Trials In Traumatic Brain Injury Research Articles

Use of magnetic resonance imaging in severe pediatric traumatic brain injury: assessment of current practice.

There is no consensus on the optimal timing and specific brain MRI sequences in the evaluation and management of severe pediatric traumatic brain injury (TBI), and information on current practices is lacking. The authors performed a survey of MRI practices among sites participating in a multicenter study of severe pediatric TBI to provide information for designing future clinical trials using MRI to assess brain injury after severe pediatric TBI. Information on current imaging practices and resources was collected from 27 institutions participating in the Approaches and Decisions after Pediatric TBI Trial. Multiple-choice questions addressed the percentage of patients with TBI who have MRI studies, timing of MRI, MRI sequences used to investigate TBI, as well as the magnetic field strength of MR scanners used at the participating institutions and use of standardized MRI protocols for imaging after severe pediatric TBI. Overall, the reported use of MRI in pediatric patients with severe TBI at participating sites was high, with 40% of sites indicating that they obtain MRI studies in > 95% of this patient population. Differences were observed in the frequency of MRI use between US and international sites, with the US sites obtaining MRI in a higher proportion of their pediatric patients with severe TBI (94% of US vs 44% of international sites reported MRI in at least 70% of patients with severe TBI). The reported timing and composition of MRI studies was highly variable across sites. Sixty percent of sites reported typically obtaining an MRI study within the first 7 days postinjury, with the remainder of responses distributed throughout the first 30-day postinjury period. Responses indicated that MRI sequences sensitive for diffuse axonal injury and ischemia are frequently obtained in patients with TBI, whereas perfusion imaging and spectroscopy techniques are less common. Results from this survey suggest that despite the lack of consensus or guidelines, MRI is commonly obtained during the acute clinical setting after severe pediatric TBI. The variation in MRI practices highlights the need for additional studies to determine the utility, optimal timing, and composition of clinical MRI studies after TBI. The information in this survey describes current clinical MRI practices in children with severe TBI and identifies important challenges and objectives that should be considered when designing future studies.

Neuroprotective Effects of Cyclosporine in a Porcine Pre-Clinical Trial of Focal Traumatic Brain Injury.

Mitochondrial dysfunction is thought to be a hallmark of traumatic brain injury (TBI) and plays a pivotal role in the resulting cellular injury. Cyclophilin D–mediated activation of the mitochondrial permeability transition pore has been suggested to contribute to this secondary injury cascade. Cyclosporine possesses neuroprotective properties that have been attributed to the desensitization of mitochondrial permeability transition pore activation. In vivo animal experiments have demonstrated neuroprotective effects of cyclosporine in more than 20 independent experimental studies in a multitude of different experimental models. However, the majority of these studies have been carried out in rodents. The aim of the present study was to evaluate the efficacy of a novel and cremophor/kolliphor EL–free lipid emulsion formulation of cyclosporine in a translational large animal model of TBI. A mild-to-moderate focal contusion injury was induced in piglets using a controlled cortical impact device. After initial step-wise analyses of pharmacokinetics and comparing with exposure of cyclosporine in clinical TBI trials, a 5-day dosing regimen with continuous intravenous cyclosporine infusion (20 mg/kg/day) was evaluated in a randomized and blinded placebo-controlled setting. Cyclosporine reduced the volume of parenchymal injury by 35%, as well as improved markers of neuronal injury, as measured with magnetic resonance spectroscopic imaging. Further, a consistent trend toward positive improvements in brain metabolism and mitochondrial function was observed in the pericontusional tissue. In this study, we have demonstrated efficacy using a novel cyclosporine formulation in clinically relevant and translatable outcome metrics in a large animal model of focal TBI.

Changes in the gray and white matter of patients with ischemic-edematous insults after traumatic brain injury.

Gray matter (GM) and white matter (WM) are vulnerable to ischemic-edematous insults after traumatic brain injury (TBI). The extent of secondary insult after brain injury is quantifiable using quantitative CT analysis. One conventional quantitative CT measure, the gray-white matter ratio (GWR), and a more recently proposed densitometric analysis are used to assess the extent of these insults. However, the prognostic capacity of the GWR in patients with TBI has not yet been validated. This study aims to test the prognostic value of the GWR and evaluate the alternative parameters derived from the densitometric analysis acquired during the acute phase of TBI. In addition, the prognostic ability of the conventional TBI prognostic models (i.e., IMPACT [International Mission for Prognosis and Analysis of Clinical Trials in TBI] and CRASH [Corticosteroid Randomisation After Significant Head Injury] models) were compared to that of the quantitative CT measures. Three hundred patients with TBI of varying ages (92 pediatric, 94 adult, and 114 geriatric patients) and admitted between 2008 and 2013 were included in this retrospective cohort study. The normality of the density of the deep GM and whole WM was evaluated as the proportion of CT pixels with Hounsfield unit values of 31-35 for GM and 26-30 for WM on CT images of the entire supratentorial brain. The outcome was evaluated using the Glasgow Outcome Scale (GOS) at discharge (GOS score ≤ 3, n = 100). Lower proportions of normal densities in the deep GM and whole WM indicated worse outcomes. The proportion of normal WM exhibited a significant prognostic capacity (area under the curve [AUC] = 0.844). The association between the outcome and the normality of the WM density was significant in adult (AUC = 0.792), pediatric (AUC = 0.814), and geriatric (AUC = 0.885) patients. In pediatric patients, the normality of the overall density and the density of the GM were indicative of the outcome (AUC = 0.751). The average GWR was not associated with the outcome (AUC = 0.511). IMPACT and CRASH models showed adequate and reliable performance in the pediatric and geriatric groups but not in the adult group. The highest overall predictive performance was achieved by the densitometry-augmented IMPACT model (AUC = 0.881). Both deep GM and WM are susceptible to ischemic-edematous insults during the early phase of TBI. The extent of the secondary injury was better evaluated by analyzing the normality of the deep GM and WM rather than by calculating the GWR.

Randomized Controlled Trials in Adult Traumatic Brain Injury: A Systematic Review on the Use and Reporting of Clinical Outcome Assessments.

As part of efforts to improve study design, the use of outcome measures in randomized controlled trials (RCTs) in traumatic brain injury (TBI) is receiving increasing attention. This review aimed to assess how clinical outcome assessments (COAs) have been used and reported in RCTs in adult TBI. Systematic literature searches were conducted to identify medium to large (n ≥ 100) acute and post-acute TBI trials published since 2000. Data were extracted independently by two reviewers using a set of structured templates. Items from the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement and CONSORT patient-reported outcomes (PROs) extension were used to evaluate reporting quality of COAs. Glasgow Outcome Scale/Extended (GOS/GOSE) data were extracted using a checklist developed specifically for the review. A total of 126 separate COAs were identified in 58 studies. The findings demonstrate heterogeneity in the use of TBI outcomes, limiting comparisons and meta-analyses of RCT findings. The GOS/GOSE was included in 39 studies, but implemented in a variety of ways, which may not be equivalent. Multi-dimensional outcomes were used in 30 studies, and these were relatively more common in rehabilitation settings. The use of PROs was limited, especially in acute study settings. Quality of reporting was variable, and key information concerning COAs was often omitted, making it difficult to know how precisely outcomes were assessed. Consistency across studies would be increased and future meta-analyses facilitated by (a) using common data elements (CDEs) recommendations for TBI outcomes and (b) following CONSORT guidelines when publishing RCTs.

Incidence and impact of withdrawal of life-sustaining therapies in clinical trials of severe traumatic brain injury: A systematic review.

Background Most deaths following severe traumatic brain injury follow decisions to withdraw life-sustaining therapies. However, the incidence of the withdrawal of life-sustaining therapies and its potential impact on research data interpretation have been poorly characterized. The aim of this systematic review was to assess the reporting and the impact of withdrawal of life-sustaining therapies in randomized clinical trials of patients with severe traumatic brain injury. Methods We searched Medline, Embase, Cochrane Central, BIOSIS, and CINAHL databases and references of included trials. All randomized controlled trials published between January 2002 and August 2015 in the six highest impact journals in general medicine, critical care medicine, and neurocritical care (total of 18 journals) were considered for eligibility. Randomized controlled trials were included if they enrolled adult patients with severe traumatic brain injury (Glasgow Coma Scale ≤ 8) and reported data on mortality. Our primary objective was to assess the proportion of trials reporting the withdrawal of life-sustaining therapies in a publication. Our secondary objectives were to describe the overall mortality rate, the proportion of deaths following the withdrawal of life-sustaining therapies, and to assess the impact of the withdrawal of life-sustaining therapies on trial results. Results From 5987 citations retrieved, we included 41 randomized trials (n = 16,364, ranging from 11 to 10,008 patients). Overall mortality was 23% (range = 3%-57%). Withdrawal of life-sustaining therapies was reported in 20% of trials (8/41, 932 patients in trials) and the crude number of deaths due to the withdrawal of life-sustaining therapies was reported in 17% of trials (7/41, 884 patients in trials). In these trials, 63% of deaths were associated with the withdrawal of life-sustaining therapies (105/168). An analysis carried out by imputing a 4% differential rate in instances of withdrawal of life-sustaining therapies between study groups yielded different results and conclusions in one third of the trials. Conclusion Data on the withdrawal of life-sustaining therapies are incompletely reported in randomized controlled trials of patients with severe traumatic brain injury. Given the high proportion of deaths due to the withdrawal of life-sustaining therapies in severe traumatic brain injury patients, and the potential of this medical decision to influence the results of clinical trials, instances of withdrawal of life-sustaining therapies should be systematically reported in clinical trials in this group of patients.

Optimizing Outcome Assessment in Multicenter TBI Trials: Perspectives From TRACK-TBI and the TBI Endpoints Development Initiative.

Traumatic brain injury (TBI) is a global public health problem that affects the long-term cognitive, physical, and psychological health of patients, while also having a major impact on family and caregivers. In stark contrast to the effective trials that have been conducted in other neurological diseases, nearly 30 studies of interventions employed during acute hospital care for TBI have failed to identify treatments that improve outcome. Many factors may confound the ability to detect true and meaningful treatment effects. One promising area for improving the precision of intervention studies is to optimize the validity of the outcome assessment battery by using well-designed tools and data collection strategies to reduce variability in the outcome data. The Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, conducted at 18 sites across the United States, implemented a multidimensional outcome assessment battery with 22 measures aimed at characterizing TBI outcome up to 1 year postinjury. In parallel, through the TBI Endpoints Development (TED) Initiative, federal agencies and investigators have partnered to identify the most valid, reliable, and sensitive outcome assessments for TBI. Here, we present lessons learned from the TRACK-TBI and TED initiatives aimed at optimizing the validity of outcome assessment in TBI.

Continuous Infusion of Phenelzine, Cyclosporine A, or Their Combination: Evaluation of Mitochondrial Bioenergetics, Oxidative Damage, and Cytoskeletal Degradation following Severe Controlled Cortical Impact Traumatic Brain Injury in Rats.

To date, all monotherapy clinical traumatic brain injury (TBI) trials have failed, and there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies for the acute treatment of severe TBI. Due to the complex secondary injury cascade following injury, there is a need to develop multi-mechanistic combinational neuroprotective approaches for the treatment of acute TBI. As central mediators of the TBI secondary injury cascade, both mitochondria and lipid peroxidation-derived aldehydes make promising therapeutic targets. Cyclosporine A (CsA), an FDA-approved immunosuppressant capable of inhibiting the mitochondrial permeability transition pore, and phenelzine (PZ), an FDA-approved monoamine oxidase inhibitor capable of scavenging neurotoxic lipid peroxidation-derived aldehydes, have both been shown to be partially neuroprotective following experimental TBI. Therefore, it follows that the combination of PZ and CsA may enhance neuroprotection over either agent alone through the combining of distinct but complementary mechanisms of action. Additionally, as the first 72 h represents a critical time period following injury, it follows that continuous drug infusion over the first 72 h following injury may also lead to optimal neuroprotective effects. This is the first study to examine the effects of a 72 h subcutaneous continuous infusion of PZ, CsA, and the combination of these two agents on mitochondrial respiration, mitochondrial bound 4-hydroxynonenal (4-HNE), and acrolein, and α-spectrin degradation 72 h following a severe controlled cortical impact injury in rats. Our results indicate that individually, both CsA and PZ are able to attenuate mitochondrial 4-HNE and acrolein, PZ is able to maintain mitochondrial respiratory control ratio and cytoskeletal integrity but together, PZ and CsA are unable to maintain neuroprotective effects.

IMPACT Score for Traumatic Brain Injury: Validation of the Prognostic Tool in a Spanish Cohort.

The aim of this work was to validate the IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in TBI) model in a Spanish cohort of patients with moderate-severe TBI (traumatic brain injury). Two level I neurotrauma centers. Patients admitted to these hospitals between 2011 and 2014 with a diagnosis of TBI and a Glasgow Coma Scale score of 12 or less. Prospective observational study. We collected prospectively the clinical variables included in the IMPACT models. Outcome evaluation was prospectively done at 6-month follow-up according to the Glasgow Outcome Scale. A total of 290 patients were included in the study. Forty-seven patients (16.2%) died within 6 months post-TBI, and 74 patients (25.5%) had an unfavorable outcome. The Hosmer-Lemeshow test revealed that there was no difference between observed and predicted outcomes; hence, the 3 models displayed adequate calibration for predicting 6-month mortality or unfavorable outcome. The receiver operating characteristic curve indicated that the 3 models (Core, Extended, and Lab) could accurately discriminate between favorable and unfavorable outcomes, as well as between survival and mortality (P < .001). The IMPACT model validates prediction of 6-month outcomes in a Spanish population of moderate-severe TBI. IMPACT Lab model is the one that presents a higher discriminative capacity. These results encourage the implementation of the IMPACT model as a prognostic tool in the management of patients with TBI.

Targeting microthrombosis and neuroinflammation with vepoloxamer for therapeutic neuroprotection after traumatic brain injury.

Targeting microthrombosis and neuroinflammation with vepoloxamer for therapeutic neuroprotection after traumatic brain injury.

Efficacy of decompressive craniectomy in the management of intracranial pressure in severe traumatic brain injury.

Traumatic brain injury (TBI) is a common cause of permanent disability for which clinical management remains suboptimal. Elevated intracranial pressure (ICP) is a common sequela following TBI leading to death and permanent disability if not properly managed. While clinicians often employ stepwise acute care algorithms to reduce ICP, a number of patients will fail medical management and may be considered for surgical decompression. Decompressive craniectomy (DC) involves removing a component of the bony skull to allow cerebral tissue expansion in order to reduce ICP. However, the impact of DC, which is performed in the setting of neurological instability, ongoing secondary injury, and patient resuscitation, has been challenging to study and outcomes are not well understood. This review summarizes historical and recent studies to elucidate indications for DC and the nuances, risks and complications in its application. The pathophysiology driving ICP elevation, and the corresponding medical interventions for their temporization and treatment, are thoroughly described. The current state of DC - including appropriate injury classification, surgical techniques, concurrent medical therapies, mortality and functional outcomes - is presented. We also report on the recent updates from large randomized controlled trials in severe TBI (Decompressive Craniectomy [DECRA] and Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of ICP [RESCUEicp]), and recommendations for early DC to treat refractory ICP elevations in malignant middle cerebral artery syndrome. Limitations for DC, such as the equipoise between immediate reduction in ICP and clinically meaningful functional outcomes, are discussed in support of future investigations.

Behavioral Clinical Trials in Moderate to Severe Pediatric Traumatic Brain Injury: Challenges, Potential Solutions, and Lessons Learned.

: The purpose of this commentary is to outline the challenges encountered when conducting clinical trials of interventions for pediatric traumatic brain injury (TBI) and share potential solutions for surmounting these issues. This commentary grows out of our experience implementing 8 randomized clinical trials (RCTs) of family-centered interventions to reduce child behavior problems and caregiver/parent distress following pediatric brain injury. These studies, involving more than 600 participants from 8 clinical centers, support the feasibility of conducting RCTs with children who have sustained TBIs while highlighting potential challenges and threats to validity. The challenges of behavioral trials for pediatric TBI are apparent but not insurmountable. Careful consideration of the clinical trial issues outlined in this commentary can inform design choices and analyses when planning a clinical trial. It is critically important that investigators share their failures as well their successes to move the field of pediatric TBI intervention research forward.

Cause and Timing of Death and Subgroup Differential Effects of Erythropoietin in the EPO-TBI Study.

The EPO-TBI study randomized 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal, or death during maximal care) and non-cerebral (death following withdrawal or during maximal care, which had a non-cerebral cause). The study included 305 patients treated with EPO and 297 treated with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (interquartile range [IQR] 5-16) compared with 29 days (IQR 7-56) (p = 0.01) for non-cerebral COD. When assessing subgroups by admission CT scan injury findings, we found no significant differential effects of EPO compared with placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to intensive care unit (ICU) admission (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.14-0.61, p = 0.001, p for interaction = 0.003) and in this subgroup, fewer patients died of cerebral causes in the EPO than in the placebo group (5% compared with 14%, p = 0.03). In conclusion, most TBI deaths were from cerebral causes that occurred during the first 2 weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomization.

Challenges and opportunities for pediatric severe TBI-review of the evidence and exploring a way forward.

Traumatic brain injury (TBI) is a leading killer of children in the developed and developing world. Despite evidence-based guidelines and several recent clinical trials, the progress in developing best practices for children with severe TBI has been slow. This article describes (i) the burden of the disease, (ii) the inadequacies of the evidence-based guidelines, (iii) the failure of the largest clinical trials to prove their primary hypotheses, and (iv) possible advances from an observational cohort study called the Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial that has recently completed enrollment.

Models of Mortality and Morbidity in Severe Traumatic Brain Injury: An Analysis of a Singapore Neurotrauma Database.

Current prognostic models for traumatic brain injury (TBI) are developed from diverse historical data sets. We aimed to construct a prognostication tool for patients with severe TBI, as this group would benefit most from an accurate model. Model development was based on a cohort of 300 patients with severe TBI (Glasgow Coma Scale score ≤8) consecutively admitted to a neurosurgical intensive care unit at the National Neuroscience Institute (NNI), Singapore, between February 2006 and December 2009. We analyzed prospectively collected data of admission characteristics using univariate and multivariate logistic regressions to predict 14-day and 6-month mortality and 6-month unfavorable outcome. Comparison with Corticosteroid Randomization After Significant Head Injury (CRASH) and Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) models was done using Akaike information criterion. Two prediction models, NNI Clinical (age, Glasgow Coma Scale score, pupillary reactivity) and NNI+ (NNI Clinical model with addition of obliteration of third ventricle or basal cisterns, presence of subdural hemorrhage, hypoxia, and coagulopathy), were derived from this data set. Both models predicted well across 3 outcome measures with area under the curve values of 0.84-0.91, with adequate calibration. Comparison with CRASH and IMPACT models showed better performance by both derived models with lower Akaike information criterion and higher area under the curve values. Two accurate prognostic models, NNI Clinical and NNI+, were developed from our cohort of patients with severe TBI. Both models are specific to severe TBI and could be better alternatives to current available models. External validation is required to assess performance of models in a different setting.

Erythropoietin in patients with traumatic brain injury and extracranial injury-A post hoc analysis of the erythropoietin traumatic brain injury trial.

Erythropoietin (EPO) may reduce mortality after traumatic brain injury (TBI). Secondary brain injury is exacerbated by multiple trauma, and possibly modifiable by EPO. We hypothesized that EPO decreases mortality more in TBI patients with multiple trauma, than in patients with TBI alone. A post hoc analysis of the EPO-TBI randomized controlled trial conducted in 2009 to 2014. To evaluate the impact of injuries outside the brain, we calculated an extracranial Injury Severity Score (ISS) that included the same components of the ISS, excluding head and face components. We defined multiple trauma as two injured body regions with an Abbreviated Injury Scale (AIS) score of 3 or higher. Cox regression analyses, allowing for potential differential responses per the presence or absence of extracranial injury defined by these injury scores, were used to assess the effect of EPO on time to mortality. Of 603 included patients, the median extracranial ISS was 6 (interquartile range, 1-13) and 258 (43%) had an AIS score of 3 or higher in at least two body regions. On Cox regression, EPO was associated with decreased mortality in patients with greater extracranial ISS (interaction p = 0.048) and weakly associated with differential mortality with multiple trauma (AIS score > 3 or in two regions, interaction p = 0.17). At 6 months in patients with extracranial ISS higher than 6, 10 (6.8%) of 147 EPO-treated patients compared with 26 (17%) of 154 placebo-treated patients died (risk reduction, 10%; 95% confidence interval, 2.9-17%; p = 0.007). In this post hoc analysis, EPO administration was associated with a potential differential improvement in 6-month mortality in TBI patients with more severe extracranial injury. These findings need confirmation in future clinical and experimental studies. Therapeutic study, level III.

Validating Multidimensional Outcome Assessment Using the TBI Common Data Elements: An Analysis of the TRACK-TBI Pilot Sample.

The Glasgow Outcome Scale-Extended (GOSE) is often the primary outcome measure in clinical trials for traumatic brain injury (TBI). Although the GOSE's capture of global function outcome has several strengths, concerns have been raised about its limited ability to identify mild disability and failure to capture the full scope of problems patients exhibit after TBI. This analysis examined the convergence of disability ratings across a multidimensional set of outcome domains in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot study. The study collected measures recommended by the TBI Common Data Elements (CDE) Workgroup. Patients presenting to 3 emergency departments with a TBI of any severity enrolled in TRACK-TBI prospectively after injury; outcome measures were collected at 3 and six months postinjury. Analyses examined frequency of impairment and overlap between impairment status across the CDE outcome domains of Global Level of Functioning (GOSE), Neuropsychological (cognitive) Impairment, Psychological Status, TBI Symptoms, and Quality of Life. GOSE score correlated in the expected direction with other outcomes (M Spearman's rho = .21 and .49 with neurocognitive and self-report outcomes, respectively). The subsample in the Upper Good Recovery (GOSE 8) category appeared quite healthy across most other outcomes, although 19.0% had impaired executive functioning (Trail Making Test Part B). A significant minority of participants in the Lower Good Recovery subgroup (GOSE 7) met criteria for impairment across numerous other outcome measures. The findings highlight the multidimensional nature of TBI recovery and the limitations of applying only a single outcome measure.

Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury.

To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results.

Is It Reliable to Predict the Outcome of Elderly Patients with Severe Traumatic Brain Injury Using the IMPACT Prognostic Calculator?

Many investigators endeavor to predict the outcome based on admission characteristics using some established models to determine which management should be applied. However, the efficacy and applicability of the models using in the geriatric patients with severe traumatic brain injury (TBI) have not yet been evaluated. A total of 137 geriatric severe TBI patients were enrolled in this retrospective study. Receiver operating characteristic (ROC) curves were constructed to evaluate the efficacy and usability of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic model in evaluating the prognosis for these patients. The observed mortality and unfavorable outcomes at 6 months in patients with severe TBI were 54.7% and 70.8%, respectively, slightly lower than the predicted outcomes using the IMPACT model. ROC curve analysis showed areas under the curve (AUCs) for mortality of 0.76 and for unfavorable outcome of 0.80 in the Core model, of 0.76 and 0.79, respectively, in the Extended model, and of 0.73 and 0.77, respectively, in the Lab model. When expected risk of fatal outcome was >90% in any model, the true positive rate was 100%. Moreover, when the predicted risk for unfavorable outcomes was >70% in any model, the actual rate of unfavorable outcomes was >80%. The IMPACT prognosis calculator showed just fair discrimination when predicting the outcome of the elderly patients with severe TBI. Management decisions should be made on a case-by-case basis rather than by relying on the predicted risks identified by this model; conservative treatment might be preferable when expected risk of fatal outcome is >90%.

Lost and found: what we have learned from the progesterone for traumatic brain injury trials

A short opinion piece updating “Lost in translation: understanding the failure of the progesterone/traumatic brain injury Phase III trials”

Predicted Unfavorable Neurologic Outcome Is Overestimated by the Marshall Computed Tomography Score, Corticosteroid Randomization After Significant Head Injury (CRASH), and International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) Models in Patients with Severe Traumatic Brain Injury Managed with Early Decompressive Craniectomy

Traumatic brain injury (TBI) is of public health interest and produces significant mortality and disability in Colombia. Calculators and prognostic models have been developed to establish neurologic outcomes. Wetested prognostic models (the Marshall computed tomography [CT] score, International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT), and Corticosteroid Randomization After Significant Head Injury) for 14-day mortality, 6-month mortality, and 6-month outcome in patients with TBI at a university hospital in Colombia. A 127-patient cohort with TBI was treated in a regional trauma center in Colombia over 2 years and bivariate and multivariate analyses were used. Discriminatory power of the models, their accuracy, and precision was assessed by both logistic regression and area under the receiver operating characteristic curve (AUC). Shapiro-Wilk, χ2, and Wilcoxon test were used to compare real outcomes in the cohort against predicted outcomes. The group's median age was 33 years, and 84.25% were male. The injury severity score median was 25, and median Glasgow Coma Scale motor score was 3. Six-month mortality was 29.13%. Six-month unfavorable outcome was 37%. Mortality prediction by Marshall CT scorewas 52.8%, P= 0.104 (AUC 0.585; 95% confidence interval [CI] 0 0.489-0.681), the mortality prediction by CRASH prognosis calculator was59.9%, P < 0.001 (AUC 0.706; 95% CI 0.590-0.821), and theunfavorable outcome prediction by IMPACT was 77%, P<0.048 (AUC 0.670; 95% CI 0.575-0.763). In a university hospital in Colombia, the Marshall CT score, IMPACT, and Corticosteroid Randomization After Significant Head Injury models overestimated the adverse neurologic outcome in patients with severe head trauma.