intervention group and 66 (36.3%) patients in the control group (absolute difference, −2.6% [95% CI, −12.3% to 7.2%]; OR, 0.80 [95% CI, 0.51-1.26]). There was no significant difference in 6-month mortality (29 [15.9%] in the intervention group vs 37 [20.8%] in the control group; absolute difference, −4.9% [95% CI, −12.8% to 3.1%]; hazard ratio, 0.79 [95% CI, 0.48-1.28]).CONCLUSIONS AND RELEVANCE Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurological status at 6 months. However, confidence intervals for the findings were wide, and the study may have had limited power to detect a clinically important difference.

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Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial

Cited by 226 publications

References 25 publications

Erythropoietin for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Erythropoietin for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury

Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury

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