Comparison of the performances of copeptin and multiple biomarkers in long-term prognosis of severe traumatic brain injury

Enhanced blood levels of copeptin correlate with poor clinical outcomes after acute critical illness. This study aimed to compare the prognostic performances of plasma concentrations of copeptin and other biomarkers like myelin basic protein, glial fibrillary astrocyte protein, S100B, neuron-specific enolase, phosphorylated axonal neurofilament subunit H, Tau and ubiquitin carboxyl-terminal hydrolase L1 in severe traumatic brain injury. We recruited 102 healthy controls and 102 acute patients with severe traumatic brain injury. Plasma concentrations of these biomarkers were determined using enzyme-linked immunosorbent assay. Their prognostic predictive performances of 6-month mortality and unfavorable outcome (Glasgow Outcome Scale score of 1–3) were compared. Plasma concentrations of these biomarkers were statistically significantly higher in all patients than in healthy controls, in non-survivors than in survivors and in patients with unfavorable outcome than with favorable outcome. Areas under receiver operating characteristic curves of plasma concentrations of these biomarkers were similar to those of Glasgow Coma Scale score for prognostic prediction. Except plasma copeptin concentration, other biomarkers concentrations in plasma did not statistically significantly improve prognostic predictive value of Glasgow Coma Scale score. Copeptin levels may be a useful tool to predict long-term clinical outcomes after severe traumatic brain injury and have a potential to assist clinicians.     

Change in plasma visfatin level after severe traumatic brain injury

Higher plasma visfatin concentration has been associated with ischemic stroke. Thus, we sought to investigate change in plasma visfatin level after traumatic brain injury and to evaluate its relation with disease outcome. Seventy-six healthy controls and 98 patients with acute severe traumatic brain injury were recruited. Twenty-seven patients (27.6%) died and 48 patients (49.0%) suffered from unfavorable outcome (Glasgow outcome scale score of 1–3) in 6 months. On admission, plasma visfatin level was increased in patients than in healthy controls and was highly correlated with Glasgow Coma Scale score. A multivariate analysis identified plasma visfatin level as an independent predictor for 6-month mortality and unfavorable outcome. According to receiver operating characteristic curve analysis, the predictive value of the plasma visfatin concentration was similar to Glasgow Coma Scale score's. In a combined logistic-regression model, visfatin did not improve the predictive value of Glasgow Coma Scale score. Thus, increased plasma visfatin level is associated with 6-month clinical outcomes after severe traumatic brain injury.     

Relationship between plasma leptin levels and clinical outcomes of pediatric traumatic brain injury

High plasma leptin level has been associated with mortality after adult intracerebral hemorrhage. The present study was undertaken to investigate the plasma leptin concentrations in children with traumatic brain injury and to analyze the correlation of leptin with pediatric traumatic brain injury outcome. Plasma leptin concentration of eighty-nine healthy children and 142 children with acute severe traumatic brain injury was measured by enzyme-linked immunosorbent assay. Twenty-six patients (18.3%) died and 42 patients (29.6%) had an unfavorable outcome (Glasgow outcome scale score of 1-3) at 6 months after traumatic brain injury. Upon admission, plasma leptin level in patients was substantially higher than that in healthy controls. A forward stepwise logistic regression selected plasma leptin level as an independent predictor for 6-month mortality and unfavorable outcome of patients. A receiver operating characteristic curve analysis showed plasma leptin level better predicted 6-month mortality and unfavorable outcome. The prognostic value of leptin was similar to that of Glasgow Coma scale score for 6-month clinical outcomes. Thus, plasma leptin level represents a novel biomarker for predicting 6-month clinical outcome in children with traumatic brain injury.     

Copeptin is associated with one-year mortality and functional outcome in patients with acute spontaneous basal ganglia hemorrhage

High plasma copeptin levels have been found to be associated with short-term poor outcome after intracerebral hemorrhage (ICH). We furthermore evaluate the relation of plasma copeptin levels to long-term outcome and early neurological deterioration after ICH. Fifty healthy controls and 89 patients with acute spontaneous basal ganglia hemorrhage were recruited in this study. Plasma copeptin concentrations on admission measured by enzyme-linked immunosorbent assay were considerably high in patients than healthy controls. A multivariate analysis identified plasma copeptin level as an independent predictor for 1-year mortality, 1-year unfavorable outcome (modified Rankin Scale score>2) and early neurological deterioration. A receiver operating characteristic curve showed that the predictive value of plasma copeptin concentration was similar to that of National Institutes of Health Stroke Scale scores for long-term poor outcome and early neurological deterioration. However, copeptin did not obviously improve the predictive values of National Institutes of Health Stroke Scale scores. Thus, increased plasma copeptin level is an independent prognostic marker of 1-year mortality, 1-year unfavorable outcome and early neurological deterioration after ICH.     

Plasma copeptin concentration and outcome after pediatric traumatic brain injury

Higher plasma copeptin level has been associated with poor outcomes of critical illness. The present study was undertaken to investigate the plasma copeptin concentrations in children with traumatic brain injury (TBI) and to analyze the correlation of copeptin with disease outcome. Plasma copeptin concentrations of 126 healthy children and 126 children with acute severe TBI were measured by enzyme-linked immunosorbent assay. Twenty-one patients (16.7%) died and 38 patients (30.2%) had an unfavorable outcome (Glasgow Outcome Scale score of 1–3) at 6 months. Plasma copeptin level was obviously higher in patients than in healthy children (46.2 ± 20.8 pmol/L vs. 9.6 ± 3.0 pmol/L, P < 0.001). Plasma copeptin level was identified as an independent predictor for 6-month mortality [odds ratio (OR) 1.261, 95% confidence interval (CI) 1.112–1.538, P = 0.005] and unfavorable outcome (OR 1.313, 95% CI 1.146–1.659, P = 0.003). The predictive value of copeptin was similar to that of Glasgow Coma Scale (GCS) score for 6-month mortality [area under curve (AUC) 0.832, 95% CI 0.755–0.892 vs. AUC 0.873, 95% CI 0.802–0.926, P = 0.412] and unfavorable outcome (AUC 0.863, 95% CI 0.790–0.918 vs. AUC 0.885, 95% CI 0.816–0.935, P = 0.596). Copeptin improved the AUC of GCS score for 6-month unfavorable outcome (AUC 0.929, 95% CI 0.869–0.967, P = 0.013), but not for 6-month mortality (AUC 0.887, 95% CI 0.818–0.936, P = 0.600). Thus, plasma copeptin level represents a novel biomarker for predicting 6-month clinical outcome in children with TBI.     

High concentrations of visfatin in the peripheral blood of patients with acute basal ganglia hemorrhage are associated with poor outcome

Higher plasma visfatin concentration has been associated with clinical outcomes of traumatic brain injury. No published information exists to date about change in plasma visfatin after intracerebral hemorrhage. This study included one hundred and twenty-eight healthy controls and 128 patients with intracerebral hemorrhage. The unfavorable outcome was defined as modified Rankin Scale score >2 at 6 months. The patients had higher plasma visfatin measurements than control subjects. Plasma visfatin levels were highly correlated with National Institutes of Health Stroke Scale score and plasma C-reactive protein levels in the patients. A multivariate analysis identified plasma visfatin level as an independent predictor for 6-month mortality and unfavorable outcome. According to receiver operating characteristic curve analysis, the predictive value of the plasma visfatin concentration was similar to National Institutes of Health Stroke Scale score. In a combined logistic-regression model, visfatin improved the predictive value of National Institutes of Health Stroke Scale score for 6-month unfavorable outcome. Thus, increased plasma visfatin level is associated with 6-month clinical outcomes after intracerebral hemorrhage.     

Change in plasma copeptin level after acute spontaneous basal ganglia hemorrhage

High plasma copeptin levels are associated with mortality after intracerebral hemorrhage (ICH). However, there is a paucity of data available on whether copeptin is an independent prognostic marker of mortality. Thus, we sought to furthermore evaluate this relation. Thirty healthy controls and 86 patients with acute ICH were included. Plasma samples were obtained on admission and at days 1, 2, 3, 5, and 7 after ICH. Its concentration was measured by enzyme-linked immunosorbent assay. After ICH, plasma copeptin level in patients increased during the 6-h period immediately, peaked in 24 h, decreased gradually thereafter, and was substantially higher than that in healthy controls during the 7-day period. A multivariate analysis showed plasma copeptin level was an independent predictor for 1-week mortality (odds ratio, 1.013; 95% confidence interval (CI), 1.003-1.023; P = 0.009) and positively associated with hematoma volume (t = 6.616, P < 0.001). A receiver operating characteristic curve identified that a baseline plasma copeptin level >577.5 pg/mL predicted 1-week mortality with 87.5% sensitivity and 72.2% specificity (area under curve (AUC), 0.873; 95% CI, 0.784-0.935). The AUC of the copeptin concentration was similar to those of Glasgow Coma Scale (GCS) scores and hematoma volumes (P = 0.136 and 0.280). However, copeptin did not statistically significantly improve the AUCs of GCS scores and hematoma volumes (P = 0.206 and 0.333). Hence, increased plasma copeptin level is associated with hematoma volume and an independent prognostic marker of mortality after ICH.     

Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics

Background

Traumatic brain injury (TBI) is a leading cause of death and disability. A reliable prediction of outcome on admission is of great clinical relevance. We aimed to develop prognostic models with readily available traditional and novel predictors.

Methods and Findings

Prospectively collected individual patient data were analyzed from 11 studies. We considered predictors available at admission in logistic regression models to predict mortality and unfavorable outcome according to the Glasgow Outcome Scale at 6 mo after injury. Prognostic models were developed in 8,509 patients with severe or moderate TBI, with cross-validation by omission of each of the 11 studies in turn. External validation was on 6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial. We found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and CT characteristics, including the presence of traumatic subarachnoid hemorrhage. A prognostic model that combined age, motor score, and pupillary reactivity had an area under the receiver operating characteristic curve (AUC) between 0.66 and 0.84 at cross-validation. This performance could be improved (AUC increased by approximately 0.05) by considering CT characteristics, secondary insults (hypotension and hypoxia), and laboratory parameters (glucose and hemoglobin). External validation confirmed that the discriminative ability of the model was adequate (AUC 0.80). Outcomes were systematically worse than predicted, but less so in 1,588 patients who were from high-income countries in the CRASH trial.

Conclusions

Prognostic models using baseline characteristics provide adequate discrimination between patients with good and poor 6 mo outcomes after TBI, especially if CT and laboratory findings are considered in addition to traditional predictors. The model predictions may support clinical practice and research, including the design and analysis of randomized controlled trials.     

Neuroglobin and Nogo-a as biomarkers for the severity and prognosis of traumatic brain injury

Abstract

Objective: To identify the early changes of serum neuroglobin and Nogo-A concentrations and the relations to traumatic brain injury (TBI) severity and prognosis.

Methods: Serum samples were obtained and analyzed from 34 patients with TBI within the first 96?h after injury. Comparative analysis combined with Glasgow Coma Scale (GCS) scores and the 6-month prognosis of these patients was performed.

Results: Significant correlations were found between peak serum neuroglobin and Nogo-A concentrations and a patient’s GCS score on admission (p?<?0.001). The mean peak serum neuroglobin and Nogo-A concentrations were both significantly higher in patients with an unfavorable outcome at 6 months after injury (p?<?0.05).

Conclusions: Serum neuroglobin and Nogo-A levels could be suggested as biomarkers for predicting TBI severity and prognosis.

Trial registration: ClinicalTrials.gov identifier: NCT02229643.     

Prognostic value of leptin: 6-Month outcome in patients with intracerebral hemorrhage

Leptin has recently been discussed as a novel biomarker for the clinical outcome of critical illness. This study aims to investigate the prognostic value of leptin with regard to long-term clinical outcomes in patients with intracerebral hemorrhage. In 50 healthy controls and 92 patients with acute spontaneous basal ganglia hemorrhage presenting to the emergency department of a large primary care hospital, we measured plasma leptin levels using an enzyme-linked immunosorbent assay in a blinded fashion. Plasma leptin levels on admission were considerably higher in patients than healthy controls. A significant correlation emerged between plasma leptin level and National Institutes of Health Stroke Scale score. A multivariate analysis identified plasma leptin level as an independent predictor for 6-month clinical outcomes including 6-month mortality and unfavorable outcome (Modified Rankin Scale score > 2). Using receiver operating characteristic curves, we calculated areas under the curve for 6-month clinical outcomes. The predictive performance of leptin was similar to, but did not obviously improve that of National Institutes of Health Stroke Scale scores. Thus, leptin may help in the prediction of 6-month mortality and unfavorable outcome after intracerebral hemorrhage.     

The Prognostic Value of Serum Neuron-Specific Enolase in Traumatic Brain Injury: Systematic Review and Meta-Analysis

Background

Several studies have suggested that neuron-specific enolase (NSE) in serum may be a biomarker of traumatic brain injury. However, whether serum NSE levels correlate with outcomes remains unclear. The purpose of this review was to evaluate the prognostic value of serum NSE protein after traumatic brain injury.

Methods

PubMed and Embase were searched for relevant studies published up to October 2013. Full-text publications on the relationship of NSE to TBI were included if the studies concerned patients with closed head injury, NSE levels in serum after injury, and Glasgow Outcome Scale (GOS) or Extended GOS (GOSE) scores or mortality. Study design, inclusion criteria, assay, blood sample collection time, NSE cutoff, sensitivity and specificity of NSE for mortality prediction (if sufficient information was provided to calculate these values), and main outcomes were recorded.

Results

Sixteen studies were eligible for the current meta-analysis. In the six studies comparing NSE concentrations between TBI patients who died and those who survived, NSE concentrations correlated with mortality (M.D. 0.28, 95% confidence interval (CI), 0.21 to 0.34; I² 55%). In the eight studies evaluating GOS or GOSE, patients with unfavorable outcomes had significantly higher NSE concentrations than those with favorable outcomes (M.D. 0.24, 95% CI, 0.17 to 0.31; I² 64%). From the studies providing sufficient data, the pooled sensitivity and specificity for mortality were 0.79 and 0.50, and 0.72 and 0.66 for unfavorable neurological prognosis, respectively. The areas under the SROC curve (AUC) of NSE concentrations were 0.73 (95% CI, 0.66–0.80) for unfavorable outcome and 0.76 (95% CI, 0.62–0.90) for mortality.

Conclusions

Mortality and unfavorable outcome were significantly associated with greater NSE concentrations. In addition, NSE has moderate discriminatory ability to predict mortality and neurological outcome in TBI patients. The optimal discrimination cutoff values and optimal sampling time remain uncertain because of significant variations between studies.     

Hypolipoproteinemia and hyperinflammatory cytokines in serum of severe and moderate traumatic brain injury (TBI) patients

Traumatic brain injury (TBI) acts as an inducer of the inflammatory reaction expressed by the release of pro-inflammatory cytokines (interleukin-1beta [IL-1beta], interleukin-6 [IL-6] and interleukin-8 [IL-8]), and causes metabolic alterations in the early, post-traumatic state, either in the brain or/and the systemic circulation. The metabolic changes involve carbohydrates, proteins and lipids. We focused on the serum lipid profile, the impact of trauma on lipoproteins, and their subsequent effects, on inflammation. We investigated the role of cytokines and serum lipids, in patient outcome, reviewing 30-day mortality and the Glasgow Coma Scale (GCS). A total of 75 patients with severe or moderate TBI (GCS 相似文献   

Growth hormone and outcome in patients with intracerebral hemorrhage: a pilot study

Background: Endocrine alterations of the hypothalamic-pituitary-axis are one of the first measurable physiological changes in cerebral insults. During acute stress, human growth hormone (GH) is stimulated and has shown to have a prognostic value in various diseases. Within this pilot study, we evaluated the prognostic value of GH in patients with acute intracerebral hemorrhage (ICH).

Methods: In a prospective observational study in 40 consecutive patients with ICH, GH was measured on admission. The prognostic value of GH to predict 30-day mortality and 90-day functional outcome was assessed. Favorable functional outcome was defined as Barthel Index score >85 points and Modified Rankin Scale <3 points.

Results: GH levels were increased in patients who died within 30 days as compared to survivors (0.45 (IQR 0.20–1.51) vs. 1.51 (IQR 0.91–4.08) p?=?0.03), and in patients with an unfavorable functional outcome as compared to patients with a favorable functional outcome after 90 days 0.28 (IQR 0.16–0.61) vs. 0.78 (IQR 0.31–1.99) p?=?0.03). For mortality prediction, receiver-operating-characteristics revealed an area under the curve (AUC) on admission for GH of 0.78 (95% CI 0.60–0.96), which was in the range of the Glasgow Coma Score (GCS) (AUC 0.82 (95% CI 0.59–1.00) p?=?0.80). For functional outcome prediction, GH had an AUC of 0.71 (95% CI 0.54–0.87), which was statistically not different from the GCS (AUC 0.81 (95% CI 0.68–0.94) p?=?0.36).

Conclusions: In our small cohort of patients with acute ICH, elevated GH level were associated with increased mortality and worse outcome. If confirmed in a larger study, GH levels may be used as an additional prognostic factor in ICH patients. (ClincalTrials.gov number NCT00390962).     

CT follow-up and clinical outcome in severe traumatic brain injury patients

Determining a patient's prognosis after severe traumatic brain injury remains difficult and complex. The purpose of the present study was following up patients with severe traumatic brain injury by correlating their clinical outcome and sequential computer tomography (CT) findings. We investigated 51 patients who survived the first year following an accident. All patients underwent successive CT examinations within a maximum period of 2 years. The patients' outcomes depended on the underlying brain damage and are presented by the Glasgow Outcome Scale. Based on the investigated data we concluded that the worst outcomes were experienced by patients with initial massive cerebral edema, extensive subdural hematoma and intraventricular hemorrhage, followed by stroke as subacute CT finding and cerebral atrophy as chronic finding visible at follow-up CT scans. The majority of lesions identified by CT scan were found in the frontal lobes, basal ganglia, and temporal lobes. We suggest that CT examination still represents a simple and useful tool in attempting to predict the clinical outcome in patients with severe traumatic brain injury.     

Plasma values of oxidants and antioxidants in acute brain hemorrhage

The levels of oxidants xanthine oxidase (XO), nitric oxide (NO), and malondialdehyde (MDA) and of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione reductase (GRD) were determined in plasma within 24 h after onset of hemorrhagic stroke in 17 patients (9 men and 8 women, aged 60.7+/-11.5 yr) and in 20 healthy controls (12 men and 8 women, aged 62.5+/-8.3 yr). Compared to controls, the plasma SOD and total superoxide scavenger activities (TSSA) were significantly lower and the NO levels were significantly higher among the stroke patients. XO showed a slight, nonsignificant increase in the patients, but the levels of MDA, NSSA, GRD, and GSH-Px did not show any significant differences between the two groups. The hemorrhage volume was negatively correlated with the initial score of the Glasgow Coma Scale and a positive correlation with lethal outcome, but it did not correlate significantly with any of the measured parameters. The results suggest that free radicals might play a role in the development of brain injury following brain hemorrhage.     

The Impact of Surgical Experience on Major Intraoperative Aneurysm Rupture and Their Consequences on Outcome: A Multivariate Analysis of 538 Microsurgical Clipping Cases

The incidence and associated mortality of major intraoperative rupture (MIOR) in intracranial aneurysm surgery is diverse. One possible reason is that many studies failed to consider and properly adjust the factor of surgical experience in the context. We conducted this study to clarify the role of surgical experience on MIOR and associated outcome. 538 consecutive intracranial aneurysm surgeries performed on 501 patients were enrolled in this study. Various potential predictors of MIOR were evaluated with stratified analysis and multivariate logistic regression. The impact of surgical experience and MIOR on outcome was further studied in a logistic regression model with adjustment of each other. The outcome was evaluated using the Glasgow Outcome Scale one year after the surgery. Surgical experience and preoperative Glasgow Coma Scale (GCS) were identified as independent predictors of MIOR. Experienced neurovascular surgeons encountered fewer cases of MIOR compared to novice neurosurgeons (MIOR, 18/225, 8.0% vs. 50/313, 16.0%, P = 0.009). Inexperience and MIOR were both associated with a worse outcome. Compared to experienced neurovascular surgeons, inexperienced neurosurgeons had a 1.90-fold risk of poor outcome. On the other hand, MIOR resulted in a 3.21-fold risk of unfavorable outcome compared to those without it. Those MIOR cases managed by experienced neurovascular surgeons had a better prognosis compared with those managed by inexperienced neurosurgeons (poor outcome, 4/18, 22% vs. 30/50, 60%, P = 0.013).     

Phase Synchronization in Electroencephalographic Recordings Prognosticates Outcome in Paediatric Coma

Brain injury from trauma, cardiac arrest or stroke is the most important cause of death and acquired disability in the paediatric population. Due to the lifetime impact of brain injury, there is a need for methods to stratify patient risk and ultimately predict outcome. Early prognosis is fundamental to the implementation of interventions to improve recovery, but no clinical model as yet exists. Healthy physiology is associated with a relative high variability of physiologic signals in organ systems. This was first evaluated in heart rate variability research. Brain variability can be quantified through electroencephalographic (EEG) phase synchrony. We hypothesised that variability in brain signals from EEG recordings would correlate with patient outcome after brain injury. Lower variability in EEG phase synchronization, would be associated with poor patient prognosis. A retrospective study, spanning 10 years (2000–2010) analysed the scalp EEGs of children aged 1 month to 17 years in coma (Glasgow Coma Scale, GCS, <8) admitted to the paediatric critical care unit (PCCU) following brain injury from TBI, cardiac arrest or stroke. Phase synchrony of the EEGs was evaluated using the Hilbert transform and the variability of the phase synchrony calculated. Outcome was evaluated using the 6 point Paediatric Performance Category Score (PCPC) based on chart review at the time of hospital discharge. Outcome was dichotomized to good outcome (PCPC score 1 to 3) and poor outcome (PCPC score 4 to 6). Children who had a poor outcome following brain injury secondary to cardiac arrest, TBI or stroke, had a higher magnitude of synchrony (R index), a lower spatial complexity of the synchrony patterns and a lower temporal variability of the synchrony index values at 15 Hz when compared to those patients with a good outcome.     

Leptin as a marker for severity and prognosis of aneurysmal subarachnoid hemorrhage

Leptin has been identified as a plasma marker for outcomes in traumatic brain injury and intracerebral hemorrhage. We further investigated whether leptin might serve as a marker for severity and prognosis in aneurysmal subarachnoid hemorrhage. One hundred and eight consecutive patients and 108 sex and age – matched healthy subjects were recruited. Plasma leptin levels were measured by enzyme-linked immunosorbent assay. Clinical severity was assessed using World Federation of Neurological Surgeons score and Fisher score. Mortality and poor long-term outcome (Glasgow outcome scale scores of 1–3) at 6 months were recorded. Plasma leptin levels on admission were substantially higher in patients than in healthy controls, and were significantly associated with the clinical severity. There was also a significant association between leptin levels and clinical outcomes at 6 months in multivariate logistic regression analysis. Using receiver operating characteristic curves, we calculated areas under the curve for clinical outcomes at 6 months. The predictive performance of leptin was similar to, but did not obviously improve those of World Federation of Neurological Surgeons score and Fisher score. Thus, leptin may indicate clinical severity of the initial bleeding and also have prognostic value for clinical outcomes in aneurysmal subarachnoid hemorrhage and may therefore help in guiding treatment decisions in the setting of aneurysmal subarachnoid hemorrhage.     

微创血肿清除与侧脑室引流术治疗小脑出血

目的：观察不同软通道微创手术方式治疗小脑出血的临床疗效。方法：高血压脑出血25例分成软通道微创血肿清除组（n=14）和侧脑室引流组（n=11）。以治疗后28天SSS和死亡率作为判断疗效的标准,比较两组的疗效。2组患者在入院时和入院后7 d行（格拉斯哥昏迷量表,Glasgow coma scale,GCS）评分,入院时和入院后14d及28d行（斯勘的纳维亚卒中量表,Scandinavianstroke scale,SSS）评分。结果：治疗组手术后SSS评分14d（t=3.65 P〈0.01）及30d（t=4.01,P〈0.01）,治疗组明显优于对照组。两组总有效率比较有显著差异（P〈0.05）。结论：软通道微创血肿清除术疗效优于单纯侧脑室引流术,其作为治疗小脑出血的微创治疗技术总体上是安全、有效的,明显降低了患者死亡率,提高了患者生存质量。     

CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial

ABSTRACT: BACKGROUND: Worldwide, over 10 million people are killed or hospitalized because of traumatic brain injury each year. About 90% of deaths occur in low- and middle-income countries. The condition mostly affects young adults, and many experience long lasting or permanent disability. The social and economic burden is considerable. Tranexamic acid (TXA) is commonly given to surgical patients to reduce bleeding and the need for blood transfusion. It has been shown to reduce the number of patients receiving a blood transfusion by about a third, reduces the volume of blood transfused by about one unit, and halves the need for further surgery to control bleeding in elective surgical patients. Methods/design The CRASH-3 trial is an international, multicenter, pragmatic, randomized, double-blind, placebo-controlled trial to quantify the effects of the early administration of TXA on death and disability in patients with traumatic brain injury. Ten thousand adult patients who fulfil the eligibility criteria will be randomized to receive TXA or placebo. Adults with traumatic brain injury, who are within 8 h of injury and have any intracranial bleeding on computerized tomography (CT scan) or Glasgow Coma Score (GCS) of 12 or less can be included if the responsible doctor is substantially uncertain as to whether or not to use TXA in this patient. Patients with significant extracranial bleeding will be excluded since there is evidence that TXA improves outcome in these patients. Treatment will entail a 1 g loading dose followed by a 1 g maintenance dose over 8 h. The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses for the primary outcome will be based on time from injury to randomization, the severity of the injury, location of the bleeding, and baseline risk. Interaction tests will be used to test whether the effect of treatment differs across these subgroups. A study with 10,000 patients will have approximately 90% power to detect a 15% relative reduction from 20% to 17% in all-cause mortality. Trial registration Current Controlled Trials ISRCTN15088122; Clinicaltrials.gov NCT01402882.