Philip F. Stahel

Management of bleeding following major trauma: an updated European guideline

IntroductionEvidence-based recommendations are needed to guide the acute management of the bleeding trauma patient, which when implemented may improve patient outcomes.MethodsThe multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing a guideline for the management of bleeding following severe injury. This document presents an updated version of the guideline published by the group in 2007. Recommendations were formulated using a nominal group process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.ResultsKey changes encompassed in this version of the guideline include new recommendations on coagulation support and monitoring and the appropriate use of local haemostatic measures, tourniquets, calcium and desmopressin in the bleeding trauma patient. The remaining recommendations have been reevaluated and graded based on literature published since the last edition of the guideline. Consideration was also given to changes in clinical practice that have taken place during this time period as a result of both new evidence and changes in the general availability of relevant agents and technologies.ConclusionsThis guideline provides an evidence-based multidisciplinary approach to the management of critically injured bleeding trauma patients.

Inflammatory response in acute traumatic brain injury: a double-edged sword

Inflammation is an important part of the pathophysiology of traumatic brain injury. Although the central nervous system differs from the other organs because of the almost complete isolation from the blood stream mediated by the blood–brain barrier, the main steps characterizing the immune activation within the brain follow a scenario similar to that in other organs. The key players in these processes are the numerous immune mediators released within minutes of the primary injury. They guide a sequence of events including expression of adhesion molecules, cellular infiltration, and additional secretion of inflammatory molecules and growth factors, resulting in either regeneration or cell death. The question is this: to what extent is inflammation beneficial for the injured brain tissue, and how does it contribute to secondary brain damage and progressive neuronal loss? This review briefly reports recent evidence supporting the dual, the beneficial, or the deleterious role of neuroinflammation after traumatic brain injury.

Role of cerebral inflammation after traumatic brain injury : A revisited concept

ABSTRACT— Neuroinflammation occuring after traumatic brain injury (TBI) is a complex phenomenon comprising distinct cellular and molecular events involving the injured as well as the healthy cerebral tissue. Although immunoactivation only represents a one of the many cascades initiated in the pathophysiology of TBI, the exact function of each mediator, activated cell types or pathophysiological mechanism, needs to be further elucidated. It is widely accepted that inflammatory events display dual and opposing roles promoting, on the one hand, the repair of the injured tissue and, on the other hand, causing additional brain damage mediated by the numerous neurotoxic substances released. Most of the date supporting these hypotheses derive from experimental work based on both animal models and cultured neuronal cells. More recently, evidence has been provided that a complete elimination of selected inflammatory mediators is rather detrimental as shown by the attenuation of neurological recovery. However, there are conflicting results reported on this issue which strongly depend on the experimental setting used. The history of immunoactivation in neurotrauma is the subject of this review article, giving particular emphasis to the comparison of clinical versus experimental studies performed over the last 10 years. These results also are evaluated with respect to other neuropathologies, which are years ahead as compared to the research in TBI. The possible reciprocal influence of peripheral and intrathecal activation of the immune system will also be discussed. To conclude, the future directions of research in the field of neurotrauma is considered.

Analysis of Efficacy and Failure in Proximal Humerus Fractures Treated With Locking Plates

Objective: The purpose of this study was to determine the efficacy of proximal humerus locking plates (PHLP) and to clarify predictors of loss of fixation. Design: Retrospective review of patients with proximal humerus fractures fixed with a PHLP. Setting: Five Level 1 trauma centers. Patients: One hundred fifty-three patients (111 female, 42 male) 18 years or older with a displaced fracture or fracture-dislocation of the proximal humerus treated with a PHLP between January 1, 2001 and July 31, 2005. Intervention: Demographic data, trauma mechanism, surgical approach, and perioperative complications were collected from the medical records. Fracture classification according to the AO/OTA, radiographic head-shaft angle, and screw tip-articular surface distance in true anteroposterior (AP) and axillary lateral radiographs of the shoulder were measured postoperatively. Varus malreduction was defined as a head-shaft angle of <120 degrees. Main Outcome Measurements: Statistical analysis was done to establish correlations between loss of fixation and postoperative head-shaft angle in the true AP radiograph, patient age, fracture type, trauma mechanism, number of locking head screws, and type of plate. Results: The mean age was 62.3 ± 15.4 years (22-92) and the mean injury severity score (ISS) was 9.5 ± 10.16 (4-57; n = 73). The surgical approach was deltopectoral (90.2%) or transdeltoid (9.8%). No intraoperative complications were reported. The mean postoperative head-shaft angle was 130 degrees (95 degrees to 160 degrees; SD = 13). The overall incidence of loss of fixation was 13.7%. There was a statistically significant association between varus reduction (<120 degrees) and loss of fixation (30.4% when the head-shaft angle was <120 degrees versus 11% when the head-shaft angle was ≥120 degrees; P = 0.02). Conclusion: This series presents the experience using PHLP in 5 Level 1 trauma centers. There were no intraoperative complications related to the locking plate systems. Despite the use of fixed-angle devices, loss of fixation occurred, primarily in the presence of varus malreduction. Our findings suggest that avoiding varus should substantially decrease the risk of postoperative failures.

Mouse closed head injury model induced by a weight-drop device

Traumatic brain injury represents the leading cause of death in young individuals. Various animal models have been developed to mimic human closed head injury (CHI). Widely used models induce head injury by lateral fluid percussion, a controlled cortical impact or impact acceleration. The presented model induces a CHI by a standardized weight-drop device inducing a focal blunt injury over an intact skull without pre-injury manipulations. The resulting impact triggers a profound neuroinflammatory response within the intrathecal compartment with high consistency and reproducibility, leading to neurological impairment and breakdown of the blood–brain barrier. In this protocol, we define standardized procedures for inducing CHI in mice and determine various severity grades of CHI through modulation of the weight falling height. In experienced hands, this CHI model can be carried out in as little as 30 s per animal, with additional time required for subsequent posttraumatic analysis and data collection.

Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production.

Interleukin (IL) 8 was measured in CSF of 14 patients with severe traumatic brain injury. IL-8 levels were significantly higher in CSF (up to 8,000 pg/ml) than serum (up to 2,400 pg/ml) (p < 0.05), suggesting intrathecal production. Maximal IL-8 values in CSF correlated with a severe dysfunction of the blood–brain barrier. Nerve growth factor (NGF) was detected in CSF of 7 of 14 patients (range of maximal NGF: 62–12,130 pg/ml). IL-8 concentrations were significantly higher in these patients than in those without NGF (p < 0.01). CSF containing high IL-8 (3,800–7,900 pg/ml) induced greater NGF production in cultured astrocytes (202–434 pg/ml) than samples with low IL-8 (600–1,000 pg/ml), which showed a smaller NGF increase (0–165 pg/ml). Anti-IL-8 antibodies strongly reduced (52–100%) the release of NGF in the group of high IL-8, whereas in the group with low IL-8, this effect was lower (0–52%). The inability of anti-IL-8 antibodies to inhibit the synthesis of NGF completely may depend on cytokines like tumor necrosis factor α and IL-6 found in these CSF samples, which may act in association with IL-8. Thus, IL-8 may represent a pivotal cytokine in the pathology of brain injury.

Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue

A profound inflammatory response is initiated immediately following traumatic brain injury (TBI) and is characterized by the release of several cytokines with pro- and anti-inflammatory functions. In order to elucidate which cytokines are released in the human brain in response to injury as well as in the peripheral compartment, IL-1, IL-6, IL-8, IL-10, TNF-α and TGF-β were monitored in CSF and serum of severely brain-injured patients. Furthermore, we investigated the possible modulation of systemic reactions by IL-6 and the ability of IL-6 and IL-8 to promote the synthesis of nerve growth factor.

Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young people in industrialized countries. Although various anti‐inflammatory and antiapoptotic modalities have shown neuroprotective effects in experimental models of TBI, to date, no specific pharmacological agent aimed at blocking the progression of secondary brain damage has been approved for clinical use. Erythropoietin (Epo) belongs to the cytokine superfamily and has traditionally been viewed as a hematopoiesis‐regulating hormone. The newly discovered neuroprotective properties of Epo lead us to investigate its effect in TBI in a mouse model of closed head injury. Recombinant human erythropoietin (rhEpo) was injected at 1 and 24 h after TBI, and the effect on recovery of motor and cognitive functions, tissue inflammation, axonal degeneration, and apoptosis was evaluated up to 14 days. Motor deficits were lower, cognitive function was restored faster, and less apoptotic neurons and caspase‐3 expression were found in rhEpo‐treated as compared with vehicle‐treated animals (P<0.05). Axons at the trauma area in rhEpo‐treated mice were relatively well preserved compared with controls (shown by their density; P<0.01). Immunohistochemical analysis revealed a reduced activation of glial cells by staining for GFAP and complement receptor type 3 (CD11b/CD18) in the injured hemisphere of Epo‐ vs. vehicle‐treated animals. We propose that further studies on Epo in TBI should be conducted in order to consider it as a novel therapy for TBI.

The role of the complement system in traumatic brain injury.

A traumatic impact to the brain induces an intracranial inflammatory response, which consequently leads to the development of brain edema and delayed neuronal death. Evidence from experimental, clinical, and in vitro studies highlight an important role for the complement system in contributing to inflammation within the injured brain. The present review summarizes the current understanding of the mechanisms of complement-mediated secondary brain injury after head trauma.

Complement anaphylatoxin receptors on neurons: new tricks for old receptors?

Activation of the complement system has been reported in a variety of inflammatory diseases and neurodegenerative processes of the CNS. Recent evidence indicates that complement proteins and receptors are synthesized on or by glial cells and, surprisingly, neurons. Among these proteins are the receptors for the chemotactic and anaphylactic peptides, C5a and C3a, which are the most-potent mediators of complement inflammatory functions. The functions of glial-cell C3a and C5a receptors (C3aR and C5aR) appear to be similar to immune-cell C3aRs and C5aRs. However, little is known about the roles these receptors might have on neurons. Indeed, when compared with glial cells, neurons display a distinct pattern of C3aR and C5aR expression, in either the normal or the inflamed CNS. These findings suggest unique functions for these receptors on neurons.