The American Congress of Rehabilitation Medicine Diagnostic Criteria for Mild Traumatic Brain Injury.

OBJECTIVE: To develop new diagnostic criteria for mild traumatic brain injury (TBI) that are appropriate for use across the lifespan and in sports, civilian trauma, and military settings. DESIGN: Rapid evidence reviews on 12 clinical questions and Delphi method for expert consensus. PARTICIPANTS: The Mild Traumatic Brain Injury Task Force of the American Congress of Rehabilitation Medicine Brain Injury Special Interest Group convened a Working Group of 17 members and an external interdisciplinary expert panel of 32 clinician-scientists. Public stakeholder feedback was analyzed from 68 individuals and 23 organizations. RESULTS: The first 2 Delphi votes asked the expert panel to rate their agreement with both the diagnostic criteria for mild TBI and the supporting evidence statements. In the first round, 10 of 12 evidence statements reached consensus agreement. Revised evidence statements underwent a second round of expert panel voting, where consensus was achieved for all. For the diagnostic criteria, the final agreement rate, after the third vote, was 90.7%. Public stakeholder feedback was incorporated into the diagnostic criteria revision prior to the third expert panel vote. A terminology question was added to the third round of Delphi voting, where 30 of 32 (93.8%) expert panel members agreed that 'the diagnostic label 'concussion' may be used interchangeably with 'mild TBI' when neuroimaging is normal or not clinically indicated.' CONCLUSIONS: New diagnostic criteria for mild TBI were developed through an evidence review and expert consensus process. Having unified diagnostic criteria for mild TBI can improve the quality and consistency of mild TBI research and clinical care.

Adjusting for confounding by indication in observational studies: a case study in traumatic brain injury.

INTRODUCTION: Observational studies of interventions are at risk for confounding by indication. The objective of the current study was to define the circumstances for the validity of methods to adjust for confounding by indication in observational studies. PATIENTS AND METHODS: We performed post hoc analyses of data prospectively collected from three European and North American traumatic brain injury studies including 1,725 patients. The effects of three interventions (intracranial pressure [ICP] monitoring, intracranial operation and primary referral) were estimated in a proportional odds regression model with the Glasgow Outcome Scale as ordinal outcome variable. Three analytical methods were compared: classical covariate adjustment, propensity score matching and instrumental variable (IV) analysis in which the percentage exposed to an intervention in each hospital was added as an independent variable, together with a random intercept for each hospital. In addition, a simulation study was performed in which the effect of a hypothetical beneficial intervention (OR 1.65) was simulated for scenarios with and without unmeasured confounders. RESULTS: For all three interventions, covariate adjustment and propensity score matching resulted in negative estimates of the treatment effect (OR ranging from 0.80 to 0.92), whereas the IV approach indicated that both ICP monitoring and intracranial operation might be beneficial (OR per 10% change 1.17, 95% CI 1.01-1.42 and 1.42, 95% CI 0.95-1.97). In our simulation study, we found that covariate adjustment and propensity score matching resulted in an invalid estimate of the treatment effect in case of unmeasured confounders (OR ranging from 0.90 to 1.03). The IV approach provided an estimate in the similar direction as the simulated effect (OR per 10% change 1.04-1.05) but was statistically inefficient. CONCLUSION: The effect estimation of interventions in observational studies strongly depends on the analytical method used. When unobserved confounding and practice variation are expected in observational multicenter studies, IV analysis should be considered.

Factors Influencing the Reliability of the Glasgow Coma Scale: A Systematic Review.

BACKGROUND: The Glasgow Coma Scale (GCS) characterizes patients with diminished consciousness. In a recent systematic review, we found overall adequate reliability across different clinical settings, but reliability estimates varied considerably between studies, and methodological quality of studies was overall poor. Identifying and understanding factors that can affect its reliability is important, in order to promote high standards for clinical use of the GCS. OBJECTIVE: The aim of this systematic review was to identify factors that influence reliability and to provide an evidence base for promoting consistent and reliable application of the GCS. METHODS: A comprehensive literature search was undertaken in MEDLINE, EMBASE, and CINAHL from 1974 to July 2016. Studies assessing the reliability of the GCS in adults or describing any factor that influences reliability were included. Two reviewers independently screened citations, selected full texts, and undertook data extraction and critical appraisal. Methodological quality of studies was evaluated with the consensus-based standards for the selection of health measurement instruments checklist. Data were synthesized narratively and presented in tables. RESULTS: Forty-one studies were included for analysis. Factors identified that may influence reliability are education and training, the level of consciousness, and type of stimuli used. Conflicting results were found for experience of the observer, the pathology causing the reduced consciousness, and intubation/sedation. No clear influence was found for the professional background of observers. CONCLUSION: Reliability of the GCS is influenced by multiple factors and as such is context dependent. This review points to the potential for improvement from training and education and standardization of assessment methods, for which recommendations are presented.

New considerations in the design of clinical trials for traumatic brain injury.

Randomized controlled trials in traumatic brain injury (TBI) pose several complicated methodological challenges related to the heterogeneity of the population. Several strategies have been proposed to deal with these challenges. Recommendations presented by the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) study group include the use of relatively broad enrollment criteria combined with covariate adjustment for strong predictors of outcome in the analysis phase, rather than the use of strict enrollment criteria. Furthermore, an ordinal rather than a dichotomized analysis of the Glasgow Outcome Scale - the outcome measure in most TBI trials - will increase the statistical power significantly. This review discusses the issue of heterogeneity in TBI trials and summarizes the value of different innovative methods for the design and statistical analysis of randomized controlled trials in TBI. Future directions highlight the opportunities offered by alternative strategies, such as comparative effectiveness research, to investigate the clinical benefits of established and novel therapies in TBI.

Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study.

BACKGROUND: Pathological waves of spreading mass neuronal depolarisation arise repeatedly in injured, but potentially salvageable, grey matter in 50-60% of patients after traumatic brain injury (TBI). We aimed to ascertain whether spreading depolarisations are independently associated with unfavourable neurological outcome. METHODS: We did a prospective, observational, multicentre study at seven neurological centres. We enrolled 109 adults who needed neurosurgery for acute TBI. Spreading depolarisations were monitored by electrocorticography during intensive care and were classified as cortical spreading depression (CSD) if they took place in spontaneously active cortex or as isoelectric spreading depolarisation (ISD) if they took place in isoelectric cortex. Investigators who treated patients and assessed outcome were masked to electrocorticographic results. Scores on the extended Glasgow outcome scale at 6 months were fitted to a multivariate model by ordinal regression. Prognostic score (based on variables at admission, as validated by the IMPACT studies) and spreading depolarisation category (none, CSD only, or at least one ISD) were assessed as outcome predictors. FINDINGS: Six individuals were excluded because of poor-quality electrocorticography. A total of 1328 spreading depolarisations arose in 58 (56%) patients. In 38 participants, all spreading depolarisations were classified as CSD; 20 patients had at least one ISD. By multivariate analysis, both prognostic score (p=0·0009) and spreading depolarisation category (p=0·0008) were significant predictors of neurological outcome. CSD and ISD were associated with an increased risk of unfavourable outcome (common odds ratios 1·56 [95% CI 0·72-3·37] and 7·58 [2·64-21·8], respectively). Addition of depolarisation category to the regression model increased the proportion of variance in outcome that could be attributed to predictors from 9% to 22%, compared with the prognostic score alone. INTERPRETATION: Spreading depolarisations were associated with unfavourable outcome, after controlling for conventional prognostic variables. The possibility that spreading depolarisations have adverse effects on the traumatically injured brain, and therefore might be a target in the treatment of TBI, deserves further research. FUNDING: US Army CDMRP PH/TBI research programme.

The added value of ordinal analysis in clinical trials: an example in traumatic brain injury.

INTRODUCTION: In clinical trials, ordinal outcome measures are often dichotomized into two categories. In traumatic brain injury (TBI) the 5-point Glasgow outcome scale (GOS) is collapsed into unfavourable versus favourable outcome. Simulation studies have shown that exploiting the ordinal nature of the GOS increases chances of detecting treatment effects. The objective of this study is to quantify the benefits of ordinal analysis in the real-life situation of a large TBI trial. METHODS: We used data from the CRASH trial that investigated the efficacy of corticosteroids in TBI patients (n = 9,554). We applied two techniques for ordinal analysis: proportional odds analysis and the sliding dichotomy approach, where the GOS is dichotomized at different cut-offs according to baseline prognostic risk. These approaches were compared to dichotomous analysis. The information density in each analysis was indicated by a Wald statistic. All analyses were adjusted for baseline characteristics. RESULTS: Dichotomous analysis of the six-month GOS showed a non-significant treatment effect (OR = 1.09, 95% CI 0.98 to 1.21, P = 0.096). Ordinal analysis with proportional odds regression or sliding dichotomy showed highly statistically significant treatment effects (OR 1.15, 95% CI 1.06 to 1.25, P = 0.0007 and 1.19, 95% CI 1.08 to 1.30, P = 0.0002), with 2.05-fold and 2.56-fold higher information density compared to the dichotomous approach respectively. CONCLUSIONS: Analysis of the CRASH trial data confirmed that ordinal analysis of outcome substantially increases statistical power. We expect these results to hold for other fields of critical care medicine that use ordinal outcome measures and recommend that future trials adopt ordinal analyses. This will permit detection of smaller treatment effects.

Current recommendations for neurotrauma.

Diagnostic and monitoring procedures for patients with head injury are aimed at early detection of mass lesions and secondary insults. Our therapeutic approach is based on our understanding of pathophysiologic mechanisms that cause secondary brain damage, and includes evacuation of mass lesions and prevention of secondary insults. Basic research has greatly increased our knowledge of these pathophysiologic mechanisms and has prompted the development of many neuroprotective agents, targeted to selected mechanisms. Unfortunately, it has proved difficult to demonstrate the benefit of such agents in the overall population of head-injured patients. Clinical research has emphasized the importance of ischemia in head injury and has demonstrated the deleterious effect of secondary insults on outcome. Medical management of patients with head injury has consequently focused on prevention of secondary insults, treatment of raised intracranial pressure, and maintenance of adequate cerebral perfusion pressure. The introduction of new monitoring techniques in head-injured patients offers the possibilities of more targeted therapy in individual patients, in contrast to the current practice of a staircase approach to treatment of raised intracranial pressure.In the US, an evidence-based approach has resulted in the wide acceptance of general principles, but at the same time highlighted the lack of hard evidence for the use of many therapeutic modalities. Practical guidelines, developed and published by the European Brain Injury Consortium, are based on expert opinion and consensus. Surveys have shown considerable variation in monitoring techniques and treatment. There is still considerable need for further improvements, both from a medical scientific perspective and from an organizational aspect. Particularly relevant are early resuscitation and stabilization at the scene of the accident, the organization of emergency services, admission policy to the intensive care unit, and improved policy for early identification of patients with operable intracranial hematoma. Further dissemination and general acceptance of already published guidelines may be expected to significantly improve care in head injury.