Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making

PURPOSE OF REVIEW: Emerging data suggest that biomarkers of brain injury have potential utility as diagnostic, prognostic, and therapeutic adjuncts in the setting of traumatic and ischemic brain injury. Two approaches are being used, namely, assessing markers of structural damage and quantifying mediators of the cellular, biochemical, or molecular cascades in secondary injury or repair. Novel proteomic, multiplex, and lipidomic methods are also being applied. RECENT FINDINGS: Biochemical markers of neuronal, glial, and axonal damage such as neuron-specific enolase, S100B, and myelin basic protein, respectively, are readily detectable in biological samples such as serum or cerebrospinal fluid and are being studied in patients with ischemic and traumatic brain injury. In addition, a number of studies have demonstrated that novel tools to assess simultaneously multiple biomarkers can provide unique insight such as details on specific molecular participants in cell death cascades, inflammation, or oxidative stress. SUMMARY: Multifaceted cellular, biochemical, and molecular monitoring of proteins and lipids is logical as an adjunct to guiding therapies and improving outcomes in traumatic and ischemic brain injury and we appear to be on the verge of a breakthrough with the use of these markers as diagnostic, prognostic, and monitoring adjuncts, in neurointensive care.     

The ischemic threshold of the extremity

Military efforts to limit ischemic time and reperfusion injury are being investigated with a focus on functional limb salvage as opposed to the more historic statistical salvage, since a dysfunctional limb may be a worse outcome than amputation. Translatable animal research, supported by reports from forward deployed surgeons in the field, is needed to improve care. Current studies have determined the threshold for meaningful recovery is less than 6 hours. Attempts at modeling vascular injury and ischemia reperfusion can be divided into 2 categories: chronic ischemia that mimics human age related disease and acute vascular injury that represents traumatic injury. A swine model to evaluate battlefield injuries and scenarios encountered in traumatic extremity vascular injury with a focus on functional limb salvage has been developed. Future endeavors should focus on understanding the factors that affect ischemic threshold as well as testing therapeutic and physical maneuvers to prolong this threshold.     

Non-viral transfer of BDNF and uPA stimulates peripheral nerve regeneration

Peripheral nerves connect brain and spinal cord with the extremities and inner organs, and nerves injury can lead the disability and social exclusion. Growth factors and other natural stimulators of regeneration processes look very promising as future medicines. In our study, we tested the influence of genetic constructions that contain genes of brain-derived neurotrophic factor and urokinase plasminogen activator on nerve's structure and function after traumatic and ischemic injuries. Injection of pVax1-hBDNF and pVax1-muPA after traumatic injury led to better restoration of nerve's structure and function compared to similar parameters of control group mice. In ischemic injury model pVax1-hBDNF and pVax1-muPA slowed and reduced the damage progression and stimulated nerve regeneration as well. However, the treatment with pVax1-muPA was less effective after the traumatic injury. As we chose a non-viral method of gene delivery during our study the optimal conditions of plasmid intramuscular delivery were also determined.     

Isolated basilar artery dissection following blunt trauma challenging the Glasgow coma score: A case report

Blunt cerebrovascular injury is a very rare complication of blunt trauma and a diagnostic challenge. A 14 year old male fell 10 m sustaining multi system trauma. The atypical Glasgow Coma Score was six with a fully preserved eye component. Initial whole-body CT scanning demonstrated multiple injuries but no obvious brain injury. Trauma management involved non-operative resuscitation and was successful, however profound coma occurred and brain stem reflexes disappeared on day two. Repeat brain CT scan demonstrated multiple cerebral and cerebellar ischemic lesions and no opacification of the vertebral or basilar arteries. Secondary analysis of the first CT scan demonstrated a small focal basilar artery dissection not initially reported.Our case report highlights an unusual cause of coma after traumatic brain injury where the clinical scenario mimics locked in syndrome. In such circumstances cerebrovascular injury, and in particular traumatic basilar artery dissection, must be actively excluded.     

Neuroprotection in acute brain injury: an up-to-date review

Neuroprotective strategies that limit secondary tissue loss and/or improve functional outcomes have been identified in multiple animal models of ischemic, hemorrhagic, traumatic and nontraumatic cerebral lesions. However, use of these potential interventions in human randomized controlled studies has generally given disappointing results. In this paper, we summarize the current status in terms of neuroprotective strategies, both in the immediate and later stages of acute brain injury in adults. We also review potential new strategies and highlight areas for future research.     

Regional ischemia after head injury

PURPOSE OF REVIEW: To examine the evidence of regional cerebral ischemia after traumatic brain injury. RECENT FINDINGS: This review describes the mechanisms responsible for secondary brain injury and the similarities between traumatic and ischemic neuronal cell death. Cerebral ischemia is defined, and the difficulties of quantifying the burden of cerebral ischemia in the context of clinical head injury are presented. Recent clinical data obtained from monitoring brain tissue oxygenation, tissue metabolites using microdialysis, and cerebral blood flow, blood volume, oxygen metabolism, and oxygen extraction fraction using oxygen-15 positron emission tomography are discussed. These data highlight that significant episodes of regional ischemia occur within the acute phase after injury and are associated with poor outcome. Although various monitoring tools are capable of detecting significant episodes of regional ischemia, each of the currently available techniques is limited in its clinical application. SUMMARY: There is increasing evidence to suggest that a small but significant volume of brain tissue is at risk of ischemic injury after trauma. Future studies should examine the pathophysiology underlying such ischemia and how monitoring techniques can be used to direct appropriate therapy and influence outcome.     

Venous thromboembolism prophylaxis and treatment in patients with acute stroke and traumatic brain injury

PURPOSE OF REVIEW: Patients with acute stroke and traumatic brain injury are at risk to develop venous thromboembolism. This review analyzes the available literature to propose guidelines for the prevention and treatment of venous thromboembolism in these groups of patients. RECENT FINDINGS: In acute ischemic stroke, low-dose low-molecular-weight heparin has the best benefit-risk ratio to prevent venous thromboembolism. Patients with primary intracerebral hemorrhage and traumatic brain injury should receive intermittent pneumatic compression, followed by low-dose low-molecular-weight heparin or unfractioned heparin 3-4 days after stroke onset or 24 h after injury or surgery, respectively, and after cessation of bleeding. Concerning treatment, in patients with deep-vein thrombosis lower doses of heparin are indicated to prevent pulmonary embolism, and a vena cava filter should be considered. In patients with pulmonary embolism, treatment could be more aggressive, because of a high mortality risk. SUMMARY: Adequate prevention of venous thromboembolism with intermittent pneumatic compression or pharmacological prophylaxis is important. The best treatment of venous thromboembolism remains unclear. In case of pulmonary embolism, more aggressive treatment is warranted.     

Cerebral microdialysis of patients with severe traumatic brain injury exhibits highly individualistic patterns as visualized by cluster analysis with self-organizing maps

OBJECTIVE: To analyze patterns of cerebral microdialysis in patients with traumatic brain injury and, with a neural network methodology, investigate pattern relationships to intracranial pressure and cerebral perfusion pressure. DESIGN: Retrospective. SETTING: University hospital, adult neurosurgical intensive care unit. PATIENTS: Twenty-six patients with severe traumatic brain injury. All consecutive traumatic brain injured patients (Glasgow Coma Scale < or =8) with microdialysis monitoring, analyzing glutamate, lactate, pyruvate, and glucose in both penumbral and nonpenumbral tissue. INTERVENTIONS: None; patients received the unit's standard neurointensive care procedure. MEASUREMENTS AND MAIN RESULTS: We used 2084 hrs of complete microdialysis data sets (eight markers) to train Kohonen self-organizing maps. The self-organizing map algorithm is a data-clustering method that reduces high-dimensional information to a two-dimensional representation on a grid (map), retaining local relationships in the data. Maps were colored (overlaid) for intracranial pressure, cerebral perfusion pressure, and outcome, to explore relationships with underlying microdialysis patterns. The maps exhibited a striking clustering of patients, with unique microdialysis patterns that were recognizable throughout the analysis period. This also held true for most microdialysis patterns characteristic of ischemia. These patients with ischemic patterns can have good outcomes, suggesting a disparity between microdialysis values and severity of traumatic brain injury. CONCLUSION: Using an artificial neural network-like clustering technique, Kohonen self-organizing maps, we have shown that cerebral microdialysis, in traumatic brain injury, exhibits strikingly individualistic patterns that are identifiable throughout the analysis period. Because patients form their own clusters, microdialysis patterns, during periods of increased intracranial pressure or decreased cerebral perfusion pressure, will be found within these clusters. Consequently, no common pattern of microdialysis can be seen among patients within the range of our data. We suggest that these individualistic patterns reflect not only metabolic states of traumatic brain injury but also local gradients seen with small volume sampling. Future investigation should focus on relating these patterns, and movement within and from clusters, to metabolic states of the complex pathophysiology of traumatic brain injury.     

The meaning of feeling well in people with moderate or severe traumatic brain injury

Aim. The aim of this study was to elucidate the meaning of feeling well for people with moderate or severe traumatic brain injury. Background. Considerable attention has been given to research consequences, quality of life and satisfaction with life in people with traumatic brain injury. Most studies reveal negative aspects of living with traumatic brain injury. Knowledge that provides an understanding of the meaning of feeling well for people with a traumatic brain injury entails the possibility that they could receive support to feel well, despite their injury. Design. This study used a qualitative research approach, as the aim was to elucidate meaning. Methods. Data were collected through qualitative research interviews with two women and six men with moderate or severe traumatic brain injury who had lived with the injury for between 7–15 years. A phenomenological hermeneutic method was used to interpret the data. Results. The meaning of feeling well for people with moderate or severe traumatic brain injury was that the initially unfamiliar life with traumatic brain injury became familiar. This included finding strength, regaining control over everyday life, being close to someone and being good enough. People with traumatic brain injury felt well when they became reconciled with the circumstances of their life and created a new entity in that life, in which their complete health had been lost. Relevance to clinical practice. This study helps professionals to enhance their understanding and awareness of the possibilities for people with moderate or severe traumatic brain injury to feel well. The study showed that people with traumatic brain injury needed a lot of strength to achieve this. Professionals can help them to feel well by getting to know them and thus find ways to support the person’s feeling of wellbeing.     

Traumatic brain injury is under-diagnosed in patients with spinal cord injury.

OBJECTIVE: To investigate the occurrence and severity of traumatic brain injury in patients with traumatic spinal cord injury. DESIGN: Cross-sectional study with prospective neurological, neuropsychological and neuroradiological examinations and retrospective medical record review. PATIENTS: Thirty-one consecutive, traumatic spinal cord injury patients on their first post-acute rehabilitation period in a national rehabilitation centre. METHODS: The American Congress of Rehabilitation Medicine diagnostic criteria for mild traumatic brain injury were applied. Assessments were performed with neurological and neuropsychological examinations and magnetic resonance imaging 1.5T. RESULTS: Twenty-three of the 31 patients with spinal cord injury (74%) met the diagnostic criteria for traumatic brain injury. Nineteen patients had sustained a loss of consciousness or post-traumatic amnesia. Four patients had a focal neurological finding and 21 had neuropsychological findings apparently due to traumatic brain injury. Trauma-related magnetic resonance imaging abnormalities were detected in 10 patients. Traumatic brain injury was classified as moderate or severe in 17 patients and mild in 6 patients. CONCLUSION: The results suggest a high frequency of traumatic brain injury in patients with traumatic spinal cord injury, and stress a special diagnostic issue to be considered in this patient group.     

Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system

CONTEXT: Elevated temperature worsens injury in experimental focal and global ischemia and brain trauma. Fever is common in patients with acute neurologic illness and independently predicts poor outcome. Conventional means of treating fever are not very effective in this population. OBJECTIVE: To study the effectiveness of a catheter-based heat exchange system in reducing elevated temperatures in critically ill neurologic and neurosurgical patients. DESIGN, INTERVENTION, SETTING, AND POPULATION: This was a prospective randomized, non-blinded trial that compared conventional treatment of fever (acetaminophen and cooling blankets) with conventional treatment plus an intravascular catheter-based heat exchange system (Alsius, Irvine, CA). Patients admitted to one of 13 neurologic intensive care units in academic medical centers were eligible if they a) suffered subarachnoid hemorrhage, intracerebral hemorrhage, ischemic infarction, or traumatic brain injury; b) had a temperature >38 degrees C on two occasions or for >4 continuous hrs; and c) required central venous access. MAIN OUTCOME MEASURE: The fever burden (area under the curve >38 degrees C) for 72 hrs was compared in an intention to treat analysis. Safety of the catheter system was monitored. RESULTS: A total of 296 patients were enrolled over 20 months. Forty-one percent had subarachnoid hemorrhage, 24% had traumatic brain injury, 23% had intracerebral hemorrhage, and 13% had ischemic stroke. The groups were matched in terms of age, body mass index, sex, and Glasgow Coma Scale score distribution. Fever burden was 7.92 vs. 2.87 degrees C-hrs in the conventional group and catheter groups, respectively (64% reduction, p <.01). There was no higher rate of infection or the use of sedatives, narcotics, or antibiotics in the catheter group. The catheter did not significantly increase risk to the patient beyond that of a central catheter. CONCLUSIONS: The addition of this catheter-based cooling system to conventional management significantly improves fever reduction in neurologic intensive care unit patients.     

Quelles cibles d’hémoglobine pour les pathologies cérébrales ?

Anaemia is a frequent complication in patients suffering from primary brain injuries and often considered as a burden for secondary brain insult. The optimal haemoglobin level in these patients remains unknown. Red blood cells transfusions in patients with traumatic brain injury, subarachnoid haemorrhage, and ischemic cerebrovascular accident can improve cerebral oxygen delivery but also result in significant complications. The aim of this review is to report the most important data on the role of anaemia and blood transfusion in the critically ill patients with acute brain damage.     

Hypothermia and injury

PURPOSE OF REVIEW: Recent studies demonstrating that mild therapeutic hypothermia can improve the outcome from several ischemic and traumatic insults have led to increased interest in the potential benefits of hypothermia after injury. Previous clinical studies, however, have suggested that hypothermia is detrimental to trauma patients. This most likely is a result of differences in the physiologic effects between uncontrolled exposure hypothermia and controlled therapeutic hypothermia. The laboratory and clinical data regarding traumatic hemorrhagic shock and hypothermia are presented, as well as a novel approach to the patient with exsanguinating trauma: suspended animation. Therapeutic hypothermia for traumatic brain injury is discussed. RECENT FINDINGS: Laboratory studies of hemorrhagic shock demonstrate improved survival with mild hypothermia. For the first time, this was shown in a study in a large animal outcome model of hemorrhagic shock with trauma and intensive care. Because clinical studies continue to suggest an association between the development of hypothermia and worse outcomes in trauma patients, clinicians are continuing efforts to prevent and treat hypothermia. For exsanguination cardiac arrest, laboratory studies have demonstrated the feasibility of inducing hypothermic preservation via a rapid aortic flush (suspended animation). For traumatic brain injury, the most recent clinical trial did not show an overall benefit, but it seems that patients who arrive mildly hypothermic have better outcomes if hypothermia is maintained. SUMMARY: The dichotomy between laboratory findings that show a benefit of hypothermia and clinical findings that suggest detrimental effects remains difficult to explain. For now, preventing hypothermia remains prudent. Suspended animation seems promising for patients with exsanguinating trauma. Clinical trials of mild hypothermia during hemorrhagic shock and suspended animation for exsanguination are indicated. Clinical trials of hypothermia for traumatic brain injury are in progress.     

Traumatic brain injury: the silent epidemic.

It is difficult to accurately determine the number of people affected annually by the devastating effects of traumatic brain injury. It is clear, however, that the impact of traumatic brain injury exceeds the financial cost of acute health care. The long-term outcome of patients with traumatic brain injury has been targeted specifically for improvement during this decade. The initial brain injury--known as the primary injury--may occur in one area of the brain (focal injury) or may affect the entire brain (diffuse injury). The outcome depends on many factors, including the severity of the brain injury and the effectiveness of the interventions received. Accurate assessment of the scope of the problem would be improved by the development of a national database and the standardization of assessment practices. Critical care nurses can contribute skill and knowledge in the care of patients with traumatic brain injury and in efforts to prevent the accidents and violence that cause traumatic brain injury.     

Genetic influences on outcome following acute neurological insults

PURPOSE OF REVIEW: To examine the evidence for a genetic influence on clinical outcome after a variety of acute neurologic events. RECENT FINDINGS: Clinical outcome after brain injury is variable and cannot easily be predicted. It has been proposed that genetic polymorphisms may have an important role in determining outcome from a number of conditions, including acute neurologic events. Apolipoprotein E, an important mediator of cholesterol and lipid transport in the brain, is coded by a polymorphic gene (APOE). The APOE epsilon4 allele has been associated with unfavorable outcome after traumatic brain injury (TBI), hemorrhagic stroke and subarachnoid hemorrhage (SAH). Genes involved in other pathophysiological processes, such as cytokine genes in neuroinflammation, are now being implicated. For example interleukin-6 (IL-6) promoter polymorphisms are a risk factor for poor outcome after ischemic stroke, and may have an effect after traumatic brain injury. The emerging importance of a number of other gene polymorphisms is outlined in the review. SUMMARY: There is evidence demonstrating the epsilon4 allele of APOE predisposes to poor outcome after TBI, hemorrhagic stroke and SAH, but not ischemic stroke. The reason for this difference is unclear but it suggests there may be differences in the key mechanisms underlying the response to different types of insult. The role of other gene polymorphisms is being increasingly explored but there is still a need for larger prospective studies looking at larger panels of gene polymorphisms.     

Acute Management of Hemostasis in Patients With Neurological Injury

Neurological injuries can be divided into those with traumatic and nontraumatic causes. The largest groups are traumatic brain injury (TBI) and nontraumatic stroke. TBI patients may present with intracranial hemorrhages (contusions, or subdural or epidural hematomas). Strokes are ischemic or hemorrhagic. In all these disorders, thrombosis and hemostasis play a major role. Treatment aims to either cease bleeding and/or restore perfusion. We reviewed hemostatic and thrombolytic therapies in patients with neurological injuries by MEDLINE and EMBASE search using various key words for neurological disorders and hemostatic therapies restricted to English language and human adults. Review of articles fulfilling inclusion criteria and relevant references revealed that, in patients with ischemic stroke, intravenous thrombolytic therapy with recombinant tissue plasminogen activator within 4.5-5 hours after onset of symptoms improves clinical outcome. In contrast, there are no hemostatic therapies that are proven to improve clinical outcome of patients with hemorrhagic stroke or TBI. In patients with hemorrhagic stroke who use vitamin K antagonist or direct oral anticoagulants, there is evidence that specific reversal therapies improve hemostatic laboratory parameters but without an effect on clinical recovery. In patients with hemorrhagic stroke or TBI who use concomitant antiplatelet therapy, there is evidence for harm of platelet transfusion. In patients with aneurysmal subarachnoid hemorrhage, tranexamic acid was shown to reduce rebleeding rate without improving clinical outcome. The effects of tranexamic acid in patients with TBI are still under investigation. We conclude that, in patients with ischemic stroke, thrombolytic therapy improves outcome when given within 4.5-5 hours. In hemorrhagic stroke and TBI, most hemostatic therapies improved or corrected laboratory parameters but not clinical outcome. Currently, in several trials, the effects of tranexamic acid are being studied of which the results are eagerly awaited. Because improving clinical outcome should be the goal of new therapies, we encourage to use clinical outcome scales as the primary outcome measure in trials that investigate effects of hemostatic therapies in patients with neurological injury.     

Coping with illness after brain diseases--a comparison between patients with malignant brain tumors, stroke, Parkinson's disease and traumatic brain injury

Purpose: This study investigates coping styles in patients suffering from different brain disorders (malignant brain tumors, stroke, Parkinson's disease and traumatic brain injury). Method: In a combined analysis of four prospective studies we investigated 21 patients with malignant glioma at the end radiochemotherapy, 30 patients one year after ischemic stroke, 54 patients suffering from various stages of Parkinson's disease, and 58 patients 6 to 8.5 months after traumatic brain injury. The assessment of coping with illness was based on the Freiburg Questionnaire on Coping with illness. Results: With few exceptions, coping styles did not differ across the various brain pathologies. Differences occurred with respect to 'active, problem-oriented coping' (decreased in stroke patients), and coping by search for religious relief or quest for sense (increased in patients with Parkinson's disease). Conclusion: Differences in coping styles could be mainly related to age and social factors. Individual coping strategies seem only to be little related to the type of brain pathology.     

Traumatic Brain Injury,Neuroinflammation, and Post‐Traumatic Headaches

Concussions following head and/or neck injury are common, and although most people with mild injuries recover uneventfully, a subset of individuals develop persistent post‐concussive symptoms that often include headaches. Post‐traumatic headaches vary in presentation and may progress to become chronic and in some cases debilitating. Little is known about the pathogenesis of post‐traumatic headaches, although shared pathophysiology with that of the brain injury is suspected. Following primary injury to brain tissues, inflammation rapidly ensues; while this inflammatory response initially provides a defensive/reparative function, it can persist beyond its beneficial effect, potentially leading to secondary injuries because of alterations in neuronal excitability, axonal integrity, central processing, and other changes. These changes may account for the neurological symptoms often observed after traumatic brain injury, including headaches. This review considers selected aspects of the inflammatory response following traumatic brain injury, with an emphasis on the role of glial cells as mediators of maladaptive post‐traumatic inflammation.     

神经生长因子与表皮生长因子干预创伤性脑损伤后内源性神经干细胞的增殖

背景：表皮生长因子、神经生长因子可促进神经干细胞增殖,但对创伤性脑损伤后成年大鼠脑内内源性干细胞的影响研究甚少。目的：观察创伤性脑损伤后神经生长因子和表皮生长因子对内源性神经干细胞增殖的影响。方法：采用改良Feeney氏法自由落体撞击的方法建立大鼠创伤性脑损伤模型,48只大鼠随机抽签法分为4组,外伤后24h分别行神经生长因子、表皮生长因子单独或联合注射,对照组注射等量生理盐水。结果与结论：神经生长因子组、表皮生长因子组和联合组前肢放置实验及平衡实验评分均优于对照组,联合组优于单独治疗组（P〈0.05）。单独治疗组和联合组大鼠室管膜下区、海马和损伤区域出现的BrdU阳性细胞数明显多于对照组,联合治疗组多于单独治疗组（P〈0.05）。提示创伤性脑损伤后使用神经生长因子、表皮生长因子均可增加大鼠模型内源性神经干细胞的增殖和肢体功能的恢复,而且两种神经营养因子联合应用使这种效果更为明显。