Traumatic brain injury advancements

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1 REVIEW C URRENT OPINION Traumatic brain injury advancements Bellal Joseph, Ansab Haider, and Peter Rhee Purpose of review Traumatic brain injury (TBI) remains the leading cause of morbidity and mortality in the United States. Over the last decade, several advancements have been made in the field of TBI all aimed at improving outcomes. Recent findings Advancements in the management of TBI have been made possible through improved understanding of basic pathophysiology associated with this condition. The aim of this review is to briefly highlight the underlying pathophysiology of TBI and the most recent advancements and novel strategies being used in its treatment. We also briefly discuss coagulopathy of TBI, clinical management of TBI and how it has evolved recently. Summary The mortality associated with TBI continues to remain high and several novel strategies have emerged as potential candidates for the treatment of secondary brain injury. The clinical management of TBI and associated coagulopathy has evolved allowing for a more tailored approach toward its management. Keywords novel strategies for traumatic brain injury, pathophysiology of traumatic brain injury, repeat imaging, traumatic brain injury advancements, traumatic brain injury coagulopathy INTRODUCTION Trauma-related deaths continue to rise and traumatic brain injury (TBI) with its devastating consequences remains the most common cause of injury-related deaths [1,2]. In the United States, 1.7 million people suffer from TBI every year, of which die, are hospitalized and nearly 1.4 million are treated and discharged from the emergency department (ED) [3]. These patients have severe physical, psychological and emotional consequences and the society as a whole bears the enormous economic burden associated with TBI. For years, scientists have attempted to develop strategies to treat the primary insult associated with TBI; however, no definitive cure has been found. Therefore, the only alternative approach has been to develop preventive strategies to minimize the primary insult and ameliorate factors that may exacerbate primary injury. The development of these strategies and treatment options for TBI requires a thorough understanding of the mechanisms associated with TBI. With the improvement in clinical, laboratory and imaging technology over the last several years, our understanding of TBI has improved significantly. This has led to several changes in the way we manage these patients. The aim of this review is to focus on the recent advancements in the management of TBI and highlight some of the newly emerging avenues that offer promising treatment options. CLASSIFICATION OF BRAIN INJURY Recovery after TBI depends on two factors; the severity of the primary insult (primary brain injury) and factors that exacerbate the primary brain injury (secondary brain injury) [4]. Primary brain injury is the insult to the brain at the time of the injury such as concussion, contusion, intracranial hemorrhage and diffuse axonal injury. Secondary brain injury or delayed neuronal damage is produced by factors that are initiated at the time of the primary insult but does not manifest clinically for up to days after Division of Trauma and Acute Care Surgery, Department of Surgery, University of Arizona Medical Center, Tucson, Arizona, USA Correspondence to Bellal Joseph, MD, Division of Trauma and Acute Care Surgery, Department of Surgery, University of Arizona Medical Center, Tucson, AZ, USA. Tel: ; fax: ; bjoseph@surgery.arizona.edu Curr Opin Crit Care 2015, 21: DOI: /MCC Volume 21 Number 6 December 2015

2 Traumatic brain injury advancements Joseph et al. KEY POINTS Treatment focus for TBI remains primary prevention and reduction of secondary brain injury. Several novel strategies have emerged as likely candidates; however, no definitive evidence exists for any of these strategies. The clinical management of TBI should be tailored based on clinical examination, risk factors and initial intracranial injury characteristics. the injury. Factors that exacerbate secondary brain injury include hypotension, hypertension, hyperglycemia, hypoglycemia, hypoxemia, inflammation and raised intracranial pressure [5]. Although no strategies except prevention exist for primary brain injury, most of the research is focused on reducing the secondary brain injury that can have dramatic effects on the final outcome of the patient [6 ]. THE ROLE OF INFLAMMATION AND EXCITOTOXICITY Inflammation, both local and systemic, plays a central role in the post-traumatic phase and is a critical determinant of outcomes after TBI. This can be described as a cerebral counter part of systemic inflammatory response syndrome that occurs peripherally after trauma. The first consequence of a traumatic insult to brain is the break down of the blood brain barrier which results in a bidirectional permeability [7]. Brain which is immunologically isolated because of an intact blood brain barrier is now exposed to the immune system which now reacts to the brain tissue as a foreign entity. This post-traumatic immune response is reflected peripherally in the form of raised levels of proinflammatory cytokines [interleukin-1 (IL-1), IL-6, IL-8, IL-10 and IL-1b] [8] and markers of neuronal breakdown such as S100-B, neuron specific enolase (NSE), and glial fibrillary acidic protein. Several studies have shown a direct correlation between the levels of these inflammatory markers and clinical outcomes after TBI [6,9]. Neuronal damage during trauma is associated with a massive release of excitatory neurotransmitters most important of which is glutamate. The excess of these excitatory neurotransmitter results in overstimulation of the neurons and glial cells which results in massive influx of cellular cations such as Ca þþ,na þ and K þ. Massive shifts in cellular ionic balance trigger apoptosis and neuronal cell death. For these reasons, a major focus of TBI therapy has been the reduction in post-traumatic inflammation and excitotoxicity to preserve neuronal function. Many treatment strategies have demonstrated this reduction in the inflammatory cytokines; however, very few have demonstrated any change in clinically meaningful parameters such as mortality and Glasgow Outcome Score [10,11]. Steroids Steroids have been used for decades to treat TBI patients and have been thought to lower mortality. Several randomized-controlled trials demonstrated benefits with the use of methylprednisolone for 24 h; however, a meta-analysis of these randomized trials failed to demonstrate a conclusive benefit with the use of methylprednisolone in TBI [12]. The most conclusive evidence was brought forward after the CRASH (Corticosteroid randomization after significant head injury) trial in over TBI patients that demonstrated an 18% higher risk of death 2 weeks after injury in patients who were randomized to receive corticosteroids for 48 h [13]. Hypertonic saline Hypotension and raised intracranial pressure are one of the most important factors that can exacerbate secondary brain injury. Several studies have compared the effectiveness of hypertonic saline (HTS) to avoid both situations and shown it to be more effective than other isotonic solutions [14 16]. To increase the duration of its effect, HTS is sometimes combined with colloid solutions such as dextran. However, the highest survival advantage is achieved with HTS alone. In patients with TBI in the presence of hypotension, HTS has shown to reduce the mortality to half as compared with those who did not receive HTS [17]. However, no survival advantage or improved neurological outcomes could be achieved with its use in the prehospital use [18]. The most commonly used concentration of HTS is 3%; however, 5% HTS has recently gained popularity. Studies have demonstrated that 5% HTS has sustained higher serum osmolarity and serum sodium concentration within the first 72 h without any increase in adverse effects in comparison with 3% HTS [19 ]. Progesterone Several studies have demonstrated an improved survival rate after TBIs in women [20]. This has been postulated to result from the sex hormonal differences between men and women, most importantly of progesterone [21]. Several preclinical studies Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved

3 Trauma demonstrated that progesterone in preclinical models of TBI reduced inflammation [22]. At low doses, progesterone even promotes cell proliferation and is antiapoptotic. This led to several studies that tried to replicate these findings in humans and demonstrate a survival advantage with the use of progesterone in the early phase after an acute TBI [23]. The initial small-sized prospective randomizedcontrolled trials demonstrated improved neurological outcomes at 6 months with the use of progesterone in the acute phase after TBI [24,25]. However, the most recent double-blinded multicenter trial failed to demonstrate any survival advantage or improved neurological outcomes with progesterone use in moderate-to-severe TBI [26 ]. NOVEL STRATEGIES FOR NEUROPROTECTION AFTER TRAUMATIC BRAIN INJURY Sulfonylureas More recently, sulfonylurea receptor-1 has been shown to be upregulated in endothelium of cerebral vasculature after TBI causing increase in edema and hemorrhagic expansion of cerebral contusions [27]. This finding has led to the administration of sulfonylurea receptor-1 antagonists such as glibenclamide in animal models of TBI which has shown to reduce inflammation, size of the lesion and enhanced functional recovery [28,29]. These findings have not yet been translated in humans but clinical trials to explore the possible benefits are likely to be undertaken soon. Betablockers Neuroendocrine studies in animal models of TBI have shown an increase in sympatho-adrenal discharge after TBI [30]. This increase in catecholamine levels has also shown to be directly associated with increased mortality, lower neurological recovery, and increase in hospital and ICU length of stay [31]. On the basis of these observations, b blockers have been extensively studied as a potential therapeutic option after TBI. In a double-blinded randomized control trial of a mice model, propranolol-treated mice demonstrated improved histological recovery and mortality [32]. Although there are no randomized trials in humans, several prospective and retrospective studies have demonstrated an independent association of b blockers with improved survival [33 35]. Statins Statins are well-tolerated drugs that have shown several neuroprotective effects in TBI models [36]. They are known to reduce the inflammation by limiting the synthesis of IL-6, tumor necrosis factoralpha and intracellular adhesion molecule 1; reduce glial cell activation and increase blood brain barrier integrity [37]. The greatest advantage with the use of statins is that these drugs have a large therapeutic window and can be initiated as late as 24 h after TBI. The only clinical trial in humans with rosuvastatin use after TBI demonstrated an improvement in amnesia and disorientation [38]. Hypothermia Hypothermia is a potentially life-saving treatment for TBI. The benefits of therapeutic cooling were first discovered in animal models that demonstrated the benefits with cooling to C [39]. Therapeutic hypothermia has proven benefits in many clinical conditions such as cardiac arrest and stroke; however, its efficacy after TBI remains unclear. Several clinical trials have been performed to demonstrate the reduced risk of mortality after TBI; however, majority of these trials have major methodological flaws associated with them [40 ]. A more recent systematic review of hypothermia trials in children also failed to demonstrate any survival advantage or improved functional outcomes in pediatric TBI [41,42]. Remote ischemic conditioning Remote ischemic conditioning (RIC) is a novel treatment strategy whereby short periods of ischemia and reperfusion at a distant site in the body such as in the extremity result in the release of endogenous factors into the circulation whereby it confers global protection against future ischemic insults [43]. Such a strategy has proven benefits after sepsis, transplantation and myocardial infarction. More recently, this approach has been tested in humans with severe TBI. It demonstrated that specific neuronal markers of TBI such as S100B and NSE were significantly reduced in patients who underwent brief periods of RIC upon arrival in the ED [6 ]. COAGULOPATHY AFTER TRAUMATIC BRAIN INJURY TBI is often associated with abnormalities in the coagulation parameters and this may affect up to one-third of TBI patients [44]. The factors that lead to this coagulopathy remain unclear; however, several theories have been postulated to explain this phenomenon. These theories include local and systemic inflammation leading to the release of tissue factor, activation of the protein C pathways, platelet dysfunction and disseminated intravascular Volume 21 Number 6 December 2015

4 Traumatic brain injury advancements Joseph et al. coagulation. The coagulopathy after TBI is a dynamic process that goes through stages of hypercoagulability to ultimately a state of bleeding diathesis [44]. Although controversy exists in defining the true mechanisms involved in the development of this coagulopathy, what is clearly known is that it is associated with worsening secondary brain injury, bleed progression, and increased morbidity and mortality [45]. Most commonly, TBI coagulopathy is diagnosed with traditional measures of coagulation such as prothrombin time, activated partial thromboplastin time and International Normalized Ratio. The severity of coagulopathy has also shown to be associated with mortality. In recent years, viscoelastic tests such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) have been frequently used to assess the TBI coagulopathy. These coagulation tests detect both steps of fibrin formation and fibrinolysis thus providing information about the global process of coagulation and guide resuscitation. They are performed on whole blood, instead of plasma, and hence take into account the contribution of platelets to the final clot formation. TEG and ROTEM have shown to be more sensitive than conventional coagulation assays in TBI coagulopathy [46]. The reversal of TBI coagulopathy requires the replacement of coagulation factors. Classically, fresh frozen plasma (FFP) has been used to reverse both acquired and spontaneous TBI coagulopathy. More recently, with the advent of prothrombin complex concentrate (PCC) which contains the same coagulation factors in a much smaller dose, the role of FFP in reversing this coagulopathy has gradually decreased. Studies have demonstrated that PCC in conjunction with FFP is associated with quicker and more complete reversal of coagulopathy without any increase in complications [47,48,49 ]. Recombinant factor VIIa which was originally developed as a replacement factor for patients with hemophilia has also shown effectiveness in reversing coagulopathy after TBI and acts by binding to the exposed tissue factor [50]. Studies have demonstrated it to be more effective than FFP in reversing coagulopathy. However, there is no difference in its effectiveness when compared with PCC but it is associated with significantly higher cost [48,51]. CLINICAL MANAGEMENT OF TRAUMATIC BRAIN INJURY There has been a significant shift in paradigm in the management of TBI patients after their arrival at the trauma bay. Classically, patients with suspected TBI are initially seen by trauma surgeons who perform an initial evaluation with computed tomography (CT) scan. The presence of any form of acute intracranial injury regardless of its size, clinical presentation or associated risk factors calls for a Table 1. Brain injury guidelines Brain injury guidelines Variables BIG 1 BIG 2 BIG 3 LOC Yes/no Yes/no Yes/no Neurologic examination Normal Normal Abnormal Intoxication No No/yes No/yes CAMP No No Yes Skull fracture No Nondisplaced Displaced SDH 4mm 5 7 mm 8mm EDH 4mm 5 7 mm 8mm IPH 4 mm, 1 location 5 7 mm, 2 locations 8 mm, multiple locations SAH Trace Localized Scattered IVH No No Yes Therapeutic plan Hospitalization Observation (6hrs) Yes Yes RHCT No No Yes NSC No No Yes CAMP, coumadin aspirin motrin and plavix; EDH, epidural hematoma; IPH, intraparenchymal hematoma; IVH, intraventricular hemorrhage; LOC, loss of consciousness; NSC, neurosurgical consultation; RHCT, repeat head computed tomographic scan; SAH, subarachnoid hemorrhage; SDH, subdural hematoma Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved

5 Trauma neurosurgical consultation and a routine repeat CT scan within 24 h to look for any sign of bleed progression. The emerging literature has challenged this approach for two fundamental reasons. First, the vast majority of these patients never undergo any form of neurosurgical intervention regardless of a neurosurgical consultation or a repeat imaging and are managed nonoperatively by the critical care surgeons in the ICU [52]. Indiscriminate use of repeat imaging in these patients results in the valuable use of human and monetary resources. Second, TBI remains a clinical diagnosis and the need for neurosurgical intervention or a repeat CT scan can be reliably predicted by taking into account the size of initial head bleed, close clinical examination and the presence of risk factors for bleed progression such as antiplatelet and anticoagulation medication [53,54]. For these reasons, several studies have recommended that patients with TBI who are being managed nonoperatively can be reliably followed clinically for any sign of neurological deterioration without a routine repeat imaging [55,56,57,58]. Some institutes have developed their own guidelines to manage TBI patients with miniscule injuries without routine neurosurgical consultation and repeat imaging (see Table 1) [59]. These guidelines are based on established risk factors for neurosurgical consultation such as the use of antiplatelet/anticoagulant medications, intoxication and clinical examination [60,61]. This practice has resulted in a significant reduction in the use of valuable resources such as neurosurgical consultation, repeat CT scans and hospital costs without affecting patient care [62 ]. CONCLUSION During the past several years, many promising advancements have been made in understanding the mechanisms of secondary brain injury. Several novel strategies have emerged as strong candidates to reduce secondary brain injury after TBI. The clinical management of TBI is changing rapidly with a more tailored approach toward these patients that relies on clinical examination, risk factors and intracranial bleed characteristics. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. TBI Statistics The Brain Trauma Foundation. 2015; trauma.org/tbi-faqs/tbi-statistics/. [Accessed 2 August 2015] 2. Rhee P, Joseph B, Pandit V, et al. Increasing trauma deaths in the United States. Ann Surg 2014; 260: Traumatic Brain Injury In The United States. 2010; traumaticbraininjury/pdf/blue_book.pdf. 4. Uzzell BP, Stonnington HH. Recovery after traumatic brain injury. 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6 Traumatic brain injury advancements Joseph et al. 27. Simard JM, Kilbourne M, Tsymbalyuk O, et al. Key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after brain contusion. J Neurotrauma 2009; 26: Patel AD, Gerzanich V, Geng Z, Simard JM. Glibenclamide reduces hippocampal injury and preserves rapid spatial learning in a model of traumatic brain injury. J Neuropathol Exp Neurol 2010; 69: Zweckberger K, Hackenberg K, Jung CS, et al. Glibenclamide reduces secondary brain damage after experimental traumatic brain injury. Neuroscience 2014; 272: Clifton GL, Ziegler MG, Grossman RG. Circulating catecholamines and sympathetic activity after head injury. Neurosurgery 1981; 8: Haider W, Benzer H, Krystof G, et al. Urinary catecholamine excretion and thyroid hormone blood level in the course of severe acute brain damage. Eur J Intensive Care Med 1975; 1: Liu M. Protective effects of propranolol on experimentally head-injured mouse brains. 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JAMA Surg 2015; 150: This study demonstrated that a guideline-based protocol for the use of repeat head CT scans and neurological consultation in mild TBI can significantly reduce the use of hospital resources without affecting patient outcomes Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved