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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. 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. 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.

We studied the prognostic value of a wide range of conventional and novel prognostic factors on admission after traumatic brain injury (TBI) using both univariate and multivariable analysis. The outcome measure was Glasgow Outcome Scale at 6 months after injury. Individual patient data were available on a cohort of 8686 patients drawn from eight randomized controlled trials and three observational studies. The most powerful independent prognostic variables were age, Glasgow Coma Scale (GCS) motor score, pupil response, and computerized tomography (CT) characteristics, including the Marshall CT classification and traumatic subarachnoid hemorrhage. Prothrombin time was also identified as a powerful independent prognostic factor, but it was only available for a limited number of patients coming from three of the relevant studies. Other important prognostic factors included hypotension, hypoxia, the eye and verbal components of the GCS, glucose, platelets, and hemoglobin. These results on prognostic factors will underpin future work on the IMPACT project, which is focused on the development of novel approaches to the design and analysis of clinical trials in TBI. In addition, the results provide pointers to future research, including further analysis of the prognostic value of prothrombin time, and the evaluation of the clinical impact of intervening aggressively to correct abnormalities in hemoglobin, glucose, and coagulation.

We studied the prognostic strength of the individual components of the Glasgow Coma Scale (GCS) and pupil reactivity to Glasgow Outcome Score (GOS) at 6 months post-injury. A total of 8721 moderate or severe traumatic brain injury (TBI) patient data from the IMPACT database on traumatic brain injury comprised the study cohort. The associations between motor score and pupil reactivity and 6-month GOS were analyzed by binary logistic regression and proportional odds methodology. The strength of prognostic effects were expressed as the unadjusted odds ratios presented for all individual studies as well as in meta-analysis. We found a consistent strong association between motor score and 6-month GOS across all studies (OR 1.74–7.48). The Eye and Verbal components were also strongly associated with GOS. In the pooled population, one or both un-reactive pupils and lower motor scores were significantly associated with unfavorable outcome (range 2.71–7.31). We also found a significant change in motor score from pre-hospital direct to study hospital enrollment ( p < 0.0001) and from the first in-hospital to study enrollment scores (p < 0.0001). Pupil reactivity was more robust between these time points. It is recommended that the study hospital enrollment GCS and pupil reactivity be used for prognostic analysis.

Traumatic brain injury (TBI) is a major health and socio-economic problem throughout the world. Many randomized controlled trials (RCTs) have been performed to investigate the effectiveness of new therapies, but none have convincingly demonstrated benefit. Clinical trials in TBI pose complex methodological challenges and meeting these requires new approaches. The challenges are related to the heterogeneity of head injuries, to optimum analysis of outcome and to aspects of the design of trials. To address these, we have created the IMPACT database on TBI through merging individual patient data from eight RCTs and three observational surveys. This database forms a culture medium in which innovative approaches to improving trial design and analysis are being explored. We hypothesize that the statistical power of TBI trials may be increased by adjusting for heterogeneity with covariate adjustment and/or prognostic targeting, by exploiting the ordinal nature of the Glasgow Outcome Scale and by relating the outcome obtained in individual patients to their baseline prognostic risk. Extensive prognostic analysis was required as a first step towards our aim of optimizing the chance of demonstrating benefit of new therapies in future trials. The fruits of this analysis are reported in detail in the subsequent reports in this issue of the Journal of Neurotrauma. The results will lead to the development and validation of new prognostic models, which will be applied to deal with heterogeneity. The findings will be synthesized into recommendations for the design and analysis of future RCTs, with the expectation of increasing the likelihood of demonstrating the benefit of a truly effective new therapy or therapeutic agent in victims of a head injury.

We determined the relationship between secondary insults (hypoxia, hypotension, and hypothermia) occurring prior to or on admission to hospital and 6-month outcome after traumatic brain injury (TBI). A meta-analysis of individual patient data, from seven Phase III randomized clinical trials (RCT) in moderate or severe TBI and three TBI population-based series, was performed to model outcome as measured by the Glasgow Outcome Scale (GOS). Proportional odds modeling was used to relate the probability of a poor outcome to hypoxia (N = 5661), hypotension ( N = 6629), and hypothermia ( N = 4195) separately. We additionally analyzed the combined effects of hypoxia and hypotension and performed exploratory analysis of associations with computerized tomography (CT) classification and month of injury. Having a pre-enrollment insult of hypoxia, hypotension or hypothermia is strongly associated with a poorer outcome (odds ratios of 2.1 95% CI [1.7–2.6], 2.7 95% CI [2.1–3.4], and 2.2 95% CI [1.6–3.2], respectively). Patients with both hypoxia and hypotension had poorer outcomes than those with either insult alone. Radiological signs of raised intracranial pressure (CT class III or IV) were more frequent in patients who had sustained hypoxia or hypotension. A significant association was observed between month of injury and hypothermia. The occurrence of secondary insults prior to or on admission to hospital in TBI patients is strongly related to poorer outcome and should therefore be a priority for emergency department personnel.

Computerized tomography (CT) scanning provides an objective assessment of the structural damage to the brain following traumatic brain injury (TBI). We aimed to describe and quantify the relationship between CT characteristics and 6-month outcome, assessed by the Glasgow Outcome Scale (GOS). Individual patient data from the IMPACT database were available on CT classification (N = 5209), status of basal cisterns ( N = 3861), shift ( N = 4698), traumatic subarachnoid hemorrhage (tSAH) ( N = 7407), and intracranial lesions ( N = 7613). We used binary logistic and proportional odds regression for prognostic analyses. The CT classification was strongly related to outcome, with worst outcome for patients with diffuse injuries in CT class III (swelling; OR 2.50; CI 2.09–3.0) or CT class IV (shift; OR 3.03; CI 2.12–4.35). The prognosis in patients with mass lesions was better for patients with an epidural hematoma (OR 0.64; CI 0.56–0.72) and poorer for an acute subdural hematoma (OR 2.14; CI 1.87–2.45). Partial obliteration of the basal cisterns (OR 2.45; CI 1.88–3.20), tSAH (OR 2.64; CI 2.42–2.89), or midline shift (1–5 mm—OR 1.36; CI 1.09–1.68); >5 mm—OR 2.20; CI 1.64–2.96) were strongly related to poorer outcome. Discrepancies were found between the scoring of basal cisterns/shift and the CT classification, indicating observer variation. These were less marked in studies that had used a central review process. Multivariable analysis indicated that individual CT characteristics added substantially to the prognostic value of the CT classification alone. We conclude that both the CT classification and individual CT characteristics are important predictors of outcome in TBI. For clinical trials, a central review process is advocated to minimize observer variability in CT assessment.

The eight-point extended Glasgow Outcome Scale (GOSE) is commonly used as the primary outcome measure in traumatic brain injury (TBI) clinical trials. The outcome is conventionally collected through a structured interview with the patient alone or together with a caretaker. Despite the fact that using the structured interview questionnaires helps reach agreement in GOSE assessment between raters, significant variation remains among different raters. We introduce an alternate GOSE rating system as an aid in determining GOSE scores, with the objective of reducing inter-rater variation in the primary outcome assessment in TBI trials. Forty-five trauma centers were randomly assigned to three groups to assess GOSE scores on sample cases, using the alternative GOSE rating system coupled with central quality control (Group 1), the alternative system alone (Group 2), or conventional structured interviews (Group 3). The inter-rater variation between an expert and untrained raters was assessed for each group and reported through raw agreement and with weighted kappa (κ) statistics. Groups 2 and 3 without central review yielded inter-rater agreements of 83% (weighted κ = 0.81; 95% CI 0.69, 0.92) and 83% (weighted κ = 0.76, 95% CI 0.63, 0.89), respectively, in GOS scores. In GOSE, the groups had an agreement of 76% (weighted κ = 0.79; 95% CI 0.69, 0.89), and 63% (weighted κ = 0.70; 95% CI 0.60, 0.81), respectively. The group using the alternative rating system coupled with central monitoring yielded the highest inter-rater agreement among the three groups in rating GOS (97%; weighted κ = 0.95; 95% CI 0.89, 1.00), and GOSE (97%; weighted κ = 0.97; 95% CI 0.91, 1.00). The alternate system is an improved GOSE rating method that reduces inter-rater variations and provides for the first time, source documentation and structured narratives that allow a thorough central review of information. The data suggest that a collective effort can be made to minimize inter-rater variation.

Outcome following traumatic brain injury (TBI) is not only dependent on the nature and severity of injury and subsequent treatment, but also on constituent characteristics of injured individuals. We aimed to describe and quantify the relationship between demographic characteristics and six month outcome assessed by the Glasgow Outcome Scale (GOS) after TBI. Individual patient data on age (n = 8719), gender (n = 8720), race (n = 5320), and education (n = 2201) were extracted from eight therapeutic Phase III randomized clinical trials and three surveys in moderate or severe TBI, contained in the IMPACT database. The strength of prognostic effects was analyzed with binary and proportional odds regression analysis and expressed as an odds ratio. Age was analyzed as a continuous variable with spline functions, and the odds ratio calculated over the difference between the 75 th and 25 th percentiles. Associations with other predictors were explored. Increasing age was strongly related to poorer outcome (OR 2.14; 95% CI 2.00–2.28) in a continuous fashion that could be approximated by a linear function. No gender differences in outcome were found (OR: 1.01; CI 0.92–1.11), and exploratory analysis failed to show any gender/age interaction. The studies included predominantly Caucasians (83%); outcome in black patients was poorer relative to this group (OR 1.30; CI 1.09–1.56). This relationship was sustained on adjusted analyses, and requires further study into mediating factors. Higher levels of education were weakly related to a better outcome (OR: 0.70; CI 0.52–0.94). On multivariable analysis adjusting for age, motor score, and pupils, the prognostic effect of race and education were sustained. We conclude that outcome following TBI is dependent on age, race, to a lesser extent on education, but not on gender.

The objective of this report is to describe the design and content of the International Mission for Prognosis And Clinical Trial (IMPACT) database of traumatic brain injury which contains the complete dataset from most clinical trials and organized epidemiologic studies conducted over the past 20 years. This effort, funded by the U.S. National Institutes of Health, has led to the accumulation thus far of data from 9205 patients with severe and moderate brain injuries from eight randomized placebo controlled trials and three observational studies. Data relevant to the design and analysis of pragmatic Phase III clinical trials, including pre-hospital, admission, and post-resuscitation assessments, information on the acute management, and short-and long-term outcome were merged into a top priority data set (TPDS). The major emphasis during the first phase of study is on information from time of injury to post-resuscitation and outcome at 6 months thereby providing a unique resource for prognostic analysis and for studies aimed at optimizing the design and analysis of Phase III trials in traumatic brain injury.

Background The hormone and neuropeptide arginine-vasopressin is designated to the maintenance of osmotic homoeostasis and blood pressure regulation. While experimental data show vasopressin V 1A receptors to regulate aquaporin (AQP)4 water channel dependent brain water movement, the specific role in vasogenic and cytotoxic edema formation remains unclear. The present study was designed to quantify the V 1A receptor mediated regional brain edema formation in two clinically relevant experimental models, brain injury combined with secondary insult and focal ischemia. Methods Male Sprague–Dawley rats were randomly assigned to a continuous infusion of vehicle (1 % DMSO) or the selective non-peptide V 1A antagonist SR49059 (83nM = 1 mg/kg) starting before controlled cortical impact (CCI) injury plus hypoxia and hypotension (HH, 30 min), or middle cerebral artery (MCA) occlusion (2 h + 2 h reperfusion). Results A global analysis of brain water content by the wet/dry weight method allowed optimizing the SR49059 dosage, and demonstrated the down-regulation of brain AQP4 expression by immunoblotting. Microgravimetrical quantification in 64 one mm 3 samples per animal ( n  = 6 per group) from bregma +2.7 to −6.3 mm analysis demonstrated brain edema to be reduced at 4 h by SR49059 treatment in the injured and contralateral cortex following CCI + HH ( p  = 0.007, p  < 0.001) and in the infarct area following MCA occlusion ( p  = 0.013, p  = 0.002, p  = 0.004). Conclusions Our findings demonstrate that an early cytotoxic brain edema component following brain injury plus secondary insult or focal ischemia results from a vasopressin V 1A receptor mediated response, and occurs most likely through AQP4 up-regulation. The V 1A antagonist SR49059 offers a new avenue in brain edema treatment and prompts further study into the role of vasopressin following brain injury.