A systematic review finds methodological improvements necessary for prognostic models in determining traumatic brain injury outcomes.

OBJECTIVES: To describe the modeling techniques used for early prediction of outcome in traumatic brain injury (TBI) and to identify aspects for potential improvements. STUDY DESIGN AND SETTING: We reviewed key methodological aspects of studies published between 1970 and 2005 that proposed a prognostic model for the Glasgow Outcome Scale of TBI based on admission data. RESULTS: We included 31 papers. Twenty-four were single-center studies, and 22 reported on fewer than 500 patients. The median of the number of initially considered predictors was eight, and on average five of these were selected for the prognostic model, generally including age, Glasgow Coma Score (or only motor score), and pupillary reactivity. The most common statistical technique was logistic regression with stepwise selection of predictors. Model performance was often quantified by accuracy rate rather than by more appropriate measures such as the area under the receiver-operating characteristic curve. Model validity was addressed in 15 studies, but mostly used a simple split-sample approach, and external validation was performed in only four studies. CONCLUSION: Although most models agree on the three most important predictors, many were developed on small sample sizes within single centers and hence lack generalizability. Modeling strategies have to be improved, and include external validation.

Adjustment for strong predictors of outcome in traumatic brain injury trials: 25% reduction in sample size requirements in the IMPACT study.

The aim of this study was to quantify the potential reduction in sample size that can be achieved by adjustment for predictors of outcome in traumatic brain injury (TBI) trials. We used individual patient data from seven therapeutic phase III randomized clinical trials (RCTs; n = 6166) in moderate or severe TBI, and three TBI surveys (n = 2238). The primary outcome was the dichotomized Glasgow Outcome Scale at 6 months (favorable/unfavorable). Baseline predictors of outcome considered were age, motor score, pupillary reactivity, computed tomography (CT) classification, traumatic subarachnoid hemorrhage, hypoxia, hypotension, glycemia, and hemoglobin. We calculated the potential sample size reduction obtained by adjustment of a hypothetical treatment effect for one to seven predictors with logistic regression models. The distribution of predictors was more heterogeneous in surveys than in trials. Adjustment of the treatment effect for the strongest predictors (age, motor score, and pupillary reactivity) yielded a reduction in sample size of 16-23% in RCTs and 28-35% in surveys. Adjustment for seven predictors yielded a reduction of about 25% in most studies: 20-28% in RCTs and 32-39% in surveys. A major reduction in sample size can be obtained with covariate adjustment in TBI trials. Covariate adjustment for strong predictors should be incorporated in the analysis of future TBI trials.

Misclassification and treatment effect on primary outcome measures in clinical trials of severe neurotrauma.

The power of clinical trials depends mainly on the choice of the primary outcome measure, the statistical test, and the sample size. The most widely used outcome measure has been the five-category Glasgow Outcome Scale (GOS). Contrary to intuition, we show that more categories do not necessarily increase the power of a trial and actually can decrease power. This is so for two reasons. The more categories of outcome measure used, the more the likelihood for misclassifications. The effect of 0%, 10%, and 20% misclassification rate upon power is illustrated. Misclassification rates in two completed trials are examined based on comparative overlap in GOS and Disability Rating Scale (DRS) categories. The outcome results of the "National Acute Brain Injury Study: Hypothermia" indicate that the ideal number of categories also depends upon the effect of study treatment. In the recently completed hypothermia trial, the use of a dichotomized GOS (good recovery/moderate disability versus severe disability/vegetative/dead) is shown to be more sensitive than use of three or more categories of the GOS. The results point to the importance of training study investigators who will collect the outcome data. The results also indicate that the number of categories should be carefully determined using the pilot data or the data from phase II trials.

Hypothermia on admission in patients with severe brain injury.

Data from the "National Acute Brain Injury Study: Hypothermia" were examined to identify the impact of hypothermia on admission. In all patients, temperature was measured at randomization using bladder catheters with thermistors. Patients assigned to hypothermia were cooled using fluid-circulating pads. Outcome was assessed at 6 months using the dichotomized Glasgow Outcome Scale (good outcome = good recovery/moderate disability; poor outcome = severe disability/vegetative/dead). One-hundred and two patients (hypothermia, 62; normothermia, 40) were hypothermic on admission (< or =35.0 degrees C). Hypothermia-on-admission patients assigned to normothermia (n = 40) had a 78% poor outcome, and normothermia-on-admission patients assigned to normothermia had a 52% poor outcome (p < 0.004). Hypothermia-on-admission patients assigned to hypothermia had a lower percentage of poor outcomes than those assigned to normothermia (hypothermia, 61%; normothermia, 78%; p = 0.09). Patients over 45 years of age had an adverse effect of hypothermia regardless of admission temperature due to medical complications. Patients who were hypothermic on admission, age < or = 45 years (n = 81), and assigned to hypothermia had a significantly lower percentage of poor outcomes than those assigned to normothermia (hypothermia, 52%; normothermia, 76%; p = 0.02). Factors associated with hypothermia on admission were increased age, prehospital hypotension, smaller size, positive blood alcohol, larger volume of pre-hospital fluids, slightly higher injury severity, and winter enrollment The treatment effect was found in all of the four centers, which randomized the majority (80%) of the patients. It is unclear whether the improved outcome when hypothermia is maintained is a beneficial effect of very early hypothermia induction or an adverse effect of permitting the patients to rewarm passively.

Clinical trials in head injury.

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate significant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.

Clinical trials in traumatic brain injury: lessons for the future.

Thus far, none of the neuroprotective drugs that have been tested to reduce or prevent secondary ischemic brain damage have been shown clear benefit. We will attempt to identify factors that may be responsible for some of these failures. We also will give our thoughts on how to prevent these pitfalls in the usefulness and criteria for use of animal models for traumatic brain injury to depict human head injury are discussed. Clearly, mechanism-driven trials, in which individual pathophysiological mechanisms are targeted, are more likely to show benefit in this heterogeneous patient population. Other factors, such as the effect of brain penetration, safety and tolerability of the compound, and the interface between the pharmaceutical industry and academics are a major influence in the success of these trials. Furthermore, the way trials have been analyzes in the past may not always have been be the most appropriate to show benefits. It is clear that a multi-targeted approach is necessary to address the complicated and closely related mechanisms seen after traumatic and or ischemic brain damage.

Outcome measures for clinical trials in neurotrauma.

Under the auspices of the American Brain Injury Consortium and the Joint Section of Neurotrauma and Critical Care of the American Association of Neurological Surgeons, the authors have reviewed and formulated opinions based on the evidence on protocol design and the outcome measures used for clinical trials in patients with a severe or moderate traumatic brain injury (TBI). First, in view of the heterogeneity of the population under study, the authors suggest that block randomization and stratification should always be used in the design of neurotrauma trials. Second, although the Glasgow Outcome Scale (GOS) remains the most widely used and accepted instrument for TBI trials, the authors believe the eight-point expanded scale that has recently been designed will ultimately provide greater discrimination, and narrower categories and will ultimately prove superior for detecting more subtle changes in outcome. Furthermore, the authors recommend, in view of the profound cognitive impairment in survivors of TBI, that neuropsychological tests be explored further as an adjunct to the GOS. Future research should focus on the development of more sensitive and specific surrogate outcome measures such as magnetic resonance imaging, neurochemical, neuropsychological, and quality of life measures in order to detect a neuroprotective effect in patients with TBI.

Fluid thresholds and outcome from severe brain injury.

OBJECTIVE: To determine, by retrospective analysis, critical thresholds for intracranial pressure, mean arterial pressure, cerebral perfusion pressure, and fluid balance associated with poor outcome in patients with severe brain injury. DESIGN: Retrospective review of patient data from the prospective, randomized, multicenter National Acute Brain Injury Study: Hypothermia, comparing outcome results at 6 months after injury with intracranial pressure, mean arterial pressure, cerebral perfusion pressure, and fluid balance measurements recorded during the 96-hr period after randomization. SETTING: Emergency departments and intensive care units in 11 metropolitan tertiary care university hospitals. PATIENTS: A total of 392 patients, aged 16-65 yrs, with severe, nonpenetrating brain injuries and a Glasgow Coma Scale score of 3-8 after resuscitation, who were enrolled in a study designed to determine the treatment effect of moderate hypothermia in patients with severe brain injury. INTERVENTION: Standard brain injury treatment for 193 randomly assigned patients and standard treatment plus hypothermia for 48 hrs for 199 patients. MEASUREMENTS AND MAIN RESULTS: Intracranial pressure levels of 20, 25, and 30 mm Hg, mean arterial pressure levels of 70 and 80 mm Hg, cerebral perfusion pressure levels of 50, 60, and 70 mm Hg, and fluid balance levels in quartiles were examined for their effect on outcome as measured by the Glasgow Outcome Scale at 6 months after injury. When considered separately, any of the following-intracranial pressure >25 mm Hg, mean arterial pressure <70 mm Hg, or cerebral perfusion pressure <60 mm Hg and fluid balance lower than -594 mL-was associated with an increased percentage of patients with poor outcome. When the variables were combined into a stepwise logistic regression model, Glasgow Coma Scale score at admission, age, mean arterial pressure <70 mm Hg, fluid balance lower than -594 mL, and intracranial pressure > 25 mm Hg, in that order, were the most powerful variables in determining outcome. CONCLUSIONS: Exceeding thresholds of intracranial pressure, mean arterial pressure, cerebral perfusion pressure, and fluid volume may be detrimental to severe brain injury outcome. Fluid balance lower than -594 mL was associated with an adverse effect on outcome, independent of its relationship to intracranial pressure, mean arterial pressure, or cerebral perfusion pressure.