Andrew I.R. Maas

Moderate and severe traumatic brain injury in adults

Traumatic brain injury (TBI) is a major health and socioeconomic problem that affects all societies. In recent years, patterns of injury have been changing, with more injuries, particularly contusions, occurring in older patients. Blast injuries have been identified as a novel entity with specific characteristics. Traditional approaches to the classification of clinical severity are the subject of debate owing to the widespread policy of early sedation and ventilation in more severely injured patients, and are being supplemented with structural and functional neuroimaging. Basic science research has greatly advanced our knowledge of the mechanisms involved in secondary damage, creating opportunities for medical intervention and targeted therapies; however, translating this research into patient benefit remains a challenge. Clinical management has become much more structured and evidence based since the publication of guidelines covering many aspects of care. In this Review, we summarise new developments and current knowledge and controversies, focusing on moderate and severe TBI in adults. Suggestions are provided for the way forward, with an emphasis on epidemiological monitoring, trauma organisation, and approaches to management.

Clinical Trials in Head Injury

Secondary brain damage, following severe head injury is considered to be a major cause for bad outcome. Impressive reductions of the extent of brain damage in experimental studies have raised high expectations for cerebral neuroprotective treatment, in the clinic. Therefore multiple compounds were and are being evaluated in trials. In this review we discuss the pathomechanisms of traumatic brain damage, based upon their clinical importance. The role of hypothermia, mannitol, barbiturates, steroids, free radical scavengers, arachidonic acid inhibitors, calcium channel blockers, N-methyl-D-aspartate (NMDA) antagonists, and potassium channel blockers, will be discussed. The importance of a uniform strategic approach for evaluation of potentially interesting new compounds in clinical trials, to ameliorate outcome in patients with severe head injury, is proposed. To achieve this goal, two nonprofit organizations were founded: the European Brain Injury Consortium (EBIC) and the American Brain Injury Consortium (ABIC). Their aim lies in conducting better clinical trials, which incorporate lessons learned from previous trials, such that the succession of negative, or incomplete studies, as performed in previous years, will cease.

Classification of Traumatic Brain Injury for Targeted Therapies

The heterogeneity of traumatic brain injury (TBI) is considered one of the most significant barriers to finding effective therapeutic interventions. In October, 2007, the National Institute of Neurological Disorders and Stroke, with support from the Brain Injury Association of America, the Defense and Veterans Brain Injury Center, and the National Institute of Disability and Rehabilitation Research, convened a workshop to outline the steps needed to develop a reliable, efficient and valid classification system for TBI that could be used to link specific patterns of brain and neurovascular injury with appropriate therapeutic interventions. Currently, the Glasgow Coma Scale (GCS) is the primary selection criterion for inclusion in most TBI clinical trials. While the GCS is extremely useful in the clinical management and prognosis of TBI, it does not provide specific information about the pathophysiologic mechanisms which are responsible for neurological deficits and targeted by interventions. On the premise that brain injuries with similar pathoanatomic features are likely to share common pathophysiologic mechanisms, participants proposed that a new, multidimensional classification system should be developed for TBI clinical trials. It was agreed that preclinical models were vital in establishing pathophysiologic mechanisms relevant to specific pathoanatomic types of TBI and verifying that a given therapeutic approach improves outcome in these targeted TBI types. In a clinical trial, patients with the targeted pathoanatomic injury type would be selected using an initial diagnostic entry criterion, including their severity of injury. Coexisting brain injury types would be identified and multivariate prognostic modeling used for refinement of inclusion/exclusion criteria and patient stratification. Outcome assessment would utilize endpoints relevant to the targeted injury type. Advantages and disadvantages of currently available diagnostic, monitoring, and assessment tools were discussed. Recommendations were made for enhancing the utility of available or emerging tools in order to facilitate implementation of a pathoanatomic classification approach for clinical trials.

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.

EBIC-Guidelines for Management of Severe Head Injury in Adults

SummaryGuidelines for the management of severe head injury in adults as evolved by the European Brain Injury Consortium are presented and discussed. The importance of preventing and treating secondary insults is emphasized and the principles on which treatment is based are reviewed. Guidelines presented are of a pragmatic nature, based on consensus and expert opinion, covering the treatment from accident site to intensive care unit. Specific aspects pertaining to the conduct of clinical trials in head injury are highlighted. The adopted approach is further discussed in relation to other approaches to the development of guidelines, such as evidence based analysis.

Changing patterns in the epidemiology of traumatic brain injury

Traumatic brain injury (TBI) is a critical public health and socio-economic problem throughout the world. Reliable quantification of the burden caused by TBI is difficult owing to inadequate standardization and incomplete capture of data on the incidence and outcome of brain injury, with variability in the definition of TBI being partly to blame. Reports show changes in epidemiological patterns of TBI: the median age of individuals who experience TBI is increasing, and falls have now surpassed road traffic incidents as the leading cause of this injury. Despite claims to the contrary, no clear decrease in TBI-related mortality or improvement of overall outcome has been observed over the past two decades. In this Perspectives article, we discuss the strengths and limitations of epidemiological studies, address the variability in its definition, and highlight changing epidemiological patterns. Taken together, these analyses identify a great need for standardized epidemiological monitoring in TBI.

Position Statement: Definition of Traumatic Brain Injury

A clear, concise definition of traumatic brain injury (TBI) is fundamental for reporting, comparison, and interpretation of studies on TBI. Changing epidemiologic patterns, an increasing recognition of significance of mild TBI, and a better understanding of the subtler neurocognitive neuroaffective deficits that may result from these injuries make this need even more critical. The Demographics and Clinical Assessment Working Group of the International and Interagency Initiative toward Common Data Elements for Research on Traumatic Brain Injury and Psychological Health has therefore formed an expert group that proposes the following definition: In this article, we discuss criteria for considering or establishing a diagnosis of TBI, with a particular focus on the problems how a diagnosis of TBI can be made when patients present late after injury and how mild TBI may be differentiated from non-TBI causes with similar symptoms. Technologic advances in magnetic resonance imaging and the development of biomarkers offer potential for improving diagnostic accuracy in these situations.

Prediction of outcome in traumatic brain injury with computed tomographic characteristics: a comparison between the computed tomographic classification and combinations of computed tomographic predictors.

BACKGROUND AND OBJECTIVE: The Marshall computed tomographic (CT) classification identifies six groups of patients with traumatic brain injury (TBI), based on morphological abnormalities on the CT scan. This classification is increasingly used as a predictor of outcome. We aimed to examine the predictive value of the Marshall CT classification in comparison with alternative CT models. METHODS: The predictive value was investigated in the Tirilazad trials (n = 2269). Alternative models were developed with logistic regression analysis and recursive partitioning. Six month mortality was used as outcome measure. Internal validity was assessed with bootstrapping techniques and expressed as the area under the receiver operating curve (AUC). RESULTS: The Marshall CT classification indicated reasonable discrimination (AUC = 0.67), which could be improved by rearranging the underlying individual CT characteristics (AUC = 0.71). Performance could be further increased by adding intraventricular and traumatic subarachnoid hemorrhage and by a more detailed differentiation of mass lesions and basal cisterns (AUC = 0.77). Models developed with logistic regression analysis and recursive partitioning showed similar performance. For clinical application we propose a simple CT score, which permits a more clear differentiation of prognostic risk, particularly in patients with mass lesions. CONCLUSION: It is preferable to use combinations of individual CT predictors rather than the Marshall CT classification for prognostic purposes in TBI. Such models should include at least the following parameters: status of basal cisterns, shift, traumatic subarachnoid or intraventricular hemorrhage, and presence of different types of mass lesions.

Brain oxygen tension in severe head injury.

OBJECTIVE Ensuring adequate cerebral oxygenation and perfusion is of fundamental importance in the treatment of patients with acute cerebral disorders. Online continuous monitoring of brain oxygenation is possible with a parenchymal microelectrode that measures local brain oxygen tension. The ultimate question is whether therapeutic approaches can be targeted on the basis of such monitoring. Before this question can be addressed, the technique requires validation in the clinical setting. The frequency of occurrence of low values and its relation to outcome need to be established. METHODS One hundred one comatose head-injured patients (Glasgow Coma Scale score < or = 8) were studied. Local brain oxygen tension probes were inserted in an undamaged part of the frontal region. Patients were treated in conformance with the European Brain Injury Consortium guidelines. Outcome at 6 months was determined by Glasgow Outcome Scale score. RESULTS Early brain tissue hypoxia was frequently observed, despite aggressive treatment for intracranial pressure and cerebral perfusion pressure. Values lower than 15 mm Hg, for a duration longer than 30 minutes, were observed in 57 patients. Values lower than 10 mm Hg in 42 patients, and lower than 5 mm Hg in 22 patients, were observed during the first 24 hours. Depth and duration of tissue hypoxia were related to outcome and proved to be an independent predictor of unfavorable outcome and death. CONCLUSION Monitoring the partial oxygen pressure of local brain tissue is a safe and reliable method for regulating cerebral oxygenation. Because brain tissue hypoxia occurs frequently and is significantly related to poor outcome, future efforts should be aimed at the treatment of brain tissue hypoxia. The effects of such brain hypoxia-targeted treatment need to be established in a multicenter study.

Continuous monitoring of partial pressure of brain tissue oxygen in patients with severe head injury

ISCHEMIA IS ONE of the major factors causing secondary brain damage after severe head injury. We have investigated the value of continuous partial pressure of brain tissue oxygen (P br O2) monitoring as a parameter for cerebral oxygenation in 22 patients with severe head injury(Glasgow Coma Scale score, <=8). Jugular bulb oxygenation, intracranial pressure, and cerebral perfusion pressure were simultaneously recorded. O 2 and CO 2 reactivity tests were performed daily to evaluate oxygen autoregulatory mechanisms. P br O2 monitoring was started an average of 7.0 hours after trauma with a mean duration of 74.3 hours. No complications were seen, and the calibration of the catheters after measurement showed a zero drift of 1.2 ± 0.8 mm Hg and a sensitivity drift of 9.7 ± 5.3%. In 86% of the patients, P br O2 was<20 mm Hg in the acute phase. Mean P br O2 significantly increased during the first 24 hours after injury. Two distinct patterns of change of Pbr O2 over time were noted. The first pattern was characterized by normal stable levels after 24 hours, and the second was characterized by transiently elevated levels of P br O2 during the second and third days. P br O2 values <=5 mm Hg within 24 hours after trauma negatively correlated with outcome. O 2 reactivity was significantly lower in patients with good outcomes. CO 2 reactivity showed no constant pattern of change over time and was not correlated with outcome. Increased hyperventilation was shown to decrease P br O2 in some patients. Accurate detection of the moment of cerebral death was possible on the basis of the P br O2 measurements. The correlation between P br O2 and other parameters, such as intracranial pressure and cerebral perfusion pressure, was weak. We conclude that Pbr O2 monitoring is a safe and clinically applicable method in patients with severe head injury. The early occurrence of ischemia after head injury can be monitored on a continuous basis. Deficiency of oxygen autoregulatory mechanisms can be demonstrated, and their occurrence is inversely related to outcome. For practical clinical use, the method seemed to be superior to jugular oximetry.Ischemia is one of the major factors causing secondary brain damage after severe head injury. We have investigated the value of continuous partial pressure of brain tissue oxygen (PbrO2) monitoring as a parameter for cerebral oxygenation in 22 patients with severe head injury (Glasgow Coma Scale score, < or = 8). Jugular bulb oxygenation, intracranial pressure, and cerebral perfusion pressure were simultaneously recorded. O2 and CO2 reactivity tests were performed daily to evaluate oxygen autoregulatory mechanisms. PbrO2 monitoring was started an average of 7.0 hours after trauma with a mean duration of 74.3 hours. No complications were seen, and the calibration of the catheters after measurement showed a zero drift of 1.2 +/- 0.8 mm Hg and a sensitivity drift of 9.7 +/- 5.3%. In 86% of patients, PbrO2 was < 20 mm Hg in the acute phase. Mean PbrO2 significantly increased during the first 24 hours after injury. Two distinct patterns of change of PbrO2 over time were noted. The first pattern was characterized by normal stable levels after 24 hours, and the second was characterized by transiently elevated levels of PbrO2 during the second and third days. PbrO2 values < or = 5 mm Hg within 24 hours after trauma negatively correlated with outcome. O2 reactivity was significantly lower in patients with good outcomes. CO2 reactivity showed no constant pattern of change over time and was not correlated with outcome. Increased hyperventilation was shown to decrease PbrO2 in some patients. Accurate detection of the moment of cerebral death was possible on the basis of the PbrO2 measurements. The correlation between PbrO2 and other parameters, such as intracranial pressure and cerebral perfusion pressure, was weak. We conclude that PbrO2 monitoring is a safe and clinically applicable method in patients with severe head injury. The early occurrence of ischemia after head injury can be monitored on a continuous basis. Deficiency of oxygen autoregulatory mechanisms can be demonstrated, and their occurrence is inversely related to outcome. For practical clinical use, the method seemed to be superior to jugular oximetry.