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Special Articles   |    
Concepts and Strategies for Clinical Management of Blast-Induced Traumatic Brain Injury and Posttraumatic Stress Disorder
Yun Chen, M.D., Ph.D.; Wei Huang, M.B.; Shlomi Constantini, M.D., M.Sc.
The Journal of Neuropsychiatry and Clinical Neurosciences 2013;25:103-110. doi:10.1176/appi.neuropsych.12030058
View Author and Article Information

From BrightstarTech, Inc. Clarksburg, MD (YC); Uniformed Services University of the Health Sciences, Bethesda, MD (WH); Dept. of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel (SC).

Send correspondence to Dr. Yun Chen, BrightstarTech, Inc.; e-mail: yun.chen@brightstartechinc.com

Copyright © 2013 American Psychiatric Association

Received March 12, 2012; Accepted July 05, 2012.

After exposure of the human body to blast, kinetic energy of the blast shock waves might be transferred into hydraulic energy in the cardiovascular system to cause a rapid physical movement or displacement of blood (a volumetric blood surge). The volumetric blood surge moves through blood vessels from the high-pressure body cavity to the low-pressure cranial cavity, causing damage to tiny cerebral blood vessels and the blood–brain barrier (BBB). Large-scale cerebrovascular insults and BBB damage that occur globally throughout the brain may be the main causes of non-impact, blast-induced brain injuries, including the spectrum of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD). The volumetric blood surge may be a major contributor not only to blast-induced brain injuries resulting from physical trauma, but may also be the trigger to psychiatric disorders resulting from emotional and psychological trauma. Clinical imaging technologies, which are able to detect tiny cerebrovascular insults, changes in blood flow, and cerebral edema, may help diagnose both TBI and PTSD in the victims exposed to blasts. Potentially, prompt medical treatment aiming at prevention of secondary neuronal damage may slow down or even block the cascade of events that lead to progressive neuronal damage and subsequent long-term neurological and psychiatric impairment.

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Non-impact, blast-induced brain injuries including traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) may result from parenchymal brain damage, which is caused by the primary blast effect in war fighters exposed to a blast overpressure wave itself, but who do not sustain penetrating and blunt-impact injuries that are caused by secondary and tertiary blast effects.1 Non-impact, blast-induced TBI and PTSD have been considered as the signature injury of the wars in Iraq and Afghanistan.25 It is estimated that more than 300,000 veterans returning from Iraq and Afghanistan have suffered a TBI or PTSD or both since 2000.610 Blast-induced TBI is strongly associated with the development of PTSD. Many PTSD symptoms (such as depression, anxiety, memory and attention deficits, sleep problems, and emotional disturbances) overlap with symptoms of TBI.11,12 Some studies indicate that approximately 80% of patients with blast-induced and non-blast TBI develop chronic PTSD.1315 Blast-induced TBI and PTSD seem to have similar pathogenesis.1

 A recent study on blast shock-wave mitigation using hydraulic energy redirection and release technology suggested that a volumetric blood surge might be created when the kinetic energy of the blast shock-wave was transferred into hydraulic energy in the cardiovascular system to cause a rapid physical movement or displacement of blood.16 The volumetric blood surge has also been verified by both wound ballistics experiments in animals17 and finite-element simulation of blast loads on the torso.18 It has a strong destructive power, and can cause a non-contact, remote injury to distant organs and tissues. The volumetric blood surge can possibly be the major cause of non-impact, blast-induced brain injuries (TBI and PTSD).1 It may move through blood vessels from the high-pressure ventral body cavity (thoracic cavity and abdominal cavity) to the low-pressure cranial cavity, thus acutely increasing cerebral perfusion pressure and causing damage to both tiny cerebral blood vessels and the blood–brain barrier (BBB) in the global brain.

Global cerebrovascular insults and the BBB damage caused by the volumetric blood surge may result in diffuse cerebral edema, hyperemia, vasospasm, and microhemorrhaging in the brain, thus further triggering secondary neuronal damage (Figure 1[A]).1 The delayed neuronal damage includes excitotoxicity, inflammation, ionic imbalance, oxidative stress, apoptosis, diffuse axonal injury, and neurodegeneration. Secondary neuronal damage is an indirect consequence of initial injury (such as cerebrovascular insults and the BBB damage after exposure of the body to blast shock-wave) and a major contributor to the ultimate neuronal cell death and neural loss in the injured brain. Much of the damage done to the brain does not typically occur at the time of initial injury and does not result directly from the initial injury itself. A cascade of progressive neural injury and neuronal cell death is triggered by the initial injury and continues in the hours, days or weeks following the initial insult.19,20 This delayed secondary neuronal damage has been considered to be largely responsible for serious neurological and psychiatric impairments, including memory loss, inability to concentrate, speech problems, motor and sensory deficits, and behavioral problems (Figure 1[A]).21 However, because blast-induced brain injuries activate the cascade of progressive neuronal damage, it is difficult to separate clinical outcomes of the initial damage to tiny cerebral blood vessels and the BBB from that of secondary neuronal damage, and to separate neuropathophysiologically-based symptoms from neuropsychiatrically-based problems.

 
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FIGURE 1.Cascade of Damage Events, Medical Imaging Diagnoses, and Treatment Approaches

[A]: A secondary cascade of neuronal damage develops with time in the brain after exposure to blast shock-wave; [B]: Clinical imaging technologies such as 3-D CT or MR cerebral angiography, SPECT, and MRI-DWI/DTI may help detect tiny cerebrovascular insults, changes in blood flow, and cerebral edema; [C]: Neuroprotection strategies aiming at prevention of secondary neuronal damage (such as reducing cerebral edema and inflammatory reaction, attenuating hemorrhage, and preventing cerebral vasospasm), may need to be executed as soon as the blast-induced volumetric blood surge causes damage to tiny cerebral blood vessels and the BBB.

Some disorders, such as PTSD and memory and cognitive impairments, are more likely to be a psychological consequence of secondary neuronal damage induced by physical trauma (such as blast-induced TBI, non-blast TBI, hemorrhagic stroke, ischemic stroke, nerve-agent poisoning, prolonged hypoxia, infection, and neurological illness).2227 These psychiatric disorders can also possibly be induced by emotional and psychological trauma. These emotional and psychological traumatic events include 1) serious accidents; war or terrorist attacks; car, train, or plane crashes; the sudden death of a loved one; captivity as a hostage; serious physical illness diagnosis, medical emergencies, etc.;2832 2) devastating natural disasters, such as flood, tornado, hurricane, volcanic eruption, earthquake, landslide, etc.;3335 3) violent attacks, such as rape, sexual abuse, physical and emotional abuse, bullying, domestic violence, indoctrination, etc.;3743 and 4) other psychosocial stressors, such as marital separation, divorce, family argument, dispute at work, loss of job, unemployment or underemployment, serious financial problems, poverty, retirement, socioeconomic deprivation, alcohol and drug use, etc.4449 The mechanisms underlying the psychiatric disorders induced by the emotional and psychological traumatic events may also involve a volumetric blood surge created by a sudden rise in cardiovascular pressure.

When exposed to an emotional and psychological traumatic event, the victim’s heart will beat faster and stronger than usual, and blood pressure will dramatically rise because of the increased cardiac output, which may create a volumetric blood surge in the cardiovascular system. The volumetric blood surge induced by a sudden increase in blood pressure will move quickly through blood vessels to organs and tissues (including the brain). Unlike the peripheral tissues (such as lung, liver, and stomach) that have good tolerance to volumetric blood surge, a sudden rush of blood to the brain will dramatically increase cerebral perfusion pressure, owing to the limited space inside blood vessels in the brain. The extremely rapid increase in cerebrovascular pressure may cause damage to both very small cerebral blood vessels and the BBB in the brain, because cerebral blood vessels and the BBB are vulnerable to sudden fluctuations in perfusion pressure. Therefore, psychiatric disorders induced by emotional and psychological trauma may potentially also be a result of secondary neuronal damage caused by volumetric blood surge in the brain (Figure 2).

 
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FIGURE 2.A Possible Mechanism for Psychiatric Disorders Resulting From Emotional and Psychological Trauma

Because chronic disability after brain damage is largely attributable to mental sequelae, rather than focal motor or sensory neurological deficits in humans,50 psychiatric disorders should be the long-term prominent clinical manifestations of the victims of brain damage induced by either physical trauma or emotional and psychological trauma. These chronic psychiatric consequences are serious public health problems caused by various types of brain damage, which result in the loss of many years of productive life and incur large healthcare costs.

Blast-induced brain injuries (TBI and PTSD) are typically difficult to detect by using traditional neuroimaging techniques (i.e., computed tomography [CT], magnetic resonance imaging [MRI], and angiography), because the damage to tiny cerebral blood vessels and the BBB might be the initial injuries induced by blast shock-wave in the brain.1 Much of neuronal damage can be seen only under a microscope. Changes in both cerebral blood vessels and cerebral blood flow and vasogenic cerebral edema should be the most common pathophysiological characteristics of cerebrovascular insults and BBB damage.5153 Focused clinical diagnostic techniques that are able to sensitively detect tiny cerebral blood vessels, blood flow, and edema may be helpful for diagnosis of blast-induced brain injuries.

Using single-photon emission computerized tomography (SPECT) that is able detect the level of perfusion or blood flow inside the brain, decreased levels of blood flow in the temporal lobes that contain the cortex and the limbic system (the amygdala, hippocampus, gyrus cinguli, thalamus, and kleinhirn) were detected in a soldier who was exposed to a blast in Afghanistan and was diagnosed with both mild TBI and PTSD.54 Diffusion tensor imaging (DTI), an advanced form of MRI that produces in-vivo images of the white-matter brain tissues weighted with the local microstructural characteristics of water diffusion, is sensitive to measurement of the restricted diffusion of water in the brain. Using DTI, marked persistent abnormalities in the middle cerebellar peduncles, cingulum bundles, and the right orbitofrontal white matter were observed in 18 of the 63 U.S. military personnel with blast-induced mild TBI within 90 days after the injury. The persistent abnormalities in the brain may involve diffuse axonal injury.55

Three medical imaging technologies that are currently used in the clinical diagnosis of diseases can be considered for use in diagnosis of blast-induced brain injuries (Figure 1[B]): 1) three-dimensional CT or MR cerebral angiography using nanosized contrast materials (dyes) can be useful for measuring damage to tiny cerebral blood vessels. Cerebral angiography is clinically helpful for detecting and diagnosing acute stroke.5658 It is used to image the blood vessels of the brain and the blood flowing through the blood vessels and to detect abnormalities in the brain's blood vessels, such as narrowing (vasospasm) or blockage (thrombosis); 2) SPECT may be an ideal diagnostic tool for detection of early changes in cerebral blood flow after blast-induced TBI because it can measure the blood perfusion level relative to the brain's current need.59,60 A decrease in blood flow levels in a region of the brain may suggest an injury to that brain region; 3) diffusion MRI, such as diffusion tensor imaging (DTI) may be beneficial to detect cerebral edema since it measures diffusion rates of water molecules in the brain parenchyma.55,61 A decreased apparent diffusion coefficient obtained by the diffusion MRI represents reduced water diffusion or mobility in the brain, which indicates that edema has formed and neuronal damage has occurred.

Brain injuries, to-date, are untreatable disorders, because no pharmacological treatment has currently been proven to prevent secondary damage processes.62 However, secondary damage process offers a potential therapeutic window of opportunity,63 in which progressive neural injury and neuronal cell death may be prevented, and the extent of disability may be reduced during the first few hours after initial injury.64 According to the AANS (American Association of Neurological Surgeons) recommendations, there is no medication or “miracle treatment” that can be given to prevent brain damage or promote neuronal healing after TBI. The primary goal in the acute management of the patient with TBI is to prevent any secondary damage to the brain.65 Therefore, neuroprotective strategies intended to halt or mitigate secondary neuronal damage at early stage of injury (2–3 hours after injury) may help block or slow down the development of subsequent neurological and neuropsychiatric impairments (including PTSD, persistent memory and cognitive deficits, nonspecific mental and emotional symptoms, chronic motor deficits, Alzheimer-like dementia, and Parkinson’s disease).

Diffuse cerebral edema, hyperemia, vasospasm, and hemorrhaging are the initial pathophysiological changes in the brain after non-impact, blast-induced brain injuries.66,67 Proper and prompt medical treatment aiming to attenuate these pathophysiological changes (Figure 1[C]) may improve clinical outcome of blast-induced brain injuries, thus leading to a significant decrease in both the direct cost for medical care and indirect cost of lost productivity resulting from blast-induced TBI and PTSD. When an effective treatment is discovered, it may be important to treat the victims exposed to blasts as soon as possible, preferably within 8 hours, and not later than 24 hours after exposure.

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Treatment for Cerebral Edema

Osmotherapy, using oral administration or intravenous injection of mannitol or diuretics (such as furosemide, bumetanide, torsemide, and ethacrynic acid) to induce dehydration, is a most common approach to treating cerebral edema and possible elevated intracranial pressure.68,69 Administration of mannitol may be an effective treatment for patients with blast-induced mild brain injuries within 8 hours after exposure to blasts. For patients with blast-induced severe brain injuries, mannitol or diuretics may need to be given intravenously as soon as possible after the injury. If needed, corticosteroids can be administered orally or intravenously, in addition to osmotherapy, to reduce brain swelling.70

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Treatment for Intracranial Hemorrhage

Medical therapy of intracranial hemorrhage is principally focused on minimizing brain damage and stabilizing the patient’s condition. Certain medications, including painkillers, corticosteroids, mannitol, or diuretics to reduce swelling, and anticonvulsants to control seizures, may be prescribed.71,72 Blood products or intravenous fluids may be administered if needed.73 Normotonic, rather than hypotonic fluids will be used to maintain brain perfusion without exacerbating brain edema.74 Antihypertensive therapy aimed at maintaining blood pressure to a mean arterial pressure (MAP) less than 130 mm Hg can be applied to patients with intracranial hemorrhage within 3 hours of onset.75 Patients may be treated with recombinant factor VIIa (rFVIIa) within 4 hours after the onset of intracerebral hemorrhage, to limit the bleeding and formation of a hematoma. However, VIIa is reported to increase the risk of thromboembolism, and may not result in improved clinical outcomes.76 Frozen plasma, vitamin K, protamine, or platelet transfusions can be given in cases of coagulopathy.77

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Treatment for Cerebral Vasospasm

Medical therapy of cerebral vasospasm will aim at limiting or reducing delayed ischemic injury due to cerebral vasospasm. Nimodipine, a dihydropyridine calcium-channel blocker, has shown good results in preventing cerebral vasospasm caused by subarachnoid hemorrhaging.78 Nimodipine can be administered orally (60 mg, every 4 hours) or intravenously (intravenous infusion at a rate of 1–2 mg/hour) based on the patient's clinical status and medication needs. Also, the condition can be treated with hypertensive hypervolemic hemodilution (HHH) therapy,79 which combines intravenous medications and large volumes of intravenous fluids to elevate cerebral blood perfusion pressure, increase cerebral blood volume, and thin the blood, thus providing blood to the affected regions of the brain. If the HHH therapy is unsuccessful, balloon angioplasty may be used to open tight, spastic vessels.80

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Anti-Inflammatory Treatment

Anti-inflammatory treatment refers to an attempted remediation that reduces or suppresses inflammation. Current anti-inflammatory drugs include steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), immune-selective anti-inflammatory derivatives (ImSAIDs), and herbs. Steroidal anti-inflammatory drugs, such as glucocorticoids, are effective in reducing inflammation or brain-tumor-associated brain swelling by binding to glucocorticoid receptors in the brain.81 NSAIDs such as aspirin, ibuprofen, naproxen, and other specific COX-inhibitors, reduce inflammation by inhibiting both the COX-1 and COX-2 enzymes that synthesize prostaglandins to create inflammation.82 ImSAIDs are a class of peptides that are reported to have anti-inflammatory effects. ImSAIDs can attenuate the amplified inflammatory response by limiting the activation and migration of inflammatory cells.83 Some herbs that contain helenalin or salicylic acid, such as harpagophytum, hyssop, ginger, turmeric, arnica Montana, and willow bark, may have anti-inflammatory effects. Cannabichromene, found in the cannabis plant, has shown the ability to reduce inflammation.84,85 These anti-inflammatory drugs may be administered or given orally within 8 hours after the injury, depending on the patient's clinical condition. However, recent clinical trials have shown that these anti-inflammatory agents may not be effective for some conditions, such as penetrating head injury and spontaneous intracerebral hemorrhage.

A volumetric blood surge may be created when the kinetic energy of a blast shock-wave is transferred into hydraulic energy in the cardiovascular system to cause a rapid physical movement or displacement of blood. It may move rapidly through blood vessels to the cranial cavity, causing damage to tiny cerebral blood vessels and the BBB and triggering a secondary cascade of neuronal damage in the brain. The volumetric blood surge may be a major contributor not only to blast-induced TBI and PTSD, but also to some psychiatric disorders induced by emotional and psychological trauma. Three-dimensional CT or MR cerebral angiography, SPECT and diffusion MRI may help detect tiny cerebrovascular insults, changes in blood flow, and cerebral edema in the brains of victims exposed to blasts. Neuroprotective strategies for victims exposed to blasts, which include but not limited to reducing cerebral edema and inflammatory reaction, attenuating hemorrhage, and preventing cerebral vasospasm, may need to be executed within 8 hours after exposure to blasts.

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Levin  HS;  Wilde  E;  Troyanskaya  M  et al:  Diffusion tensor imaging of mild to moderate blast-related traumatic brain injury and its sequelae.  J Neurotrauma 2010; 27:683–694
[CrossRef] | [PubMed]
 
Scalea  TM:  Does it matter how head injured patients are resuscitated? in  Neurotrauma: Evidence-Based Answers To Common Questions . Edited by  Valadka AB, Andrews BT .  New York,  Thieme, 2005, pp 3–4
 
Armin  SS;  Colohan  AR;  Zhang  JH:  Traumatic subarachnoid hemorrhage: our current understanding and its evolution over the past half century.  Neurol Res 2006; 28:445–452
[CrossRef] | [PubMed]
 
Marion  DW:  Pathophysiology and treatment of intracranial hypertention, in  Intensive Care in Neurosurgery.   Edited by Andrews BT. Thieme Medical, New York, 2003, pp 52–53
 
American Association of Neurological Surgeons: Traumatic Brain Injury. AANS. March, 2011; accessed September 30, 2011, at http://aans.org/en/Patient%20Information/Conditions%20and%20Treatments/Traumatic%20Brain%20Injury.aspx
 
Ling  G;  Bandak  F;  Armonda  R  et al:  Explosive blast neurotrauma.  J Neurotrauma 2009; 26:815–825
[CrossRef] | [PubMed]
 
Moore  DF;  Jérusalem  A;  Nyein  M  et al:  Computational biology: modeling of primary blast effects on the central nervous system.  Neuroimage 2009; 47(Suppl 2):T10–T20
[CrossRef] | [PubMed]
 
Steiner  T;  Ringleb  P;  Hacke  W:  Treatment options for large hemispheric stroke.  Neurology 2001; 57(Suppl 2):S61–S68
[CrossRef] | [PubMed]
 
Bhardwaj  A:  Osmotherapy in neurocritical care.  Curr Neurol Neurosci Rep 2007; 7:513–521
[CrossRef] | [PubMed]
 
Lescot  T;  Abdennour  L;  Boch  AL  et al:  Treatment of intracranial hypertension.  Curr Opin Crit Care 2008; 14:129–134
[CrossRef] | [PubMed]
 
Papangelou  A;  Lewin  JJ  3rd;  Mirski  MA  et al:  Pharmacologic management of brain edema.  Curr Treat Options Neurol 2009; 11:64–73
[CrossRef] | [PubMed]
 
Temkin  NR:  Preventing and treating posttraumatic seizures: the human experience.  Epilepsia 2009; 50(Suppl 2):10–13
[CrossRef] | [PubMed]
 
Katsuki  H:  Exploring neuroprotective drug therapies for intracerebral hemorrhage.  J Pharmacol Sci 2010; 114:366–378
[CrossRef] | [PubMed]
 
Wakade  AR;  Malhotra  RK;  Sharma  TR  et al:  Changes in tonicity of perfusion medium cause prolonged opening of calcium channels of the rat chromaffin cells to evoke explosive secretion of catecholamines.  J Neurosci 1986; 6:2625–2634
[PubMed]
 
Qureshi  AI:  Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH): rationale and design.  Neurocrit Care 2007; 6:56–66
[CrossRef] | [PubMed]
 
Yank  V;  Tuohy  CV;  Logan  AC  et al:  Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications.  Ann Intern Med 2011; 154:529–540
[CrossRef] | [PubMed]
 
Flaherty  ML:  Anticoagulant-associated intracerebral hemorrhage.  Semin Neurol 2010; 30:565–572
[CrossRef] | [PubMed]
 
Weant  KA;  Ramsey  CN  3rd;  Cook  AM:  Role of intra-arterial therapy for cerebral vasospasm secondary to aneurysmal subarachnoid hemorrhage.  Pharmacotherapy 2010; 30:405–417
[CrossRef] | [PubMed]
 
Ullman  JS;  Bederson  JB:  Hypertensive, hypervolemic, hemodilutional therapy for aneurysmal subarachnoid hemorrhage. Is it efficacious? Yes.  Crit Care Clin 1996; 12:697–707
[CrossRef] | [PubMed]
 
Santillan  A;  Knopman  J;  Zink  W  et al:  Transluminal balloon angioplasty for symptomatic distal vasospasm refractory to medical therapy in patients with aneurysmal subarachnoid hemorrhage.  Neurosurgery 2011; 69:95–101, discussion 102
[CrossRef] | [PubMed]
 
Gomes  JA;  Stevens  RD;  Lewin  JJ  3rd  et al:  Glucocorticoid therapy in neurologic critical care.  Crit Care Med 2005; 33:1214–1224
[CrossRef] | [PubMed]
 
Hoozemans  JJ;  Veerhuis  R;  Rozemuller  AJ  et al:  Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer’s disease.  Curr Drug Targets 2003; 4:461–468
[CrossRef] | [PubMed]
 
Friedle  SA;  Curet  MA;  Watters  JJ:  Recent patents on novel P2X(7) receptor antagonists and their potential for reducing central nervous system inflammation.  Recent Patents CNS Drug Discov 2010; 5:35–45
[CrossRef]
 
Kim  H:  Neuroprotective herbs for stroke therapy in traditional eastern medicine.  Neurol Res 2005; 27:287–301
[CrossRef] | [PubMed]
 
Suk  K:  Regulation of neuroinflammation by herbal medicine and its implications for neurodegenerative diseases: a focus on traditional medicines and flavonoids.  Neurosignals 2005; 14:23–33
[CrossRef] | [PubMed]
 
References Container

FIGURE 1. Cascade of Damage Events, Medical Imaging Diagnoses, and Treatment Approaches

[A]: A secondary cascade of neuronal damage develops with time in the brain after exposure to blast shock-wave; [B]: Clinical imaging technologies such as 3-D CT or MR cerebral angiography, SPECT, and MRI-DWI/DTI may help detect tiny cerebrovascular insults, changes in blood flow, and cerebral edema; [C]: Neuroprotection strategies aiming at prevention of secondary neuronal damage (such as reducing cerebral edema and inflammatory reaction, attenuating hemorrhage, and preventing cerebral vasospasm), may need to be executed as soon as the blast-induced volumetric blood surge causes damage to tiny cerebral blood vessels and the BBB.

FIGURE 2. A Possible Mechanism for Psychiatric Disorders Resulting From Emotional and Psychological Trauma
+

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[CrossRef] | [PubMed]
 
Levin  HS;  Wilde  E;  Troyanskaya  M  et al:  Diffusion tensor imaging of mild to moderate blast-related traumatic brain injury and its sequelae.  J Neurotrauma 2010; 27:683–694
[CrossRef] | [PubMed]
 
Scalea  TM:  Does it matter how head injured patients are resuscitated? in  Neurotrauma: Evidence-Based Answers To Common Questions . Edited by  Valadka AB, Andrews BT .  New York,  Thieme, 2005, pp 3–4
 
Armin  SS;  Colohan  AR;  Zhang  JH:  Traumatic subarachnoid hemorrhage: our current understanding and its evolution over the past half century.  Neurol Res 2006; 28:445–452
[CrossRef] | [PubMed]
 
Marion  DW:  Pathophysiology and treatment of intracranial hypertention, in  Intensive Care in Neurosurgery.   Edited by Andrews BT. Thieme Medical, New York, 2003, pp 52–53
 
American Association of Neurological Surgeons: Traumatic Brain Injury. AANS. March, 2011; accessed September 30, 2011, at http://aans.org/en/Patient%20Information/Conditions%20and%20Treatments/Traumatic%20Brain%20Injury.aspx
 
Ling  G;  Bandak  F;  Armonda  R  et al:  Explosive blast neurotrauma.  J Neurotrauma 2009; 26:815–825
[CrossRef] | [PubMed]
 
Moore  DF;  Jérusalem  A;  Nyein  M  et al:  Computational biology: modeling of primary blast effects on the central nervous system.  Neuroimage 2009; 47(Suppl 2):T10–T20
[CrossRef] | [PubMed]
 
Steiner  T;  Ringleb  P;  Hacke  W:  Treatment options for large hemispheric stroke.  Neurology 2001; 57(Suppl 2):S61–S68
[CrossRef] | [PubMed]
 
Bhardwaj  A:  Osmotherapy in neurocritical care.  Curr Neurol Neurosci Rep 2007; 7:513–521
[CrossRef] | [PubMed]
 
Lescot  T;  Abdennour  L;  Boch  AL  et al:  Treatment of intracranial hypertension.  Curr Opin Crit Care 2008; 14:129–134
[CrossRef] | [PubMed]
 
Papangelou  A;  Lewin  JJ  3rd;  Mirski  MA  et al:  Pharmacologic management of brain edema.  Curr Treat Options Neurol 2009; 11:64–73
[CrossRef] | [PubMed]
 
Temkin  NR:  Preventing and treating posttraumatic seizures: the human experience.  Epilepsia 2009; 50(Suppl 2):10–13
[CrossRef] | [PubMed]
 
Katsuki  H:  Exploring neuroprotective drug therapies for intracerebral hemorrhage.  J Pharmacol Sci 2010; 114:366–378
[CrossRef] | [PubMed]
 
Wakade  AR;  Malhotra  RK;  Sharma  TR  et al:  Changes in tonicity of perfusion medium cause prolonged opening of calcium channels of the rat chromaffin cells to evoke explosive secretion of catecholamines.  J Neurosci 1986; 6:2625–2634
[PubMed]
 
Qureshi  AI:  Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH): rationale and design.  Neurocrit Care 2007; 6:56–66
[CrossRef] | [PubMed]
 
Yank  V;  Tuohy  CV;  Logan  AC  et al:  Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications.  Ann Intern Med 2011; 154:529–540
[CrossRef] | [PubMed]
 
Flaherty  ML:  Anticoagulant-associated intracerebral hemorrhage.  Semin Neurol 2010; 30:565–572
[CrossRef] | [PubMed]
 
Weant  KA;  Ramsey  CN  3rd;  Cook  AM:  Role of intra-arterial therapy for cerebral vasospasm secondary to aneurysmal subarachnoid hemorrhage.  Pharmacotherapy 2010; 30:405–417
[CrossRef] | [PubMed]
 
Ullman  JS;  Bederson  JB:  Hypertensive, hypervolemic, hemodilutional therapy for aneurysmal subarachnoid hemorrhage. Is it efficacious? Yes.  Crit Care Clin 1996; 12:697–707
[CrossRef] | [PubMed]
 
Santillan  A;  Knopman  J;  Zink  W  et al:  Transluminal balloon angioplasty for symptomatic distal vasospasm refractory to medical therapy in patients with aneurysmal subarachnoid hemorrhage.  Neurosurgery 2011; 69:95–101, discussion 102
[CrossRef] | [PubMed]
 
Gomes  JA;  Stevens  RD;  Lewin  JJ  3rd  et al:  Glucocorticoid therapy in neurologic critical care.  Crit Care Med 2005; 33:1214–1224
[CrossRef] | [PubMed]
 
Hoozemans  JJ;  Veerhuis  R;  Rozemuller  AJ  et al:  Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer’s disease.  Curr Drug Targets 2003; 4:461–468
[CrossRef] | [PubMed]
 
Friedle  SA;  Curet  MA;  Watters  JJ:  Recent patents on novel P2X(7) receptor antagonists and their potential for reducing central nervous system inflammation.  Recent Patents CNS Drug Discov 2010; 5:35–45
[CrossRef]
 
Kim  H:  Neuroprotective herbs for stroke therapy in traditional eastern medicine.  Neurol Res 2005; 27:287–301
[CrossRef] | [PubMed]
 
Suk  K:  Regulation of neuroinflammation by herbal medicine and its implications for neurodegenerative diseases: a focus on traditional medicines and flavonoids.  Neurosignals 2005; 14:23–33
[CrossRef] | [PubMed]
 
References Container
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