TreatNOW



Fish and Fish Oils in Health and Disease. Edited by Susan Raatz and Doug BibusChapter 32: Utilization of Fish Oil for the Prevention and Treatment of Traumatic Brain InjuryMichael D. Lewis, MD, MPH, MBA, FACPMBrain Health Education and Research Institute10004 Weatherwood CourtPotomac, Maryland 20854 USAmlewis@+1 (240) 481-2989 mobile+1 (240) 235-4193 homeTotal Word Count: 6934Number of Tables: 3Number of Figures: 3References: 91Summary (150 words)Traumatic brain injury (TBI), with its diverse heterogeneity and prolonged secondary pathogenesis, remains a clinical challenge. Clinical studies thus far have failed to identify an effective treatment strategy when a combination of targets controlling aspects of neuroprotection, neuroinflammation, and neuroregeneration is needed. Omega-3 fatty acids (ω-3FA) offer the advantage of this approach. Although further clinical trial research is needed, there is a growing body of strong preclinical evidence and clinical experience suggests that benefits may be possible from aggressively adding substantial amounts of ω-3FA to optimize the nutritional foundation of TBI , concussion, and post-concussion syndrome patients. Early and optimal doses of ω-3FA, even in the pre-hospital or emergency department setting, has the potential to improve outcomes from this potentially devastating public health problem. With evidence of unsurpassed safety and tolerability, ω-3FA should be considered mainstream, conventional medicine, if conventional medicine can overcome its inherent bias against nutritional, non-pharmacologic therapies.Key Words: Omega-3, decosahexanoic acid, DHA, TBI, brain injury, concussion, neuroregeneration, neuroinflammation, neuroprotectionIntroductionOmega-3 polyunsaturated fatty acids (ω-3FA), particularly decosahexanoic acid (DHA), are structural components of cell membranes, most concentrated in the brain and retina. Emerging science on the ability of ω-3FA to be beneficial to the nervous system during and after acute traumatic brain injury (TBI) is acknowledged, mainly in preclinical studies, but now in clinical experience and case reports. TBI has long been recognized as a leading cause of traumatic death and disability.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Selassie", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zaloshnja", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Langlois", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steiner", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Head Trauma Rehabil", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "123-131", "title" : "Incidence of long-term disability following traumatic brain injury hospitalization, United States, 2003.", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zaloshnja", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Langlois", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Selassie", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Head Trauma Rehabil", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "394-400", "title" : "Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Selassie et al., 2008; Zaloshnja, Miller, Langlois, & Selassie, 2005)", "manualFormatting" : "(Selassie, 2008)", "plainTextFormattedCitation" : "(Selassie et al., 2008; Zaloshnja, Miller, Langlois, & Selassie, 2005)", "previouslyFormattedCitation" : "(Selassie et al., 2008; Zaloshnja, Miller, Langlois, & Selassie, 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Selassie, 2008) TBI is caused by a bump, blow or jolt to the head or a penetrating head injury that disrupts the normal function of the brain. 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Motor bikes are major causes, increasing in significance in developing countries as other causes reduce.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Reilly", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "chapter-number" : "The impact", "editor" : [ { "dropping-particle" : "", "family" : "Weber", "given" : "JT", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "5-7", "publisher" : "Academic Press", "publisher-place" : "Amsterdam", "title" : "Neurotrauma: New Insights Into Pathology and Treatment.", "type" : "chapter" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Reilly, 2007)", "plainTextFormattedCitation" : "(Reilly, 2007)", "previouslyFormattedCitation" : "(Reilly, 2007)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Reilly, 2007) Some consider TBI a global public health epidemic.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Rodr\u00edguez-Rodr\u00edguez", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Egea-Guerrero", "given" : "JJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murillo-Cabezas", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carrillo-Vico", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Curr Med Chem. 2013 Dec 17.", "id" : "ITEM-1", "issue" : "Dec 17", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "[Epub ahead of print]", "title" : "Oxidative Stress In Traumatic Brain Injury", "type" : "article-journal" }, "uris" : [ "" ] } ], 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through research", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(\u201cTraumatic brain injury: hope through research,\u201d 2002)", "manualFormatting" : "(NINDS, 2002)", "plainTextFormattedCitation" : "(\u201cTraumatic brain injury: hope through research,\u201d 2002)", "previouslyFormattedCitation" : "(\u201cTraumatic brain injury: hope through research,\u201d 2002)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(NINDS, 2002) [TABLE 32-1] It is believed that 80% or more of persons suffering a TBI would be classified as mild and do not seek medical attention.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "VG Coronado", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McGuire", "given" : "LC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" 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{ "date-parts" : [ [ "2012" ] ] }, "page" : "299-307", "title" : "Trends in Traumatic Brain Injury in the U.S. and the public health response: 1995-2009", "type" : "article-journal", "volume" : "43" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(VG Coronado et al., 2012)", "manualFormatting" : "(Coronado, 2012)", "plainTextFormattedCitation" : "(VG Coronado et al., 2012)", "previouslyFormattedCitation" : "(VG Coronado et al., 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Coronado, 2012) Most of those improve over the first few hours to days, but 5-20% may continue to have post-concussion symptoms (PCS) for an extended period following the initial injury.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Jotwani", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harmon", "given" : "HG", 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CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Ling", "given" : "GS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marshall", "given" : "SA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurol Clin", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "viii", "title" : "Management of traumatic brain injury in the intensive care unit.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(GS Ling & Marshall, 2008)", "manualFormatting" : "(Ling, 2008)", "plainTextFormattedCitation" : "(GS Ling & Marshall, 2008)", "previouslyFormattedCitation" : "(GS Ling & Marshall, 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Ling, 2008)Classification of TBIMost commonly, TBI is classified using mild, moderate, and severe categories. The Glasgow Coma Scale (GCS), the most commonly used system, grades a person's level of consciousness on a scale of 3–15 based on verbal, motor, and eye-opening reactions to stimuli. A GCS of 13 or above is considered mild, 9–12 moderate, and below 9 severe. Severe TBI is typically associated with significant neurological injury, often with abnormal neuroimaging (e.g., head CT scan revealing skull fracture, intracranial hemorrhage, and early diffuse cerebral edema) and these patients require advanced medical care.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Explosive blast traumatic brain injury (TBI) is one of the more serious wounds suffered by United States service members injured in the current conflicts in Iraq and Afghanistan. Some military medical treatments for blast TBI that have been introduced successfully in the war theater include decompressive craniectomy, cerebral angiography, transcranial Doppler, hypertonic resuscitation fluids, among others. Stateside neurosurgery, neuro-critical care, and rehabilitation for these patients have similarly progressed. With experience, military physicians have been able to clinically describe blast TBI across the entire severity spectrum. One important clinical finding is that a significant number of severe blast TBI victims develop pseudoaneurysms and vasospasm, which can lead to delayed decompensation. Another is that mild blast TBI shares clinical features with post-traumatic stress disorder (PTSD). Observations suggest that the mechanism by which explosive blast injures the central nervous system may be more complex than initially assumed. Rigorous study at the basic science and clinical levels, including detailed biomechanical analysis, is needed to improve understanding of this disease. A comprehensive epidemiological study is also warranted to determine the prevalence of this disease and the factors that contribute most to the risk of developing it. Sadly, this military-specific disease has significant potential to become a civilian one as well.", "author" : [ { "dropping-particle" : "", "family" : "Ling", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bandak", "given" : "Faris", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Armonda", "given" : "Rocco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grant", "given" : "Gerald", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ecklund", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal Of Neurotrauma", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "815-825", "publisher" : "Deutscher Taschenbuch Verlag", "title" : "Explosive blast neurotrauma.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(G Ling, Bandak, Armonda, Grant, & Ecklund, 2009)", "manualFormatting" : "(Ling, 2009)", "plainTextFormattedCitation" : "(G Ling, Bandak, Armonda, Grant, & Ecklund, 2009)", "previouslyFormattedCitation" : "(G Ling et al., 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Ling, 2009) Due to numerous problems, including timing of when the GCS is determined, the GCS grading system has limited ability to predict outcomes. Because of this, other classification systems are also used, but currently, there is no consensus. Classically, TBI is described as occurring in two phases, or on the basis of the pathophysiologic mechanism. The primary or initial injury occurs as a direct result of the traumatic event itself. A secondary injury, or phase, occurs from multiple neuropathologic processes that can continue for days to weeks following the initial insult. Primary Injury. The primary injury is immediate and not amenable to treatment, only prevention. If severe enough, death can occur almost instantaneously. The damage that occurs from the primary injury is complete by the time medical care can be instituted. High-speed collisions with very rapid deceleration are particularly injurious, but sports-related injuries also can be devastating. Because the neuronal structures reside in a fluid-filled compartment, they often lag behind the bony structure as it moves during the sudden stopping of the body in motion. The brain often strikes both in the direct and opposite plane of motion against the inner bony table. This is the coup–contre-coup pattern, where contusions to the brain are seen at the site of skull impact and 180 degrees opposite the site of impact.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Ling", "given" : "GS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marshall", "given" : "SA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurol Clin", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "viii", "title" : "Management of traumatic brain injury in the intensive care unit.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(GS Ling & Marshall, 2008)", "manualFormatting" : "(Ling, 2008)", "plainTextFormattedCitation" : "(GS Ling & Marshall, 2008)", "previouslyFormattedCitation" : "(GS Ling & Marshall, 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Ling, 2008) By far, the most devastating complication of the primary injury in an acute TBI is the development of an intracranial hematoma. [FIGURE 32-1] Early diagnosis and aggressive, often surgical management, may decrease or prevent some of the secondary problems from occurring. Computerized tomography (CT) scans are routinely used to identify intracranial hemorrhage and is essential to surgical planning.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Lee", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Newberg", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J American Society for Experimental Neurotherapeutics", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "372-383", "title" : "Neuroimaging in traumatic brain imaging", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Lee & Newberg, 2005)", "manualFormatting" : "(Lee, 2005)", "plainTextFormattedCitation" : "(Lee & Newberg, 2005)", "previouslyFormattedCitation" : "(Lee & Newberg, 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lee, 2005) While magnetic resonance imaging (MRI) may be more sensitive, conventional CT scans are far more available and cost effective for detecting acute subarachnoid or acute parenchymal hemorrhage.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Yealy", "given" : "DM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hogan", "given" : "DE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Emerg Med Clin North Am", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1991" ] ] }, "page" : "707-717", "title" : "Imaging after head trauma. Who needs what?", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Yealy & Hogan, 1991)", "manualFormatting" : "(Yealy, 1991)", "plainTextFormattedCitation" : "(Yealy & Hogan, 1991)", "previouslyFormattedCitation" : "(Yealy & Hogan, 1991)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Yealy, 1991) Secondary Injury. The secondary injury of TBI is a prolonged pathogenic process leading to cell death and worsening damage to the brain far beyond the primary injury.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Lewis", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghassemi", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibbeln", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Am J Emerg Med", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "5-8", "title" : "Therapeutic use of omega-3 fatty acids in severe head trauma.", "type" : "article-journal", "volume" : "31" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.plefa.2007.10.021", "ISSN" : "0952-3278", "PMID" : "18036801", "abstract" : "Studies with omega-3 polyunsaturated fatty acids (PUFA) have shown that these compounds have therapeutic potential in several indications in neurology and psychiatry. Acute spinal cord injury (SCI) is an event with devastating consequences, and no satisfactory treatment is available at present. The pathogenetic mechanisms associated with SCI include excitotoxicity, increased oxidation and inflammation. We review here our recent studies, which suggest that omega-3 PUFA have significant neuroprotective potential in spinal cord trauma. In a first study, we administered an intravenous bolus of alpha-linolenic acid (LNA) or docosahexaenoic acid (DHA) 30 min after spinal cord hemisection injury in adult rats. The omega-3 PUFA led to increased neuronal and glial survival, and a significantly improved neurological outcome. In subsequent studies, we tested DHA in a more severe compression model of SCI. We also explored a combined acute and chronic treatment regime using DHA. Saline or DHA was administered intravenously 30 min after compression of the spinal cord. After injury, the saline group received a standard control diet, whereas DHA-injected animals received either a control or a DHA-enriched diet for 6 weeks following injury. We assessed locomotor recovery and analysed markers for cell survival and axonal damage, and we also investigated the effects of the treatment on the inflammatory reaction and the oxidative stress that follow SCI. We showed that the acute DHA treatment is neuroprotective after compression SCI, even if the treatment is delayed up to an hour after injury. The DHA injection led to an increased neuronal and glial cell survival, and the effect of the DHA injection was amplified by addition of DHA to the diet. Rats treated with a DHA injection and a DHA-enriched diet performed significantly better at 6 weeks in terms of neurological outcome. The analysis of the tissue after DHA administration showed that the fatty acid significantly reduced lipid peroxidation, protein oxidation and RNA/DNA oxidation, and the induction of COX-2. Parallel studies in a facial nerve injury model in mice also showed pro-regenerative effects of chronic dietary administration of DHA after nerve lesion. These observations suggest that treatment with omega-3 PUFA could represent a promising therapeutic approach in the management of neurological injury.", "author" : [ { "dropping-particle" : "", "family" : "Michael-Titus", "given" : "Adina T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Prostaglandins leukotrienes and essential fatty acids", "id" : "ITEM-2", "issue" : "5-6", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "295-300", "title" : "Omega-3 fatty acids and neurological injury.", "type" : "article-journal", "volume" : "77" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(M Lewis, Ghassemi, & Hibbeln, 2013; A. T. Michael-Titus, 2007)", "manualFormatting" : "(Michael-Titus, 2007)", "plainTextFormattedCitation" : "(M Lewis, Ghassemi, & Hibbeln, 2013; A. T. Michael-Titus, 2007)", "previouslyFormattedCitation" : "(M Lewis, Ghassemi, & Hibbeln, 2013; A. T. Michael-Titus, 2007)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Michael-Titus, 2007) Secondary injury may include damage to the blood–brain barrier, ischemia, hypoxia, intracranial hypertension, hypercarbia, hyponatremia, seizures, neuroinflammation, free radical overload, and excitotoxicity.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Park", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "JD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baker", "given" : "AJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Canadian Medical Association Journal", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "1163-70", "title" : "Traumatic brain injury: Can the consequences be stopped?", "type" : "article-journal", "volume" : "178" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Saatman", "given" : "KE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Duhaime", "given" : "AC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bullock", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maas", "given" : "AI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valadka", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Manley", "given" : "GT", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Members", "given" : "Workshop Scientific Team and Advisory Panel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neurotrauma", "id" : "ITEM-2", "issue" : "7", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "719\u201338", "title" : "Classification of traumatic brain injury for targeted therapies", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Park, Bell, & Baker, 2008; Saatman et al., 2008)", "manualFormatting" : "(Saatman, 2008)", "plainTextFormattedCitation" : "(Park, Bell, & Baker, 2008; Saatman et al., 2008)", "previouslyFormattedCitation" : "(Park, Bell, & Baker, 2008; Saatman et al., 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Saatman, 2008) [FIGURE 32-2] Four categories of mechanisms can be defined in the secondary injury phase of TBI: (1) ischemia, excitotoxicity, and intracellular biochemical cascades; (2) axonal injury; (3) cerebral edema; and (4) inflammation and regeneration. Within each category, a constellation of mediators of secondary damage, neuroprotection, repair, and regeneration exist.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Kochanek", "given" : "PM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clark", "given" : "RSB", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jenkins", "given" : "LW", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "chapter-number" : "8", "container-title" : "Brain injury medicine: principles and practice", "editor" : [ { "dropping-particle" : "", "family" : "Zasler", "given" : "ND", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Katz", "given" : "DI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zafonte", "given" : "RD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "81-92", "publisher" : "Demos Medical Publishing, LLC", "publisher-place" : "New York", "title" : "TBI: Pathology", "type" : "chapter" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kochanek, Clark, & Jenkins, 2007)", "manualFormatting" : "(Kochanek, 2007)", "plainTextFormattedCitation" : "(Kochanek, Clark, & Jenkins, 2007)", "previouslyFormattedCitation" : "(Kochanek, Clark, & Jenkins, 2007)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kochanek, 2007) Ischemia. Besides the obvious causes of ischemia, underlying biochemical mechanisms leading to ischemia may also exist such as a reduction in vasodilatory response to nitric oxide and prostaglandins.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Armstead", "given" : "WM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Stroke: A Journal of Cerebral Circulation1", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1999" ] ] }, "page" : "153-159", "title" : "Superoxide generation links protein kinase C activation to imparired ATP-sensitive K+ channle function after brain injury", "type" : "article-journal", "volume" : "30" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Armstead", "given" : "WM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neurotrauma", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "1998" ] ] }, "page" : "721-729", "title" : "Brain injury impairs prostaglandin cerebrovasodilation", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Armstead, 1998, 1999)", "manualFormatting" : "(Armstead, 1999)", "plainTextFormattedCitation" : "(Armstead, 1998, 1999)", "previouslyFormattedCitation" : "(Armstead, 1998, 1999)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Armstead, 1999) Of concern to the military population, blast TBI caused cerebral vasospasm are not uncommon even weeks after the injury.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1227/01.NEU.0000249190.46033.94", "ISSN" : "1524-4040", "PMID" : "17277684", "abstract" : "OBJECTIVE: Blast-related neurotrauma is associated with the severest casualties from Operation Iraqi Freedom (OIF). A consequence of this is cerebral vasospasm. This study evaluated all inpatient neurosurgical consults related to battle injury from OIF. METHODS: Evaluation of all admissions from OIF from April 2003 to October 2005 was performed on patients with neurotrauma and a diagnostic cerebral angiogram. Differences between patients with and without vasospasm and predictors of vasospasm were analyzed. RESULTS: Fifty-seven out of 119 neurosurgical consults were evaluated. Of these, 47.4% had traumatic vasospasm; 86.7% of patients without vasospasm and 80.8% of patients with vasospasm sustained blast trauma. Average spasm duration was 14.3 days, with a range of up to 30 days. Vasospasm was associated with the presence of pseudoaneurysm (P = 0.05), hemorrhage (P = 0.03), the number of lobes injured (P = 0.012), and mortality (P = 0.029). Those with vasospasm fared worse than those without (P = 0.002). The number of lobes injured and the presence of pseudoaneurysm were significant predictors of vasospasm (P = 0.016 and 0.02, respectively). There was a significant quadratic trend towards neurological improvement for those receiving aggressive open surgical treatment (P = 0.002). In the vasospasm group, angioplasty with microballoon significantly lowered middle cerebral artery and basilar blood-flow velocities(P = 0.046 and 0.026, respectively). CONCLUSION: Traumatic vasospasm occurred in a substantial number of patients with severe neurotrauma, and clinical outcomes were worse for those with this condition. However, aggressive open surgical and endovascular treatment strategies may have improved outcome. This was the first study to analyze the effects of blast-related injury on the cerebral vasculature.", "author" : [ { "dropping-particle" : "", "family" : "Armonda", "given" : "Rocco a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Randy S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vo", "given" : "Alexander H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ling", "given" : "Geoffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "DeGraba", "given" : "Thomas J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crandall", "given" : "Benjamin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ecklund", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Campbell", "given" : "William W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurosurgery", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2006", "12" ] ] }, "page" : "1215-1225; discussion 1225", "title" : "Wartime traumatic cerebral vasospasm: recent review of combat casualties.", "type" : "article-journal", "volume" : "59" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Armonda et al., 2006)", "manualFormatting" : "(Armonda, 2006)", "plainTextFormattedCitation" : "(Armonda et al., 2006)", "previouslyFormattedCitation" : "(Armonda et al., 2006)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Armonda, 2006) The result of cerebral blood flow compromise results in metabolic responses such as increased anaerobic metabolism, and biochemical responses such as intracellular accumulation of calcium, activation of nitric oxide synthesis, and production of free radicals. These mechanisms begin to occur within minutes of the injury and progress hours and days following the insult culminating in cell injury and tissue death.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0056233", "ISSN" : "1932-6203", "PMID" : "23437099", "abstract" : "We questioned if acute administration of n-3 fatty acids (FA) carried in n-3 rich triglyceride (TG) emulsions provides neuroprotection in neonatal mice subjected to hypoxic-ischemic (H/I) brain injury. We examined specificity of FA, optimal doses, and therapeutic windows for neuroprotection after H/I. H/I insult was induced in C57BL/6J 10-day-old mice by right carotid artery ligation followed by exposure to 8% O(2) for 15 minutes at 37\u00b0C. Intraperitoneal injection with n-3-rich TG emulsions, n-6 rich TG emulsions or saline for control was administered at different time points before and/or after H/I. In separate experiments, dose responses were determined with TG containing only docosahexaenoic acid (Tri-DHA) or eicosapentaenoic acid (Tri-EPA) with a range of 0.1-0.375 g n-3 TG/kg, administered immediately after H/I insult. Infarct volume and cerebral blood flow (CBF) were measured. Treatment with n-3 TG emulsions both before- and after- H/I significantly reduced total infarct volume by a mean of 43% when administered 90 min prior to H/I and by 47% when administered immediately after H/I. In post-H/I experiments Tri-DHA, but not Tri-EPA exhibited neuroprotective effects with both low and high doses (p<0.05). Moreover, delayed post-H/I treatment with Tri-DHA significantly decreased total infarct volume by a mean of 51% when administered at 0 hr, by 46% at 1 hr, and by 51% at 2 hr after H/I insult. No protective effect occurred with Tri-DHA injection at 4 hr after H/I. There were no n-3 TG related differences in CBF. A significant reduction in brain tissue death was maintained after Tri-DHA injection at 8 wk after the initial brain injury. Thus, n-3 TG, specifically containing DHA, is protective against H/I induced brain infarction when administered up to 2 hr after H/I injury. Acute administration of TG-rich DHA may prove effective for treatment of stroke in humans.", "author" : [ { "dropping-particle" : "", "family" : "Williams", "given" : "Jill J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayurasakorn", "given" : "Korapat", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vannucci", "given" : "Susan J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mastropietro", "given" : "Christopher", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bazan", "given" : "Nicolas G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ten", "given" : "Vadim S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deckelbaum", "given" : "Richard J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2013", "1" ] ] }, "page" : "e56233", "title" : "N-3 Fatty Acid rich triglyceride emulsions are neuroprotective after cerebral hypoxic-ischemic injury in neonatal mice.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Williams et al., 2013)", "manualFormatting" : "(Williams, 2013)", "plainTextFormattedCitation" : "(Williams et al., 2013)", "previouslyFormattedCitation" : "(Williams et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Williams, 2013) Glutamate overflow from damaged cells leads to excitotoxicity, affecting neurons and glia. The influx of calcium through glutamate receptors and voltage-gated calcium channels activates calcium-dependent proteases such as phospholipase A2 (PLA2) which degrade membrane phospholipids, leading to the release of fatty acids, principally arachidonic acid (AA), an omega-6 fatty acid (ω-6FA), and DHA, an ω-3FA. Posttraumatic fatty acid alterations involve the release of both autodestructive and neuroprotective cascades.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Michael-Titus", "given" : "AT", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Priestley", "given" : "JV", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Trends Neurosci", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "30-38", "title" : "Omega-3 fatty acids and traumatic neurological injury: from neuroprotection to neuroplasticity?", "type" : "article-journal", "volume" : "37" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(A. Michael-Titus & Priestley, 2014)", "manualFormatting" : "(Michael-Titus, 2014)", "plainTextFormattedCitation" : "(A. Michael-Titus & Priestley, 2014)", "previouslyFormattedCitation" : "(A. Michael-Titus & Priestley, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Michael-Titus, 2014)Diffuse axonal injury (DAI) is a frequent result of traumatic acceleration/deceleration or rotational injuries resulting in extensive lesions in white matter tracts. Rapid deceleration, most commonly a result of high-speed motor vehicle accidents, causes shearing, inflicted as tissues of differing densities within the brain slide over other tissues, stretching axons, especially at junctions between white and gray matter.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Meythaler", "given" : "JM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peduzzi", "given" : "JD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eleftheriou", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Novack", "given" : "TA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arch Phys Med Rehabi", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2001" ] ] }, "page" : "1461-71", "title" : "Current concepts: diffuse axonal injury-associated traumatic brain injury", "type" : "article-journal", "volume" : "82" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Meythaler, Peduzzi, Eleftheriou, & Novack, 2001)", "manualFormatting" : "(Meythaler, 2001)", "plainTextFormattedCitation" : "(Meythaler, Peduzzi, Eleftheriou, & Novack, 2001)", "previouslyFormattedCitation" : "(Meythaler, Peduzzi, Eleftheriou, & Novack, 2001)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Meythaler, 2001) Classically considered a result of the physical shearing during the primary injury, it is now understood that much of DAI occurs through secondary biochemical cascades in response to the primary injury, hours to days after the initial injury. Axons are normally elastic, but when rapidly stretched they become brittle, and the axonal cytoskeleton can be broken.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Hemphill", "given" : "MA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dabiri", "given" : "BE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gabriele", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kerscher", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Franck", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goss", "given" : "JA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alford", "given" : "PW", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parker", "given" : "KK", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wanunu", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "e2289", "title" : "A Possible Role for Integrin Signaling in Diffuse Axonal Injury", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hemphill et al., 2011)", "manualFormatting" : "(Hemphill, 2011)", "plainTextFormattedCitation" : "(Hemphill et al., 2011)", "previouslyFormattedCitation" : "(Hemphill et al., 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hemphill, 2011) Ultimately, death of the axon is brought on by the neurochemical pathology as described in the previous paragraph. The axon degrades causing it to draw back toward the cell body and form a bulb. This bulb is called a retraction ball, the hallmark of diffuse axonal injury.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Smith", "given" : "DH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meaney", "given" : "DF", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuroscientist", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2000" ] ] }, "page" : "483-495", "title" : "Axonal damage in traumatic brain injury", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(D. Smith & Meaney, 2000)", "manualFormatting" : "(Smith, 2000)", "plainTextFormattedCitation" : "(D. Smith & Meaney, 2000)", "previouslyFormattedCitation" : "(D. Smith & Meaney, 2000)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Smith, 2000) Because DAI progresses over hours to days, often it is not found on CT scans done in the emergency setting. [FIGURE 32-1] Among patients with DAI, 50-80% demonstrate a normal CT scan upon in the acute setting.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "author" : [ { "dropping-particle" : "", "family" : "Wasserman", "given" : "JR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feldman", "given" : "JS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koenigsberg", "given" : "RA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Medscape", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "title" : "Diffuse Axonal Injury Imaging", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Wasserman, Feldman, & Koenigsberg, 2012)", "manualFormatting" : "(Wasserman, 2012)", "plainTextFormattedCitation" : "(Wasserman, Feldman, & Koenigsberg, 2012)", "previouslyFormattedCitation" : "(Wasserman, Feldman, & Koenigsberg, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Wasserman, 2012) DAI is most likely to be diagnosed with MRI days to weeks following the TBI. Abnormal MRI signals, bright on T2-weighted images in characteristic multifocal locations, leaves little doubt about the diagnosis of DAI. [FIGURE 32-3] 3-Tesla diffusion tensor imaging (DTI) for white matter injury, has been shown to be a more accurate imaging modality that even has utility for outcome prediction in the mild TBI.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Yuh EL1, Cooper SR, Mukherjee P, Yue JK, Lingsma HF, Gordon WA, Valadka AB, Okonkwo DO, Schnyer DM, Vassar MJ, Maas AI, Manley GT; TRACK-TBI INVESTIGATORS.", "author" : [ { "dropping-particle" : "", "family" : "Yuh", "given" : "EL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cooper", "given" : "SR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mukherjee", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yue", "given" : "JK", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lingsma", "given" : "HF", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gordon", "given" : "WA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valadka", "given" : "AB", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Okonkwo", "given" : "DO", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schnyer", "given" : "DM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vassar", "given" : "MJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maas", "given" : "AI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Manley", "given" : "GT", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "INVESTIGATORS", "given" : "TRACK-TBI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neurotrauma", "id" : "ITEM-1", "issue" : "17", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1457-77", "title" : "Diffusion tensor imaging for outcome prediction in mild traumatic brain injury: a TRACK-TBI study", "type" : "article-journal", "volume" : "31" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Yuh et al., 2014)", "manualFormatting" : "(Yuh, 2014)", "plainTextFormattedCitation" : "(Yuh et al., 2014)", "previouslyFormattedCitation" : "(Yuh et al., 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Yuh, 2014)Cerebral edema is a hallmark finding in severe TBI, often resulting in intracranial hypertension unless aggressively managed, commonly through surgical and intensive care means. Intracranial hypertension as a result of edema can compromise cerebral blood flow and result in secondary ischemia or devastating herniation syndromes. In most TBI, cytotoxic (cellular) and vasogenic cerebral edema occur together. Vasogenic edema forms in the extracellular space due to a breakdown of the blood brain barrier. Osmotic swelling also may contribute to extracellular cerebral edema.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Kochanek", "given" : "PM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clark", "given" : "RSB", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jenkins", "given" : "LW", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "chapter-number" : "8", "container-title" : "Brain injury medicine: principles and practice", "editor" : [ { "dropping-particle" : "", "family" : "Zasler", "given" : "ND", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Katz", "given" : "DI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zafonte", "given" : "RD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "81-92", "publisher" : "Demos Medical Publishing, LLC", "publisher-place" : "New York", "title" : "TBI: Pathology", "type" : "chapter" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kochanek et al., 2007)", "manualFormatting" : "(Kochanek, 2007)", "plainTextFormattedCitation" : "(Kochanek et al., 2007)", "previouslyFormattedCitation" : "(Kochanek et al., 2007)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kochanek, 2007) It may be rapid and extensive. Cellular edema, however, may be of greatest importance. Swelling of neurons and astrocytes can occur following the breakdown of sodium and calcium pumps on cell membranes. Excess glutamate uptake coupled to glucose utilization causes sodium, calcium, and water to accumulate exacerbating intracellular edema.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "G Rosenberg", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Progress in cardiovascular diseases", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1999" ] ] }, "page" : "209-16", "title" : "Ischemic Brain Edem", "type" : "article-journal", "volume" : "42" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(G Rosenberg, 1999)", "manualFormatting" : "(Rosenberg, 1999)", "plainTextFormattedCitation" : "(G Rosenberg, 1999)", "previouslyFormattedCitation" : "(G Rosenberg, 1999)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Rosenberg, 1999) Cerebral edema and intracranial hypertension are the main targets of concern and intervention in the acute intensive care setting.Neuroinflammation is complicated and beyond the scope of this chapter and covered in detail in other chapters. Inflammation is essential following any injury, yet may be detrimental if not properly modulated or appropriate sized in response to the injury. A critical balance exists between repair and proinflammatory factors that determine the outcome of neurodegenerative processes. Acute inflammation in the brain is characterized by rapid activation of the innate immune cells of the central nervous system, microglia and astrocytes.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Streit", "given" : "WJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mrak", "given" : "RE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Griffin", "given" : "WST", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neuroinflammation", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2004" ] ] }, "page" : "14.", "title" : "Microglia and neuroinflammation: a pathological perspective", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Streit, Mrak, & Griffin, 2004)", "manualFormatting" : "(Streit, 2004)", "plainTextFormattedCitation" : "(Streit, Mrak, & Griffin, 2004)", "previouslyFormattedCitation" : "(Streit, Mrak, & Griffin, 2004)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Streit, 2004) Not limited to just severe TBI, once activated, astrocytes, the most abundant cells in the brain, release various growth factors, cytokines, and chemokines that function as neuromodulators to regulate inflammation. Common cytokines produced in response to brain injury include: interleukin-6 (IL-6), which is produced during astrogliosis, and interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), which can induce neuronal cytotoxicity. Although the pro-inflammatory cytokines may cause cell death and secondary tissue damage, they are necessary to repair the damaged tissue. For example, TNF-α contributes to tissue growth at later stages of inflammation.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Ramesh", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "MacLean", "given" : "AG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philipp", "given" : "MT", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Mediators of Inflammation", "id" : "ITEM-1", "issue" : "Epub 2013 Aug 12", "issued" : { "date-parts" : [ [ "2013" ] ] }, "title" : "Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Ramesh, MacLean, & Philipp, 2013)", "manualFormatting" : "(Ramesh, 2013)", "plainTextFormattedCitation" : "(Ramesh, MacLean, & Philipp, 2013)", "previouslyFormattedCitation" : "(Ramesh, MacLean, & Philipp, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Ramesh, 2013) Chronic Traumatic Encephalopathy. The concept that TBI can lead to neurodegenerative changes was first introduced almost a century ago, first in 1926 by neurologists Osnato and Giliberti. In 1928, a New Jersey pathologist, Harrison Martland, described “punch drunk syndrome” in retired boxers who developed chronic motor and neuropsychiatric symptoms. Millspaugh introduced the term “dementia pugilistica” in 1937describing the neuropathological findings in the aftermath of repetitive TBI in boxing. The prevailing term used in modern day literature, chronic traumatic encephalopathy (CTE), was coined by British neurologist, Macdonald Critchley, in 1949. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Ling", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hardy", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zetterberg", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Mol Cell Neuroscience", "id" : "ITEM-1", "issue" : "Pt B", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "114-22", "title" : "Neurological consequences of traumatic brain injuries in sports", "type" : "article-journal", "volume" : "66" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(H. Ling, Hardy, & Zetterberg, 2015)", "manualFormatting" : "( Ling, 2015)", "plainTextFormattedCitation" : "(H. Ling, Hardy, & Zetterberg, 2015)", "previouslyFormattedCitation" : "(H. Ling, Hardy, & Zetterberg, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }( Ling, 2015) Affected individuals often exhibit disordered memory and executive functioning, behavioral and personality disturbances (e.g., apathy, depression, irritability, impulsiveness, suicidality), parkinsonism, and, occasionally, motor neuron disease. Upon autopsy, the presence of hyperphosphorylated tau protein deposition, whether it be in the form of neurofibrillary tangles (NFTs), neuropil threads (NTs), or glial tangles (GTs), is a defining feature of CTE, while neuritic β-amyloid plaques, common in Alzheimer’s Disease, are found only in a minority of cases.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Gavett", "given" : "BE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stern", "given" : "RA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McKee", "given" : "AC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical Sports Medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "179-xi", "title" : "Chronic Traumatic Encephalopathy: A Potential Late Effect of Sport-Related Concussive and Subconcussive Head Trauma", "type" : "article-journal", "volume" : "30" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Gavett, Stern, & McKee, 2011)", "manualFormatting" : "(Gavett, 2011)", "plainTextFormattedCitation" : "(Gavett, Stern, & McKee, 2011)", "previouslyFormattedCitation" : "(Gavett, Stern, & McKee, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Gavett, 2011) CTE in a retired professional American football player was first recognized in 2002 by Bennet Omalu when autopsying the brain of a deceased player.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Omalu", "given" : "BI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "DeKosky", "given" : "ST", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Minster", "given" : "RL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kamboh", "given" : "MI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hamilton", "given" : "RL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wecht", "given" : "CH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurosurgery", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "128-34", "title" : "Chronic traumatic encephalopathy in a National Football League playe", "type" : "article-journal", "volume" : "57" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Omalu et al., 2005)", "manualFormatting" : "(Omalu, 2005)", "plainTextFormattedCitation" : "(Omalu et al., 2005)", "previouslyFormattedCitation" : "(Omalu et al., 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Omalu, 2005)It has been widely believed that the blood-brain barrier completely separated the neuroimmune system from the rest of the body’s immune system, thus the accumulation of toxins and pathological proteins were believed to be an issue of overproduction rather than poor clearance from the brain. Recently, a brain-wide network of paravascular channels, termed the "glymphatic" pathway, was defined that moves cerebralspinal fluid (CSF) into and through the brain parenchyma, facilitating the clearance of toxins and proteins, including β-amyloid and tau , from the brain. After TBI however, glymphatic pathway function was reduced by ～60%, with this impairment persisting for at least 1 month post injury. Such chronic impairment of glymphatic pathway function after TBI may be a key factor that renders the post-traumatic brain vulnerable to tau aggregation and the onset of neurodegeneration.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : ". JJ1, Chen MJ2, Plog BA2, Zeppenfeld DM3, Soltero M4, Yang L2, Singh I2, Deane R2, Nedergaard M2.", "author" : [ { "dropping-particle" : "", "family" : "Iliff", "given" : "JJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "MJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plog", "given" : "BA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zeppenfeld", "given" : "DM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soltero", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yang", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singh", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deane", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nedergaard", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neuroscience", "id" : "ITEM-1", "issue" : "49", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "16180-93", "title" : "Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. Iliff", "type" : "article-journal", "volume" : "34" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Iliff et al., 2014)", "plainTextFormattedCitation" : "(Iliff et al., 2014)", "previouslyFormattedCitation" : "(Iliff et al., 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Iliff et al., 2014) Subsequently, the recent discovery of microscopic lymphatic vessels connecting the brain to the immune system may have profound implications in many disease processes involving neuroinflammation, including TBI, where the clearance of toxins and protein complexes such as phosphylated tau and β-amyloid are paramount.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Louveau", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smirnov", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keyes", "given" : "TJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eccles", "given" : "JD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rouhani", "given" : "SJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peske", "given" : "JD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Derecki", "given" : "NC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Castle", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mandell", "given" : "JW", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "KS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harris", "given" : "TH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kipnis", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7560", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "337-41", "title" : "Structural and functional features of central nervous system lymphatic vessels", "type" : "article-journal", "volume" : "523" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Louveau et al., 2015)", "manualFormatting" : "(Louveau, 2015)", "plainTextFormattedCitation" : "(Louveau et al., 2015)", "previouslyFormattedCitation" : "(Louveau et al., 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Louveau, 2015)Nearly lost in the discussions of CTE and neurodegeneration after TBI has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, neuroinflammation may be the most important cause of post-traumatic neurodegeneration. Preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insults.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Faden", "given" : "AI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loane", "given" : "DJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurotherapeutics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "143-50", "title" : "Chronic Neurodegeneration After Traumatic Brain Injury: Alzheimer Disease, Chronic Traumatic Encephalopathy, or Persistent Neuroinflammation?", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Faden & Loane, 2015)", "manualFormatting" : "(Faden, 2015)", "plainTextFormattedCitation" : "(Faden & Loane, 2015)", "previouslyFormattedCitation" : "(Faden & Loane, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Faden, 2015)The importance of the secondary injury has gained widespread recognition as a potential target of such therapeutic intervention. Although much has been learned about the molecular and cellular mechanisms of TBI in the past two decades, these advances have failed to translate into a successful clinical trial and no significant improvement in treatment beyond the acute setting.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Ling", "given" : "GS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marshall", "given" : "SA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurol Clin", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "viii", "title" : "Management of traumatic brain injury in the intensive care unit.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Saatman", "given" : "KE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Duhaime", "given" : "AC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bullock", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maas", "given" : "AI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valadka", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Manley", "given" : "GT", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Members", "given" : "Workshop Scientific Team and Advisory Panel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neurotrauma", "id" : "ITEM-2", "issue" : "7", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "719\u201338", "title" : "Classification of traumatic brain injury for targeted therapies", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(GS Ling & Marshall, 2008; Saatman et al., 2008)", "manualFormatting" : "(Ling, 2008)", "plainTextFormattedCitation" : "(GS Ling & Marshall, 2008; Saatman et al., 2008)", "previouslyFormattedCitation" : "(GS Ling & Marshall, 2008; Saatman et al., 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Ling, 2008)Failure to Find Therapeutic Interventions for TBITremendous advances in surgical and intensive care unit (ICU) management of TBI, including maintaining adequate oxygenation, controlling intracranial pressure (ICP), and ensuring proper cerebral perfusion, have resulted in reduced mortality.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Explosive blast traumatic brain injury (TBI) is one of the more serious wounds suffered by United States service members injured in the current conflicts in Iraq and Afghanistan. Some military medical treatments for blast TBI that have been introduced successfully in the war theater include decompressive craniectomy, cerebral angiography, transcranial Doppler, hypertonic resuscitation fluids, among others. Stateside neurosurgery, neuro-critical care, and rehabilitation for these patients have similarly progressed. With experience, military physicians have been able to clinically describe blast TBI across the entire severity spectrum. One important clinical finding is that a significant number of severe blast TBI victims develop pseudoaneurysms and vasospasm, which can lead to delayed decompensation. Another is that mild blast TBI shares clinical features with post-traumatic stress disorder (PTSD). Observations suggest that the mechanism by which explosive blast injures the central nervous system may be more complex than initially assumed. Rigorous study at the basic science and clinical levels, including detailed biomechanical analysis, is needed to improve understanding of this disease. A comprehensive epidemiological study is also warranted to determine the prevalence of this disease and the factors that contribute most to the risk of developing it. Sadly, this military-specific disease has significant potential to become a civilian one as well.", "author" : [ { "dropping-particle" : "", "family" : "Ling", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bandak", "given" : "Faris", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Armonda", "given" : "Rocco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grant", "given" : "Gerald", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ecklund", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal Of Neurotrauma", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "815-825", "publisher" : "Deutscher Taschenbuch Verlag", "title" : "Explosive blast neurotrauma.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(G Ling et al., 2009)", "manualFormatting" : "(Ling, 2009)", "plainTextFormattedCitation" : "(G Ling et al., 2009)", "previouslyFormattedCitation" : "(G Ling et al., 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Ling, 2009) The increasing role of specialized intensive care units with neurologically trained medical and nursing providers using evidence-based clinical management has had a favorable impact on both the consistency and level of care. Advances in neuromonitoring, neuroimaging, and early aggressive neurosurgical interventions are important contributors to improved TBI outcome.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Ling", "given" : "GS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marshall", "given" : "SA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurol Clin", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "viii", "title" : "Management of traumatic brain injury in the intensive care unit.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(GS Ling & Marshall, 2008)", "manualFormatting" : "(Ling, 2008)", "plainTextFormattedCitation" : "(GS Ling & Marshall, 2008)", "previouslyFormattedCitation" : "(GS Ling & Marshall, 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Ling, 2008) The most definitive strategy to avoid short- or long-term detrimental effects of TBI is through primary prevention, or avoidance of the injury in the first place. However, once a TBI occurs, the secondary injury represents a window of opportunity for therapeutic intervention with the potential to prevent and/or reduce brain damage and improve long-term patient outcome. Recently, treatments with broader, pleiotropic effects have been explored. Progesterone, unlike corticosteroids, is thought to not only reduce cerebral edema but to also have neuroprotective effects and was positively correlated with improved functional outcomes at up to 6 months follow-up in two randomized, double-blind, placebo-controlled phase II trials. Unfortunately, two multi-center, phase III clinical trials were recently halted due to futility. To date, no promising preclinical results have not been translated into successful clinical trials.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Stein", "given" : "DG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain Injury", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "1-14", "title" : "Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Stein, 2015)", "plainTextFormattedCitation" : "(Stein, 2015)", "previouslyFormattedCitation" : "(Stein, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Stein, 2015) This may be due in part that most interventions target a single biochemical cascade rather than multiple mechanisms of injury.Approaches that target multiple aspects of TBI are needed. The Western medical system evolved around the epidemiological triad of acute infectious diseases: one host-agent-environment and subsequently one drug to cure. Pharmaceuticals by nature are aimed at disrupting single enzymatic processes. TBI is too complicated for such a narrow minded approach. What is needed is a broad spectrum, more holistic approach. Progesterone represented a good step in that direction. Progesterone was thought to exert its neuroprotective effects by protecting or rebuilding the blood-brain barrier, decreasing development of cerebral edema, down-regulating the inflammatory cascade, and limiting cellular necrosis and apoptosis.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Stein", "given" : "DG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wright", "given" : "DW", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kellermann", "given" : "AL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Ann Emerg Med", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "164-72", "title" : "Does progesterone have neuroprotective properties?", "type" : "article-journal", "volume" : "51" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Stein, Wright, & Kellermann, 2008)", "manualFormatting" : "(Stein, 2008)", "plainTextFormattedCitation" : "(Stein, Wright, & Kellermann, 2008)", "previouslyFormattedCitation" : "(Stein, Wright, & Kellermann, 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Stein, 2008) However, progesterone must be administered by continuous intravenous infusion over the first three days following injury. It cannot be given beyond that period, nor orally, and does not have any neurorestorative properties that may improve neurological function after the patient survives the initial acute phase of TBI. Tragically, persistently negative clinical trial outcomes have led to disinvestment in new drug research by companies and policy-makers and disappointment for patients and their families.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Stein", "given" : "DG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Brain Injury", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "1-14", "title" : "Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Stein, 2015)", "plainTextFormattedCitation" : "(Stein, 2015)", "previouslyFormattedCitation" : "(Stein, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Stein, 2015)Interventions targeting all aspects of the four mechanisms of secondary injury, plus repair, regeneration, and protection of the brain are desperately needed. Mechanisms that are potential drug targets include angiogenesis, axon remodeling, remyelination, neurogenesis, and synaptogenesis. Therapies may also target regeneration by enhancing the ability of pluripotent cells to differentiate into neurons, glia, and vascular endothelium. Effective interventions should also treat the persistent symptoms associated with the long-term effects of TBI (e.g., memory disturbances, depression, headache).ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Diaz-Arrastia", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kochanek", "given" : "PM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bergold", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kenney", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marx", "given" : "CE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grimes", "given" : "JB", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loh", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Adam", "given" : "GE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oskvig", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curley", "given" : "KC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salzer", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neurotrauma", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "e-ppub ahead of print", "title" : "Pharmacotherapy of Traumatic Brain Injury: State of the Science and the Road Forward Report of the Department of Defense Neurotrauma Pharmacology Workgroup", "type" : "article-journal", "volume" : "August" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Diaz-Arrastia et al., 2013)", "manualFormatting" : "(Diaz-Arrastia, 2013)", "plainTextFormattedCitation" : "(Diaz-Arrastia et al., 2013)", "previouslyFormattedCitation" : "(Diaz-Arrastia et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Diaz-Arrastia, 2013) Omega-3 PUFAs and TBIIf one were to take a blank sheet of paper and design an intervention for TBI, it is possible it would look similar to omega-3 fatty acids. [TABLE 32-2] EPA and DHA have the ability to impact all four main mechanisms of the secondary injury phase of TBI; has neuroregenerative properties; is well-known to benefit cardiovascular and mental health; is well-studied as a substance in the scientific literature; a safety profile beyond compare such that DHA is added to 100% of all infant formulations in the United States; is available in oral, enteral, and intravenous (in Europe) forms; can be given to a patient during the acute phase of injury and continued throughout the patient’s entire rehabilitation; and can be used prophylactically prior to injury in populations at risk of TBI. It is a ubiquitous substance that has been around longer than mankind and consumed by people worldwide. Some argue evolution of the human brain could not have occurred without the access to EPA and DHA from fish.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Bradbury", "given" : "Joanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nutrients", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "529-554", "title" : "Docosahexaenoic Acid (DHA): An Ancient Nutrient for the Modern Human Brain", "type" : "article-journal", "volume" : "3" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Bradbury, 2011)", "plainTextFormattedCitation" : "(Bradbury, 2011)", "previouslyFormattedCitation" : "(Bradbury, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Bradbury, 2011) The FDA recognizes ω-3FA as generally recognizable as safe (GRAS) up to 3000 milligrams per day while the European Food Safety Authority recognizes up to 5000 mg.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "EFSA", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "EFSA Journal", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "2815", "title" : "Scientific Opinion on the Tolerable Upper Intake Level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA)", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(EFSA, 2012)", "plainTextFormattedCitation" : "(EFSA, 2012)", "previouslyFormattedCitation" : "(EFSA, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(EFSA, 2012) In 2011, the FDA approved investigational new drug (IND) status for up to 9000 mg of EPA/DHA.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Katz", "given" : "Russell", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2011" ] ] }, "publisher-place" : "Silver Spring, MD", "title" : "Investigational New Drug submission", "type" : "report" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Katz, 2011)", "plainTextFormattedCitation" : "(Katz, 2011)", "previouslyFormattedCitation" : "(Katz, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Katz, 2011)Omega-3 for neurotrauma use in preclinical studies generally separate into several categories of interest to include TBI, stroke, and spinal cord injury, as well as post-injury treatment and pre-injury administration.Post-injury administration. Gomez-Pinilla and colleagues have shown in several TBI treatment studies that dietary DHA following experimental TBI in rats counteracts broad and fundamental aspects of TBI pathology. In fluid percussion injury studies of rats, they demonstrated that DHA normalized levels of BDNF, synapsin I (Syn-1), cAMP-responsive element-binding protein (CREB), and calcium/calmodulin-dependent kinase II (CaMKII), and improved learning ability. The DHA diet counteracted the reduction of superoxide dismutase (SOD) and SIR-2 that follows TBI. Furthermore, DHA normalized levels of PLA2 and syntaxin-3, which may help preserve membrane homeostasis and function after injury.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1089/neu.2007.0313", "ISSN" : "0897-7151", "PMID" : "17970622", "abstract" : "Traumatic brain injury (TBI) produces a state of vulnerability that reduces the brain capacity to cope with secondary insults. The silent information regulator 2 (Sir2) has been implicated with maintaining genomic stability and cellular homeostasis under challenging situation. Here we explore the possibility that the action of Sir2alpha (mammalian Sir2) in the brain can extend to serve neuronal plasticity. We provide novel evidence showing that mild TBI reduces the expression of Sir2alpha in the hippocampus, in proportion to increased levels of protein oxidation. In addition, we show that dietary supplementation of omega-3 fatty acids that ameliorates protein oxidation was effective to reverse the reduction of Sir2alpha level in injured rats. Given that oxidative stress is a subproduct of dysfunctional energy homeostasis, we measured AMP-activated protein kinase (AMPK) and phosphorylated-AMPK (p-AMPK) to have an indication of the energy status of cells. Hippocampal levels of total and phosphorylated AMPK were reduced after TBI and levels were normalized by omega-3 fatty acts supplements. Further, we found that TBI reduced ubiquitous mitochondrial creatine kinase (uMtCK), an enzyme implicated in the energetic regulation of Ca2+-pumps and in the maintenance of Ca2+-homeostasis. Omega-3 fatty acids supplements normalized the levels of uMtCK after lesion. Furthermore, we found that the correlation between Sir2alpha and AMPK or p-AMPK was disrupted by TBI, but restored by omega-3 fatty acids supplements. Our results suggest that TBI may compromise neuronal protective mechanisms by involving the action of Sir2alpha. In addition, results show the capacity of omega-3 fatty acids to counteract some of the effects of TBI by normalizing levels of molecular systems associated with energy homeostasis.", "author" : [ { "dropping-particle" : "", "family" : "Wu", "given" : "Aiguo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ying", "given" : "Zhe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gomez-Pinilla", "given" : "Fernando", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal Of Neurotrauma", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2007", "10" ] ] }, "page" : "1587-1595", "title" : "Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury.", "type" : "article-journal", "volume" : "24" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1089/neu.2011.1872", "ISSN" : "1557-9042", "PMID" : "21851229", "abstract" : "The pathology of traumatic brain injury (TBI) is characterized by the decreased capacity of neurons to metabolize energy and sustain synaptic function, likely resulting in cognitive and emotional disorders. Based on the broad nature of the pathology, we have assessed the potential of the omega-3 fatty acid docosahexaenoic acid (DHA) to counteract the effects of concussive injury on important aspects of neuronal function and cognition. Fluid percussion injury (FPI) or sham injury was performed, and rats were then maintained on a diet high in DHA (1.2% DHA) for 12 days. We found that DHA supplementation, which elevates brain DHA content, normalized levels of brain-derived neurotrophic factor (BDNF), synapsin I (Syn-1), cAMP-responsive element-binding protein (CREB), and calcium/calmodulin-dependent kinase II (CaMKII), and improved learning ability in FPI rats. It is known that BDNF facilitates synaptic transmission and learning ability by modulating Syn-I, CREB, and CaMKII signaling. The DHA diet also counteracted the FPI-reduced manganese superoxide dismutase (SOD) and Sir2 (a NAD+-dependent deacetylase). Given the involvement of SOD and Sir2 in promoting metabolic homeostasis, DHA may help the injured brain by providing resistance to oxidative stress. Furthermore, DHA normalized levels of calcium-independent phospholipase A2 (iPLA2) and syntaxin-3, which may help preserve membrane homeostasis and function after FPI. The overall results emphasize the potential of dietary DHA to counteract broad and fundamental aspects of TBI pathology that may translate into preserved cognitive capacity.", "author" : [ { "dropping-particle" : "", "family" : "Wu", "given" : "Aiguo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ying", "given" : "Zhe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gomez-Pinilla", "given" : "Fernando", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal Of Neurotrauma", "id" : "ITEM-2", "issue" : "10", "issued" : { "date-parts" : [ [ "2011", "10" ] ] }, "page" : "2113-22", "publisher" : "Journal of neurotrauma", "title" : "The salutary effects of DHA dietary supplementation on cognition, neuroplasticity, and membrane homeostasis after brain trauma.", "type" : "article-journal", "volume" : "28" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.arr.2007.04.003", "ISSN" : "1568-1637", "PMID" : "17604236", "abstract" : "It is likely that the capacity of the brain to remain healthy during aging depends upon its ability to adapt and nurture in response to environmental challenges. In these terms, main principles involved in hormesis can be also applied to understand relationships at a higher level of complexity such as those existing between the CNS and the environment. This review emphasizes the ability of diet, exercise, and other lifestyle adaptations to modulate brain function. Exercise and diet are discussed in relationship to their aptitude to impact systems that sustain synaptic plasticity and mental health, and are therefore important for combating the effects of aging. Mechanisms that interface energy metabolism and synaptic plasticity are discussed, as these are the frameworks for the actions of cellular stress on cognitive function. In particular, neurotrophins are emerging as main factors in the equation that may connect lifestyle factors and mental health.", "author" : [ { "dropping-particle" : "", "family" : "Gomez-Pinilla", "given" : "Fernando", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Ageing Research Reviews", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2008", "1" ] ] }, "page" : "49-62", "title" : "The influences of diet and exercise on mental health through hormesis.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Gomez-Pinilla, 2008; Aiguo Wu, Ying, & Gomez-Pinilla, 2007, 2011)", "manualFormatting" : "(Gomez-Pinilla, 2008)", "plainTextFormattedCitation" : "(Gomez-Pinilla, 2008; Aiguo Wu, Ying, & Gomez-Pinilla, 2007, 2011)", "previouslyFormattedCitation" : "(Gomez-Pinilla, 2008; Aiguo Wu, Ying, & Gomez-Pinilla, 2007, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Gomez-Pinilla, 2008) Additionally, the same group found effects of TBI were optimally counteracted by the combination of DHA and exercise.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Wu", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ying", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gomez-Pinilla", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuroscience", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "655-663", "title" : "Exercise facilitates the action of dietary DHA on functional recovery after brain trauma", "type" : "article-journal", "volume" : "248" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(A Wu, Ying, & Gomez-Pinilla, 2013)", "manualFormatting" : "(Wu, 2013)", "plainTextFormattedCitation" : "(A Wu, Ying, & Gomez-Pinilla, 2013)", "previouslyFormattedCitation" : "(A Wu, Ying, & Gomez-Pinilla, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Wu, 2013) Shin and Dixon also investigated the supplementation of ω-3FA and found they restored dopamine transmission deficits after TBI.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Shin", "given" : "SS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dixon", "given" : "CE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurosci Lett", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "168-171", "title" : "Oral fish oil restores striatal dopamine release after traumatic brain injury", "type" : "article-journal", "volume" : "496" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Shin & Dixon, 2011)", "manualFormatting" : "(Shin, 2011)", "plainTextFormattedCitation" : "(Shin & Dixon, 2011)", "previouslyFormattedCitation" : "(Shin & Dixon, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Shin, 2011) In two separate experiments using an impact acceleration injury model in rats, Bailes and colleagues used four groups of animals: two groups that were injured then gavaged with 10 or 40 mg/kg/day of ω-3FA consisting of EPA and DHA for thirty days; an unsupplemented control group that received an injury; and an unsupplemented sham group that was not injured.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3171/2010.5.JNS08914", "ISSN" : "1933-0693", "PMID" : "20635852", "abstract" : "Traumatic brain injury remains the most common cause of death in persons under 45 years of age in the Western world. Recent evidence from animal studies suggests that supplementation with omega-3 fatty acid (O3FA) (particularly eicosapentaenoic acid EPA and docosahexaenoic acid DHA) improves functional outcomes following focal neural injury. The purpose of this study is to determine the benefits of O3FA supplementation following diffuse axonal injury in rats.", "author" : [ { "dropping-particle" : "", "family" : "Mills", "given" : "James D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bailes", "given" : "Julian E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sedney", "given" : "Cara L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hutchins", "given" : "Heather", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sears", "given" : "Barry", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal Of Neurosurgery", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2011", "1" ] ] }, "page" : "77-84", "title" : "Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model.", "type" : "article-journal", "volume" : "114" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Mills, Bailes, Sedney, Hutchins, & Sears, 2011)", "manualFormatting" : "(Mills, 2011)", "plainTextFormattedCitation" : "(Mills, Bailes, Sedney, Hutchins, & Sears, 2011)", "previouslyFormattedCitation" : "(Mills, Bailes, Sedney, Hutchins, & Sears, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Mills, 2011) A second study was done using DHA only.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1089/neu.2009.1239", "ISSN" : "1557-9042", "PMID" : "20597639", "abstract" : "Traumatic brain injury (TBI) remains the most common cause of death in persons under age 45 in the Western world. Recent evidence from animal studies suggests that supplementation with omega-3 fatty acids (O3FA) improves functional outcomes following focal neural injury. The purpose of this study is to determine the benefits of DHA supplementation following diffuse axonal injury in rats. Four groups of 10 adult male Sprague-Dawley rats were subjected to an impact acceleration injury and then received 30 days of supplementation with either 10mg/kg/d or 40mg/kg/d of docosahexaenoic acid (DHA). Serum fatty acid levels were determined from the isolated plasma phospholipids prior to injury and at the end of the 30 days of DHA supplementation. Following sacrifice, brainstem white matter tracts underwent fluorescent immunohistochemical processing for labeling of \u03b2-amyloid precursor protein (APP), a marker of axonal injury. Dietary supplementation with either 10mg/kg/d or 40mg/kg/d of DHA for 30 days results in significantly (p<0.05) increased DHA serum levels of 123% and 175% over baseline, respectively. Immunohistochemical analysis reveals significantly (p<0.05) decreased numbers of APP-positive axons in animals receiving dietary supplementation with DHA, 26.1 (SD 5.3) for 10mg/kg/d, and 19.6 (SD 4.7) for 40mg/kg/d axons per mm(2), versus 147.7 (SD 7.1) axons in unsupplemented animals. Sham-injured animals had 6.4 (SD 13.9) APP positive axons per mm(2). Dietary supplementation with DHA increases serum levels in a dose-dependent manner. DHA supplementation significantly reduces the number of APP-positive axons at 30 days post-injury, to levels similar to seen those in uninjured animals. DHA is safe, affordable, and readily available worldwide to potentially reduce the burden of TBI.", "author" : [ { "dropping-particle" : "", "family" : "Bailes", "given" : "Julian E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mills", "given" : "James D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal Of Neurotrauma", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2010", "9" ] ] }, "page" : "1617-1624", "title" : "Docosahexaenoic acid reduces traumatic axonal injury in a rodent head injury model.", "type" : "article-journal", "volume" : "27" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Bailes & Mills, 2010)", "manualFormatting" : "(Bailes, 2010)", "plainTextFormattedCitation" : "(Bailes & Mills, 2010)", "previouslyFormattedCitation" : "(Bailes & Mills, 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Bailes, 2010) In both studies, supplementation significantly reduced the number of β-amyloid precursor protein (APP)-positive axons at 30 days post-injury, in a dose-dependent manner, to levels similar those in uninjured sham animals. More recently, compelling experiments in TBI treatment using functional outcome measures were done by Schobe and colleagues. They demonstrated that dietary DHA decreased cognitive impairment, oxidative stress, and white matter injury and improved cognitive, imaging and histologic outcomes in adult rats after TBI. DHA acutely decreased markers of oxidative stress and increased anti-inflammatory interleukin-10 in the brains following controlled cortical impact. DHA improved Morris Water Maze performance and lesion volume late after injury while decreasing T2-imaging measures of cerebral edema and decreased radial diffusivity, an index of white matter injury ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Schobe", "given" : "ME", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Requena", "given" : "DF", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abdullah", "given" : "OM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Casper", "given" : "TC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beachy", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malleske", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pauly", "given" : "JR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal Of Neurotrauma2", "id" : "ITEM-1", "issue" : "18", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "Epub ahead of print", "title" : "Dietary Docosahexaenoic Acid Improves Cognitive Function, Tissue Sparing, and Magnetic Resonance Imaging Indices of Edema and White Matter Injury in the Immature Rat after Traumatic Brain Injury", "type" : "article-journal", "volume" : "32" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Schobe et al., 2015)", "manualFormatting" : "(Schobe, 2015)", "plainTextFormattedCitation" : "(Schobe et al., 2015)", "previouslyFormattedCitation" : "(Schobe et al., 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Schobe, 2015)Eady and colleagues have reported a variety of preclinical studies administered DHA following experimentally induced ischemia in a rodent stroke model. Animals were subjected middle cerebral artery occlusion for two hours. Most recently, they demonstrated that DHA complexed to albumin (DHA-Alb) given three hours after onset of stroke is highly neuroprotective following focal cerebral ischemia in aged rats.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Eady", "given" : "TN", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khoutorova", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Obenaus", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mohd-Yusof", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bazan", "given" : "NG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belayev", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurobiol Dis", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1-7", "title" : "Docosahexaenoic acid complexed to albumin provides neuroprotection after experimental stroke in aged rats", "type" : "article-journal", "volume" : "62" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Eady et al., 2014)", "manualFormatting" : "(Eady, 2014)", "plainTextFormattedCitation" : "(Eady et al., 2014)", "previouslyFormattedCitation" : "(Eady et al., 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Eady, 2014) Infarct volumes were significantly decreased and neurological scores improved. DHA also reduced microglia infiltration and increased the number of astrocytes and neurons. The same group had previously tested young rats with similar results.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1161/01.STR.0000149620.74770.2e", "ISSN" : "1524-4628", "PMID" : "15569878", "abstract" : "BACKGROUND AND PURPOSE: High-dose human albumin therapy is strongly neuroprotective in models of brain ischemia and trauma and is currently being studied in a pilot-phase clinical stroke trial. Among its actions in ischemia, albumin induces the systemic mobilization of n-3 polyunsaturated fatty acids and may help to replenish polyunsaturated fatty acids lost from neural membranes. METHODS: We complexed 25% human albumin to docosahexaenoic acid (DHA; 22:6n-3) and compared its neuroprotective efficacy with that of native albumin in rats with 2-hour focal ischemia produced by intraluminal suture-occlusion of the middle cerebral artery. RESULTS: In animals treated with DHA-albumin, 0.63 g/kg, the improvement in neurobehavioral scores at 72 hours significantly exceeded that of other treatment groups, and the extent of histological protection (86% reduction in cortical infarction) was highly significant and tended to surpass the degree of cortical protection produced by native albumin at 1.25 g/kg (65%). DHA-albumin 0.63 g/kg, but not native albumin, also significantly reduced subcortical infarction and markedly diminished brain swelling. Lipidomic analysis of DHA-albumin-treated postischemic brains revealed a large accumulation of the neuroprotective DHA metabolite, 10,17S-docosatriene, in the ipsilateral hemisphere. CONCLUSIONS: The high-grade neuroprotection afforded by the DHA-albumin complex at relatively low albumin doses is clinically advantageous in that it might reduce the likelihood of acute intravascular volume overload and congestive heart failure sometimes induced when patients with compromised cardiovascular function are treated with high-dose albumin.", "author" : [ { "dropping-particle" : "", "family" : "Belayev", "given" : "Ludmila", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marcheselli", "given" : "Victor L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khoutorova", "given" : "Larissa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodriguez De Turco", "given" : "Elena B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Busto", "given" : "Raul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ginsberg", "given" : "Myron D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bazan", "given" : "Nicolas G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Stroke: A Journal of Cerebral Circulation", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2005", "1" ] ] }, "page" : "118-123", "title" : "Docosahexaenoic acid complexed to albumin elicits high-grade ischemic neuroprotection.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Belayev et al., 2005)", "manualFormatting" : "(Belayev, 2005)", "plainTextFormattedCitation" : "(Belayev et al., 2005)", "previouslyFormattedCitation" : "(Belayev et al., 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Belayev, 2005) Additionally, this group determined that DHA-Alb therapy is highly neuroprotective in permanent stroke (rather than transient) in rats.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Eady", "given" : "TN", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khoutorova", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anzola", "given" : "DV", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hong", "given" : "SH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Obenaus", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mohd-Yusof", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bazan", "given" : "NG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belayev", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS One", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "e77237", "title" : "Acute treatment with docosahexaenoic acid complexed to albumin reduces injury after a permanent focal cerebral ischemia in rats", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Eady et al., 2013)", "manualFormatting" : "(Eady, 2013)", "plainTextFormattedCitation" : "(Eady et al., 2013)", "previouslyFormattedCitation" : "(Eady et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Eady, 2013) When they used DHA not complexed to albumin, in addition to the previously described findings, they found that DHA also modulates the neuroinflammatory response and triggers long term restoration of synaptic circuits, even when administered up to five hours after injury. When investigating the therapeutic window for using DHA-Alb, DHA-Alb led to improved neurological score and significant reductions of infarct volumes (especially in the cortical or penumbral region), even when treatment was initiated as late as seven hours after onset of temporary middle cerebral artery occlusion.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Eady", "given" : "TN", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khoutorova", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Atkins", "given" : "KD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bazan", "given" : "NG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belayev", "given" 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"given" : "SH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belayev", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khoutorova", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Obenaus", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bazan", "given" : "NG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neurological Sciences", "id" : "ITEM-1", "issue" : "338(1-2)", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "135-41", "title" : "Docosahexaenoic acid confers enduring neuroprotection in experimental stroke", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hong, Belayev, Khoutorova, Obenaus, & Bazan, 2013)", "plainTextFormattedCitation" : "(Hong, Belayev, Khoutorova, Obenaus, & Bazan, 2013)", "previouslyFormattedCitation" : "(Hong, Belayev, Khoutorova, Obenaus, & Bazan, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hong, Belayev, Khoutorova, Obenaus, & Bazan, 2013) Most recently, the same research group reported DHA improves neurologic deficits and attenuates blood-brain barrier injury induced by focal ischemia in rats.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Hong", "given" : "SH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khoutorova", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bazan", "given" : "NG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belayev", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Experimental and Translational Stroke Medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "3-13", "title" : "Docosahexaenoic acid improves behavior and attenuates blood-brain barrier injury induced by focal cerebral ischemia in rats", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hong, Khoutorova, Bazan, & Belayev, 2015)", "manualFormatting" : "(Hong, 2015)", "plainTextFormattedCitation" : "(Hong, Khoutorova, Bazan, & Belayev, 2015)", "previouslyFormattedCitation" : "(Hong, Khoutorova, Bazan, & Belayev, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hong, 2015) When Williams, et al, evaluated an ω-3FA triglyceride emulsion administered before and after a hypoxic-ischemic (H/I) injury, they found a significantly 43% reduced total infarct when administered 90 minutes prior to H/I and 47% when administered immediately after H/I. In post-H/I experiments, the triglyceride formulation containing only DHA, but not one with only EPA, exhibited neuroprotective effects. The DHA emulsion significantly decreased total infarct volume by 51% when administered at 0 hours post-injury, 46% at 1 hour, 51% at 2 hours, and no protective effect at 4 hours.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0056233", "ISSN" : "1932-6203", "PMID" : "23437099", "abstract" : "We questioned if acute administration of n-3 fatty acids (FA) carried in n-3 rich triglyceride (TG) emulsions provides neuroprotection in neonatal mice subjected to hypoxic-ischemic (H/I) brain injury. We examined specificity of FA, optimal doses, and therapeutic windows for neuroprotection after H/I. H/I insult was induced in C57BL/6J 10-day-old mice by right carotid artery ligation followed by exposure to 8% O(2) for 15 minutes at 37\u00b0C. Intraperitoneal injection with n-3-rich TG emulsions, n-6 rich TG emulsions or saline for control was administered at different time points before and/or after H/I. In separate experiments, dose responses were determined with TG containing only docosahexaenoic acid (Tri-DHA) or eicosapentaenoic acid (Tri-EPA) with a range of 0.1-0.375 g n-3 TG/kg, administered immediately after H/I insult. Infarct volume and cerebral blood flow (CBF) were measured. Treatment with n-3 TG emulsions both before- and after- H/I significantly reduced total infarct volume by a mean of 43% when administered 90 min prior to H/I and by 47% when administered immediately after H/I. In post-H/I experiments Tri-DHA, but not Tri-EPA exhibited neuroprotective effects with both low and high doses (p<0.05). Moreover, delayed post-H/I treatment with Tri-DHA significantly decreased total infarct volume by a mean of 51% when administered at 0 hr, by 46% at 1 hr, and by 51% at 2 hr after H/I insult. No protective effect occurred with Tri-DHA injection at 4 hr after H/I. There were no n-3 TG related differences in CBF. A significant reduction in brain tissue death was maintained after Tri-DHA injection at 8 wk after the initial brain injury. Thus, n-3 TG, specifically containing DHA, is protective against H/I induced brain infarction when administered up to 2 hr after H/I injury. Acute administration of TG-rich DHA may prove effective for treatment of stroke in humans.", "author" : [ { "dropping-particle" : "", "family" : "Williams", "given" : "Jill J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayurasakorn", "given" : "Korapat", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vannucci", "given" : "Susan J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mastropietro", "given" : "Christopher", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bazan", "given" : "Nicolas G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ten", "given" : "Vadim S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deckelbaum", "given" : "Richard J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2013", "1" ] ] }, "page" : "e56233", "title" : "N-3 Fatty Acid rich triglyceride emulsions are neuroprotective after cerebral hypoxic-ischemic injury in neonatal mice.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Williams et al., 2013)", "manualFormatting" : "(Williams, 2013)", "plainTextFormattedCitation" : "(Williams et al., 2013)", "previouslyFormattedCitation" : "(Williams et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Williams, 2013) Similarly, Berman, et al, found significant improvement in functional outcome with DHA-Alb treatment following H/I in very young ratsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Berman", "given" : "DR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barks", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mozurkewich", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Am J Obstet Gynecol", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "385.e1-5", "title" : "Treatment with docosahexaenoic acid after hypoxia-ischemia improves forepaw placing in a rat model of perinatal hypoxia-ischemia", "type" : "article-journal", "volume" : "203" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(D. Berman, Liu, Barks, & Mozurkewich, 2010)", "manualFormatting" : "(Berman, 2010)", "plainTextFormattedCitation" : "(D. Berman, Liu, Barks, & Mozurkewich, 2010)", "previouslyFormattedCitation" : "(D. Berman, Liu, Barks, & Mozurkewich, 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Berman, 2010) and when combined with hypothermia, even further functional improvement and reduced brain damage.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Berman", "given" : "DR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mozurkewich", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shangguan", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barks", "given" : "JD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Silverstein", "given" : "FS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neonatology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "71-78", "title" : "Docosahexaenoic acid augments hypothermic neuroprotection in a neonatal rat asphyxia model", "type" : "article-journal", "volume" : "104" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(D. Berman et al., 2013)", "manualFormatting" : "(Berman, 2013)", "plainTextFormattedCitation" : "(D. Berman et al., 2013)", "previouslyFormattedCitation" : "(D. Berman et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Berman, 2013) In more recent studies, deSouza et al., concluded that ω-3FA, especially in the triacylglycerol form (as opposed to thyl ester form), could be a promising therapy to prevent microvascular damage induced by ischemia/reperfusion and its consequent clinical sequelae.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Souza", "given" : "Md", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Conde", "given" : "CM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lafl\u00f4r", "given" : "CM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sicuro", "given" : "FL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bouskela", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Lipids", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "23-37", "title" : "n-3 PUFA induce microvascular protective changes during ischemia/reperfusion", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(de Souza, Conde, Lafl\u00f4r, Sicuro, & Bouskela, 2015)", "manualFormatting" : "(de Souza, 2015)", "plainTextFormattedCitation" : "(de Souza, Conde, Lafl\u00f4r, Sicuro, & Bouskela, 2015)", "previouslyFormattedCitation" : "(de Souza, Conde, Lafl\u00f4r, Sicuro, & Bouskela, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(de Souza, 2015)DHA lessens neurological damage following spinal cord injury (SCI) as well. Michael-Titus et al, have conducted a series of SCI experiments. First, they administered DHA 30 minutes after SCI induced by surgical hemisection in adult rats. One week after injury, they found reduced neuronal cell loss, oligodendrocyte loss, decreased apoptosis, as well as improved functional outcome. In contrast, when the ω-6FA AA was administered after injury, it exacerbated injury, increased the size of the spinal cord lesion, decreased neuronal and glial cell survival and worsened functional outcome. Next, the same group used a more severe model of SCI, induced by compression, but also added DHA to the diet for six weeks following injury and injection at 30 minutes. Similar to the previous study, neuroprotection and maintenance of locomotion was greatly enhanced. Additional neuroprotective effect of the DHA-enriched diet, while not apparent the first week, improved functional and histological outcomes even more than bolus alone at six weeks. Of note, when DHA was given within an hour of SCI, neuromotor function was maintained but the effect was lost when treatment was delayed four hours. These findings also support the idea that treatment with ω-3FA represent a promising therapeutic approach for neurotrauma which would be easy to translate to the emergency patient-care arena considering the well-documented safety and tolerability of these compoundsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.plefa.2007.10.021", "ISSN" : "0952-3278", "PMID" : "18036801", "abstract" : "Studies with omega-3 polyunsaturated fatty acids (PUFA) have shown that these compounds have therapeutic potential in several indications in neurology and psychiatry. Acute spinal cord injury (SCI) is an event with devastating consequences, and no satisfactory treatment is available at present. The pathogenetic mechanisms associated with SCI include excitotoxicity, increased oxidation and inflammation. We review here our recent studies, which suggest that omega-3 PUFA have significant neuroprotective potential in spinal cord trauma. In a first study, we administered an intravenous bolus of alpha-linolenic acid (LNA) or docosahexaenoic acid (DHA) 30 min after spinal cord hemisection injury in adult rats. The omega-3 PUFA led to increased neuronal and glial survival, and a significantly improved neurological outcome. In subsequent studies, we tested DHA in a more severe compression model of SCI. We also explored a combined acute and chronic treatment regime using DHA. Saline or DHA was administered intravenously 30 min after compression of the spinal cord. After injury, the saline group received a standard control diet, whereas DHA-injected animals received either a control or a DHA-enriched diet for 6 weeks following injury. We assessed locomotor recovery and analysed markers for cell survival and axonal damage, and we also investigated the effects of the treatment on the inflammatory reaction and the oxidative stress that follow SCI. We showed that the acute DHA treatment is neuroprotective after compression SCI, even if the treatment is delayed up to an hour after injury. The DHA injection led to an increased neuronal and glial cell survival, and the effect of the DHA injection was amplified by addition of DHA to the diet. Rats treated with a DHA injection and a DHA-enriched diet performed significantly better at 6 weeks in terms of neurological outcome. The analysis of the tissue after DHA administration showed that the fatty acid significantly reduced lipid peroxidation, protein oxidation and RNA/DNA oxidation, and the induction of COX-2. Parallel studies in a facial nerve injury model in mice also showed pro-regenerative effects of chronic dietary administration of DHA after nerve lesion. These observations suggest that treatment with omega-3 PUFA could represent a promising therapeutic approach in the management of neurological injury.", "author" : [ { "dropping-particle" : "", "family" : "Michael-Titus", "given" : "Adina T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Prostaglandins leukotrienes and essential fatty acids", "id" : "ITEM-1", "issue" : "5-6", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "295-300", "title" : "Omega-3 fatty acids and neurological injury.", "type" : "article-journal", "volume" : "77" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Paterniti", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Impellizzeri", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paola", "given" : "R", "non-dropping-particle" : "Di", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Esposito", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gladman", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yip", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Priestley", "given" : "JV", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Michael-Titus", "given" : "AT", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cuzzocrea", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neuroinflammation", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1-18", "title" : "Docosahexaenoic acid attenuates the early inflammatory response following spinal cord injury in mice: in-vivo and in-vitro studies", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(A. T. Michael-Titus, 2007; Paterniti et al., 2014)", "manualFormatting" : "(Michael-Titus, 2007; Paterniti, 2014)", "plainTextFormattedCitation" : "(A. T. Michael-Titus, 2007; Paterniti et al., 2014)", "previouslyFormattedCitation" : "(A. T. Michael-Titus, 2007; Paterniti et al., 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Michael-Titus, 2007; Paterniti, 2014) Pre-injury administration. Preclinical studies also have demonstrated that ω-3FA can be protective when administered prior to injury. When fish oil was administered 30 minutes prior to experimental TBI, it improved functional outcome after TBI and decreased disruption of the blood-brain barrier. When rats were fed fish oil for a longer period of time (four weeks), a different research group found that in the fish oil group as compared to placebo, spatial learning and cognitive function were significantly better using the Morris Water Maze and had a higher density of hippocampal neurons on autopsy.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Wang", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Van", "given" : "KC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gavitt", "given" : "BJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grayson", "given" : "JK", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "YC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyeth", "given" : "BG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichakron", "given" : "KO", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Restor Neurol Neurosci", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "647-659", "title" : "Effect of fish oil supplementation in a rat model of multiple mild traumatic brain injuries", "type" : "article-journal", "volume" : "31" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Wang et al., 2013)", "manualFormatting" : "(Wang, 2013)", "plainTextFormattedCitation" : "(Wang et al., 2013)", "previouslyFormattedCitation" : "(Wang et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Wang, 2013) Bailes and colleagues, following their successful treatment experiments, repeated their acceleration injury model in rats using a 30-day pre-injury gavage of DHA with no post-injury supplementation. Again, they found decreased numbers of APP positive axons, most significant at 40mg/kg/day, in addition to improved Morris Water Maze testing. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1227/NEU.0b013e3181ff692b", "ISSN" : "1524-4040", "PMID" : "21135750", "abstract" : "Although various strategies for prevention of brain disease have been implemented, no substance has been found to be advantageous for prophylaxis against brain injury.", "author" : [ { "dropping-particle" : "", "family" : "Mills", "given" : "James D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hadley", "given" : "Kevin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bailes", "given" : "Julian E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurosurgery", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "2" ] ] }, "page" : "474-481; discussion 481", "title" : "Dietary supplementation with the omega-3 fatty acid docosahexaenoic acid in traumatic brain injury.", "type" : "article-journal", "volume" : "68" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Mills, Hadley, & Bailes, 2011)", "manualFormatting" : "(Mills, 2011)", "plainTextFormattedCitation" : "(Mills, Hadley, & Bailes, 2011)", "previouslyFormattedCitation" : "(Mills, Hadley, & Bailes, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Mills, 2011) If animals were deprived of DHA prior to TBI, decreased brain levels of DHA were associated with poorer sensorimotor outcomesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Russell", "given" : "KL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berman", "given" : "NE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gregg", "given" : "PR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levant", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Prostaglandins Leukot Essent Fatty Acids", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "5-11", "title" : "Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury", "type" : "article-journal", "volume" : "90" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Russell, Berman, Gregg, & Levant, 2014)", "manualFormatting" : "(Russell, 2014)", "plainTextFormattedCitation" : "(Russell, Berman, Gregg, & Levant, 2014)", "previouslyFormattedCitation" : "(Russell, Berman, Gregg, & Levant, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Russell, 2014) The effects of DHA depletion prior to TBI was confirmed by HY Kim and colleagues when they observed DHA depleted mice exhibited significantly slower recovery from motor deficits evaluated by the rotarod and the beam walk tests. Furthermore, the DHA deficient mice showed greater anxiety-like behavior tested in the open field test as well as cognitive deficits evaluated by an object recognition test.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Desai", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kevala", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "HY", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS One", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "e86472", "title" : "Depletion of brain docosahexaenoic acid impairs recovery from traumatic brain injury", "type" : "article-journal", "volume" : "27" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Desai, Kevala, & Kim, 2014)", "manualFormatting" : "(Desai, 2014)", "plainTextFormattedCitation" : "(Desai, Kevala, & Kim, 2014)", "previouslyFormattedCitation" : "(Desai, Kevala, & Kim, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Desai, 2014)With three days of pre-stroke treatment, DHA exhibited a neuroprotective effect against ischemic deficits by reduction of behavioral disturbance, brain infarction, edema and blood-brain barrier disruption.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "CY Chang", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuan", "given" : "YH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "JR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "WY", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ou", "given" : "YC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pan", "given" : "HC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liao", "given" : "SL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Raung", "given" : "SL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "CJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "CJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Nutr Biochem", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "2127-37", "title" : "Docosahexaenoic acid reduces cellular inflammatory response following permanent focal cerebral ischemia in rats", "type" : "article-journal", "volume" : "24" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(CY Chang et al., 2013)", "manualFormatting" : "(Chang, 2013)", "plainTextFormattedCitation" : "(CY Chang et al., 2013)", "previouslyFormattedCitation" : "(CY Chang et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chang, 2013) Berman’s work includes pretreatment 90 minutes prior to H/I injury. They report DHA-Alb pretreatment improves functional outcome and reduces volume loss after H/I in neonatal rats.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ajog.2009.01.020", "ISSN" : "1097-6868", "PMID" : "19254588", "abstract" : "OBJECTIVE: We hypothesized that pretreatment with docosahexaenoic acid (DHA), a potentially neuroprotective polyunsaturated fatty acid, would improve function and reduce brain damage in a rat model of perinatal hypoxia-ischemia. STUDY DESIGN: Seven-day-old rats were divided into 3 treatment groups that received intraperitoneal injections of DHA 1, 2.5, or 5 mg/kg as DHA-albumin complex and 3 controls that received 25% albumin, saline, or no injection. Subsequently, rats underwent right carotid ligation followed by 90 minutes of 8% oxygen. Rats underwent sensorimotor testing (vibrissae-stimulated forepaw placing) and morphometric assessment of right-sided tissue loss on postnatal day 14. RESULTS: DHA pretreatment improved forepaw placing response to near-normal levels (9.5 0.9 treatment vs 7.1 2.2 controls; normal = 10; P < .0001). DHA attenuated hemisphere damage compared with controls (P = .0155), with particular benefit in the hippocampus with 1 mg/kg (38% protection vs albumin controls). CONCLUSION: DHA pretreatment improves functional outcome and reduces volume loss after hypoxia-ischemia in neonatal rats.", "author" : [ { "dropping-particle" : "", "family" : "Berman", "given" : "Deborah R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mozurkewich", "given" : "Ellen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Yiqing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barks", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Obstetrics and Gynecology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "3" ] ] }, "page" : "305.e1-e6", "publisher" : "Mosby, Inc.", "title" : "Docosahexaenoic acid pretreatment confers neuroprotection in a rat model of perinatal cerebral hypoxia-ischemia.", "type" : "article-journal", "volume" : "200" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(D. R. Berman, Mozurkewich, Liu, & Barks, 2009)", "manualFormatting" : "(Berman, 2009)", "plainTextFormattedCitation" : "(D. R. Berman, Mozurkewich, Liu, & Barks, 2009)", "previouslyFormattedCitation" : "(D. R. Berman, Mozurkewich, Liu, & Barks, 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Berman, 2009) In another rat H/I study, DHA pretreatment was done one hour; three days; or daily for six weeks prior to injury. All three groups resulted in a reduction of blood–brain barrier disruption, brain edema, inflammatory cell infiltration, interleukin-6 (IL-6) expression and caspase-3 activity and an increase in antioxidative capacity.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jnutbio.2008.06.014", "ISSN" : "1873-4847", "PMID" : "18805685", "abstract" : "Evidence suggests that inactivation of cell-damaging mechanisms and/or activation of cell-survival mechanisms may provide effective preventive or therapeutic interventions to reduce cerebral ischemia/reperfusion (I/R) injuries. Docosahexaenoic acid (DHA) is an essential polyunsaturated fatty acid in the central nervous system that has been shown to possess neuroprotective effects. We examined whether different preadministrative protocols of DHA have effects on brain injury after focal cerebral I/R and investigated the potential neuroactive mechanisms involved. Sprague-Dawley rats were intraperitoneally pretreated with DHA once 1 h or 3 days being subjected to focal cerebral I/R or daily for 6 weeks before being subjected to focal cerebral I/R. Reduction of brain infarction was found in all three DHA-pretreated groups. The beneficial effect of DHA on the treatment groups was accompanied by decreases in blood-brain barrier disruption, brain edema, malondialdehyde (MDA) production, inflammatory cell infiltration, interleukin-6 (IL-6) expression and caspase-3 activity. Elevation of antioxidative capacity, as evidenced by decreased MDA level and increased superoxide dismutase activity and glutathione level, was detected only in the chronic daily-administration group. The two single-administration groups showed increased phosphorylation of extracellular-signal-regulated kinase (ERK). Elevation of Bcl-2 expression was detected in the chronic daily-administration and 3-day-administration groups. In vitro study demonstrated that DHA attenuated IL-6 production from stimulated glial cells involving nuclear factor kappaB inactivation. Therefore, the data suggest that the neuroprotective mechanisms of DHA pretreatment are, in part, mediated by attenuating damaging mechanisms through reduction of cytotoxic factor production and by strengthening survival mechanisms through ERK-mediated and/or Bcl-2-mediated prosurvival cascade.", "author" : [ { "dropping-particle" : "", "family" : "Pan", "given" : "Hung-Chuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kao", "given" : "Tsung-Kuei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ou", "given" : "Yen-Chuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yang", "given" : "Dar-Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yen", "given" : "Yu-Ju", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Chun-Chiang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chuang", "given" : "Yu-Han", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liao", "given" : "Su-Lan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Raung", "given" : "Shue-Ling", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Ching-Wen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chiang", "given" : "An-Na", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Chun-Jung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of nutritional biochemistry", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2009", "9" ] ] }, "page" : "715-725", "publisher" : "Elsevier Inc.", "title" : "Protective effect of docosahexaenoic acid against brain injury in ischemic rats.", "type" : "article-journal", "volume" : "20" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Pan et al., 2009)", "manualFormatting" : "(Pan, 2009)", "plainTextFormattedCitation" : "(Pan et al., 2009)", "previouslyFormattedCitation" : "(Pan et al., 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Pan, 2009) Figueroa et al, have performed several SCI prophylactic studies. When rats were fed an ω-3FA enriched diet for eight weeks prior to sham or a contusion SCI operation, the ω-3FA group exhibited significantly better functional outcomes including lower sensory deficits, autonomic bladder recovery, and early improvements in locomotion. They also found SCI triggers a marked DHA deficiency that was associated with dysfunction and corrected with the enriched diet. They conclude that ω-3FA prophylaxis confers resiliency to SCI mediated, at least in part, by generating a neuroprotective and restorative neurolipidome.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1089/neu.2012.2718", "ISSN" : "1557-9042", "PMID" : "23294084", "abstract" : "Abstract Omega-3 polyunsaturated fatty acids (\u03c9-3 PUFAs) confer multiple health benefits and decrease the risk of neurological disorders. Studies are needed, however, to identify promising cellular targets and to assess their prophylactic value against neurodegeneration. The present study (1) examined the efficacy of a preventive diet enriched with \u03c9-3 PUFAs to reduce dysfunction in a well-established spinal cord injury (SCI) animal model and (2) used a novel metabolomics data analysis to identify potential neurolipidomic targets. Rats were fed with either control chow or chow enriched with \u03c9-3 PUFAs (750\u2009mg/kg/day) for 8 weeks before being subjected to a sham or a contusion SCI operation. We report new evidence showing that rats subjected to SCI after being pre-treated with a diet enriched with \u03c9-3 PUFAs exhibit significantly better functional outcomes. Pre-treated animals exhibited lower sensory deficits, autonomic bladder recovery, and early improvements in locomotion that persisted for at least 8 weeks after trauma. We found that SCI triggers a robust alteration in the cord PUFA neurolipidome, which was characterized by a marked docosahexaenoic acid (DHA) deficiency. This DHA deficiency was associated with dysfunction and corrected with the \u03c9-3 PUFA-enriched diet. Multivariate data analyses revealed that the spinal cord of animals consuming the \u03c9-3 PUFA-enriched diet had a fundamentally distinct neurolipidome, particularly increasing the levels of essential and long chain \u03c9-3 fatty acids and lysolipids at the expense of \u03c9-6 fatty acids and its metabolites. Altogether, dietary \u03c9-3 PUFAs prophylaxis confers resiliency to SCI mediated, at least in part, by generating a neuroprotective and restorative neurolipidome.", "author" : [ { "dropping-particle" : "", "family" : "Figueroa", "given" : "Johnny D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cordero", "given" : "Kathia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ll\u00e1n", "given" : "Miguel S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leon", "given" : "Marino", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of neurotrauma", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013", "2", "6" ] ] }, "page" : "1-16", "title" : "Dietary Omega-3 Polyunsaturated Fatty Acids Improve the Neurolipidome and Restore the DHA Status while Promoting Functional Recovery after Experimental Spinal Cord Injury.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Figueroa, Cordero, Ll\u00e1n, & De Leon, 2013)", "manualFormatting" : "(Figueroa, 2013)", "plainTextFormattedCitation" : "(Figueroa, Cordero, Ll\u00e1n, & De Leon, 2013)", "previouslyFormattedCitation" : "(Figueroa, Cordero, Ll\u00e1n, & De Leon, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Figueroa, 2013) Omega-3 Use in Human TBI. Unfortunately, there is a significant deficit of data demonstrating the use of ω-3FA in human TBI. However, several case studies are recorded that can provide clinical guidance. In January 2006, an explosion in the Sago Mine in central West Virginia resulted in 14 trapped miners. Two days later, one lone survivor was found and brought to medical care. He had suffered hypoxia and exposure to toxic gases, dehydration, and rhabdomyolysis. The patient demonstrated many classic features of carbon monoxide toxicity, including neurologic, cardiac, and renal dysfunction as well as respiratory failure. In addition to rapid resuscitation, dialysis, and hyperbaric oxygen therapy, starting on hospital day 8, the patient was treated with 21.2 grams per day of ω-3FA that contributed to his neurological recovery following an initial presentation in deep coma. On day 21, he was transferred to a rehabilitation facility and discharged to home two months later.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jamcollsurg.2008.02.015", "ISSN" : "1879-1190", "PMID" : "18656058", "author" : [ { "dropping-particle" : "", "family" : "Roberts", "given" : "Lawrence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bailes", "given" : "Julian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dedhia", "given" : "Harakh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zikos", "given" : "Anthony", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singh", "given" : "Anil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McDowell", "given" : "Darby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Failinger", "given" : "Conrad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biundo", "given" : "Russell", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrick", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carpenter", "given" : "Jeffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American College of Surgeons", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008", "8" ] ] }, "page" : "276-83", "title" : "Surviving a mine explosion.", "type" : "article-journal", "volume" : "207" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Roberts et al., 2008)", "manualFormatting" : "(Roberts, 2008)", "plainTextFormattedCitation" : "(Roberts et al., 2008)", "previouslyFormattedCitation" : "(Roberts et al., 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Roberts, 2008)The only case report in the scientific literature on the specific use of substantial amounts of ω-3FA for TBI occurred four years later and was guided by the Sago Mine experience. In March 2010, a teenager sustained a severe TBI in a motor vehicle accident. After prolonged extrication, he was resuscitated at the scene and flown to a Level I Trauma Center. His GCS score was three. CT scan revealed panhemispheric right subdural and small temporal epidural hematomas and a three millimeter midline shift [FIGURE 32-1]. The patient underwent emergency craniotomy and ICP monitor placement. The patient was rated at Rancho Los Amigos Cognitive Scale Level I and the attending neurosurgeon's impression was that the injury was likely lethal. On hospital day ten, T2 weighted magnetic resonance imaging (MRI) revealed right cerebral convexity subdural hemorrhage and abnormal FLAIR signals consistent with diffuse axonal injury [FIGURE 32-3]. Believed to be in a permanent vegetative state, a tracheotomy and percutaneous endoscopic gastrostomy (PEG) tube were placed for custodial care and enteral feedings were started. The following day, ω-3FA were added to enteral feedings. With the cooperation of the attending neurosurgeon and hospital pharmacy, the patient began receiving 19,212 mg total ω-3FA daily via his PEG. On day 21, he was weaned off the ventilator and transported to a specialized rehabilitation institute. Notably, the patient attended his high school graduation three months after the injury. He was discharged to home four months after the injury.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Lewis", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghassemi", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibbeln", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Am J Emerg Med", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "5-8", "title" : "Therapeutic use of omega-3 fatty acids in severe head trauma.", "type" : "article-journal", "volume" : "31" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(M Lewis et al., 2013)", "manualFormatting" : "(Lewis, 2013)", "plainTextFormattedCitation" : "(M Lewis et al., 2013)", "previouslyFormattedCitation" : "(M Lewis et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lewis, 2013) The patient remained on this level of ω-3FA for more than one year, experienced no adverse effects, and remains on 15-grams of fish oil orally per day. The patient is currently a full time college student and working two part-time jobs.Subsequent to that case, and as a result of the media coverage of the previous two cases, when an 8-year-old girl sustained severe anoxic brain injury caused by prolonged cardiac and respiratory arrest secondary to a near drowning accident in August 2012, high doses of ω-3FA supplements were started post-accident day 82. The patient quickly moved from an unresponsive state to participating in in-patient rehabilitation and eventually home-care training with her parents. That case was reviewed by Sears, Bailes, and Asselin.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Sears", "given" : "Barry", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bailes", "given" : "Julian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Asselin", "given" : "Barbara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PharmaNutrition", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "86-89", "title" : "Therapeutic uses of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Sears, Bailes, & Asselin, 2013)", "manualFormatting" : "(Sears, 2013)", "plainTextFormattedCitation" : "(Sears, Bailes, & Asselin, 2013)", "previouslyFormattedCitation" : "(Sears, Bailes, & Asselin, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Sears, 2013) Media coverage of the first two cases also resulted in additional case being reported in the media, this time a16-year old male pedestrian hit-and-run victim who suffered a torn aorta, skull fractures, subarachnoid hemorrhage, compound bone fractures, and spinal fractures. When transferred to a rehabilitation hospital nine weeks post-accident, the patient, who had been on small doses of fish oil for several weeks, was put on 20-grams per day of omega-3 concentrate. Two days following the increased dosage, the patient was capable of holding a complete, intelligent conversation with his mother.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2015", "8", "23" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Smith", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "CNN", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "title" : "'He's going to be better than he was before'", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(S. Smith, 2014)", "manualFormatting" : "(Smith, 2014)", "plainTextFormattedCitation" : "(S. Smith, 2014)", "previouslyFormattedCitation" : "(S. Smith, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Smith, 2014) Guidelines and Protocols Severe TBI Protocol. Without definitive clinical trial evidence, there is no way to know if ω-3FA actually helps in any particular case of TBI. The clinical experience of the author and others is that the brain needs to be saturated with high doses of ω-3FA in order for the brain to have the opportunity to heal. Without an optimal supply of omegas, healing is less likely to happen. ω-3FA are not a drug and not a cure. Every situation is different and some patients may respond better than others. However, there is no downside to providing optimal levels of nutrition in order to give a patient the best opportunity to regain as much function as possible following a TBI.The dose that was used in the case that was reported on CNN’s Sanjay Gupta MD show << >> and also published in the American Journal of Emergency MedicineADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Lewis", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghassemi", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibbeln", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Am J Emerg Med", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "5-8", "title" : "Therapeutic use of omega-3 fatty acids in severe head trauma.", "type" : "article-journal", "volume" : "31" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(M Lewis et al., 2013)", "manualFormatting" : "(Lewis, 2013)", "plainTextFormattedCitation" : "(M Lewis et al., 2013)", "previouslyFormattedCitation" : "(M Lewis et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lewis, 2013) was: one tablespoon (15ml) concentrated fish oil twice a day for a total of 30ml per day in the feeding tube followed by a saline flush providing 9,756 mg EPA, 6,756 mg DHA, and19,212 mg total ω-3FA daily. This dose, has been used in adults. In pediatric patients, lower doses should be considered. A rudimentary, untested, and arbitrary rule used by Lewis is to divide the patient's weight in pounds by 10 to give the total number of milliliters to be given twice per day. For example, in a 100-lb child, 10ml twice a day for a total of 20ml should be considered. This dose has been frequently recommended by the author over the past five years without a single clinical report of side effects. Monitoring of applicable blood parameters should be implemented and include fatty acid profile analysis, liver functions, and bleeding time, prothrombin time (PT)/ partial thromboplastin time (PTT), or as per local protocols.Implications for critical or intensive care. Early nutritional intervention in TBI is underappreciated. Patients not fed within 5 and 7 days after TBI have a 2- and 4-fold increased likelihood of death, respectively; and decreasing amount of nutrition in the first 5 days is related to increased mortality rates.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3171/JNS/2008/109/7/0050", "ISSN" : "0022-3085", "PMID" : "18590432", "abstract" : "Traumatic brain injury (TBI) remains a serious public health crisis requiring continuous improvement in pre-hospital and inhospital care. This condition results in a hypermetabolic state that increases systemic and cerebral energy requirements, but achieving adequate nutrition to meet this demand has not been a priority in reducing death due to TBI. The effect of timing and quantity of nutrition on death within the first 2 weeks of injury was analyzed in a large prospective database of adult patients with severe TBI in New York State.", "author" : [ { "dropping-particle" : "", "family" : "H\u00e4rtl", "given" : "Roger", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gerber", "given" : "Linda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ni", "given" : "Quanhong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghajar", "given" : "Jamshid", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal Of Neurosurgery", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2008", "7" ] ] }, "page" : "50-56", "publisher" : "American Association of Neurological Surgeons", "title" : "Effect of early nutrition on deaths due to severe traumatic brain injury.", "type" : "article-journal", "volume" : "109" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(H\u00e4rtl, Gerber, Ni, & Ghajar, 2008)", "manualFormatting" : "(H\u00e4rtl, 2008)", "plainTextFormattedCitation" : "(H\u00e4rtl, Gerber, Ni, & Ghajar, 2008)", "previouslyFormattedCitation" : "(H\u00e4rtl, Gerber, Ni, & Ghajar, 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(H?rtl, 2008) Early enteral nutrition after brain injury can be accomplished by PEG or nasogastric tube, even in the emergency department. Of the 49 total recommendations published by the America Society for Parenteral and Enteral Nutrition and the Society of Critical Care Medicine, only two warrant Grade A recommendations, both of which state that immune-enhancing enteral formulations with ω-3FA should be used in critically ill surgical patients (including trauma).ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1177/0148607109335234", "ISSN" : "0148-6071", "PMID" : "19398613", "author" : [ { "dropping-particle" : "", "family" : "McClave", "given" : "Stephen a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martindale", "given" : "Robert G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vanek", "given" : "Vincent W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCarthy", "given" : "Mary", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roberts", "given" : "Pamela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Beth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ochoa", "given" : "Juan B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Napolitano", "given" : "Lena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cresci", "given" : "Gail", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JPEN. Journal of parenteral and enteral nutrition", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "277-316", "title" : "Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.).", "type" : "article-journal", "volume" : "33" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(McClave et al., 2009)", "manualFormatting" : "(McClave, 2009)", "plainTextFormattedCitation" : "(McClave et al., 2009)", "previouslyFormattedCitation" : "(McClave et al., 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(McClave, 2009) Similar recommendation exist in Europe.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.clnu.2006.01.015", "ISSN" : "0261-5614", "PMID" : "16698152", "abstract" : "Enhanced recovery of patients after surgery (\"ERAS\") has become an important focus of perioperative management. From a metabolic and nutritional point of view, the key aspects of perioperative care include: Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and if necessary tube feeding (TF) offers the possibility of increasing or ensuring nutrient intake in cases where food intake is inadequate. These guidelines are intended to give evidence-based recommendations for the use of ONS and TF in surgical patients. They were developed by an interdisciplinary expert group in accordance with officially accepted standards and are based on all relevant publications since 1980. The guideline was discussed and accepted in a consensus conference. EN is indicated even in patients without obvious undernutrition, if it is anticipated that the patient will be unable to eat for more than 7 days perioperatively. It is also indicated in patients who cannot maintain oral intake above 60% of recommended intake for more than 10 days. In these situations nutritional support should be initiated without delay. Delay of surgery for preoperative EN is recommended for patients at severe nutritional risk, defined by the presence of at least one of the following criteria: weight loss >10-15% within 6 months, BMI<18.5 kg/m(2), Subjective Global Assessment Grade C, serum albumin <30 g/l (with no evidence of hepatic or renal dysfunction). Altogether, it is strongly recommended not to wait until severe undernutrition has developed, but to start EN therapy early, as soon as a nutritional risk becomes apparent.", "author" : [ { "dropping-particle" : "", "family" : "Weimann", "given" : "a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Braga", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harsanyi", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laviano", "given" : "a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ljungqvist", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soeters", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jauch", "given" : "K W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kemen", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hiesmayr", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Horbach", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuse", "given" : "E R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vestweber", "given" : "K H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical nutrition Edinburgh Scotland", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2006", "4" ] ] }, "page" : "224-244", "title" : "ESPEN Guidelines on Enteral Nutrition: Surgery including organ transplantation.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Weimann et al., 2006)", "manualFormatting" : "(Weimann, 2006)", "plainTextFormattedCitation" : "(Weimann et al., 2006)", "previouslyFormattedCitation" : "(Weimann et al., 2006)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Weimann, 2006)One recent meta-analysis concludes early initiation of nutritional support for TBI patients can decrease mortality, reduce complications and facilitate recovery. Wang et al, also conclude that parenteral nutrition appears to be superior to enteral and immune-modulating formulas seem to be superior to standard formulas in reducing infectious complications.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Xiang Wang,#1 Yan Dong,#1,2 Xi Han,3 Xiang-Qian Qi,1 Cheng-Guang Huang,1,* and Li-Jun Hou1,*", "author" : [ { "dropping-particle" : "", "family" : "X Wang", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dong", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Han", "given" : "X", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qi", "given" : "XQ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huang", "given" : "CG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hou", "given" : "LJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS One", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "e58838", "title" : "Nutritional Support for Patients Sustaining Traumatic Brain Injury: A Systematic Review and Meta-Analysis of Prospective Studies", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(X Wang et al., 2013)", "manualFormatting" : "(Wang, 2013)", "plainTextFormattedCitation" : "(X Wang et al., 2013)", "previouslyFormattedCitation" : "(X Wang et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Wang, 2013) One reason why enteral nutrition is favored over parenteral nutrition in current clinical practice may be because of the formulations themselves. Unfortunately, the only available FDA-approved parenteral lipid emulsion in the United States is composed of soybean oil (Intralipid, Fresenius Kabi),ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Nandivada", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carlson", "given" : "SJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "MI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cowan", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gura", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puder", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Advances in Nutrition", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "711-7", "title" : "Treatment of parenteral nutrition-associated liver disease: the role of lipid emulsions", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Nandivada et al., 2013)", "manualFormatting" : "(Nandivada, 2013)", "plainTextFormattedCitation" : "(Nandivada et al., 2013)", "previouslyFormattedCitation" : "(Nandivada et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Nandivada, 2013) whereas in Europe, several formulations currently contain fish oil. As noted previously, soybean oil is a major source of AA and the pro-inflammatory properties of AA likely are more harmful than good. In 2006, Heller and his German colleagues report one study evaluating the use of a fish oil parenteral formulation in a total of 661 patients from 82 German hospitals. The retrospective study included 276 patients with abdominal sepsis, 59 after multiple trauma, and 18 with severe head injury. Administration of omega-3 fatty acid may reduced mortality, antibiotic use, and length of hospital.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/M.0000206309.83570.45", "ISSN" : "0090-3493", "PMID" : "16484909", "abstract" : "OBJECTIVE: Supplementation of clinical nutrition with omega-3 fatty acid in fish oil exerts immune-modulating and organ-protective effects, even after short-term application. The aim of this study was to evaluate dose-dependent effects of parenteral supplementation of a 10% fish oil emulsion (Omegaven, Fresenius-Kabi, Bad Homburg, Germany) on diagnosis- and organ failure-related outcome. DESIGN: Prospective, open label, multiple-center trial. PATIENTS AND METHODS: A total of 661 patients from 82 German hospitals receiving total parenteral nutrition for > or =3 days were enrolled in this study. The sample included 255 patients after major abdominal surgery, 276 with peritonitis and abdominal sepsis, 16 with nonabdominal sepsis, 59 after multiple trauma, 18 with severe head injury, and 37 with other diagnoses. The primary study end point was survival; secondary end points were length of hospital stay and use of antibiotics with respect to the primary diagnosis and the extent of organ failure. Multiple quasi-linear and logistic regression models were used for calculating diagnosis-related fish oil doses associated with best outcome. RESULTS: The patients enrolled in this survey were (mean sd) 62.8 16.5 yrs old, with a body mass index of 25.1 4.2 and Simplified Acute Physiology Score (SAPS) II score of 32.2 13.6. Length of hospital stay was 29.1 18.7 days (12.5 14.8 days in the intensive care unit). Total parenteral nutrition, including fish oil (mean, 0.11 g.kg(-1).day(-1)), was administered for 8.7 7.5 days and lowered hospital mortality as predicted by Simplified Acute Physiology Score II from 18.9% (95% confidence interval, 17.4-20.4%) to 12.0% (p < .001). The fish oil dose.kg.day did correlate with beneficial outcome (intensive care unit stay, hospital stay, mortality). Fish oil had the most favorable effects on survival, infection rates, and length of stay when administered in doses between 0.1 and 0.2 g.kg(-1).day(-1). Lower antibiotic demand by 26% was observed when doses of 0.15-0.2 g.kg(-1).day(-1) were infused as compared with doses of <0.05 g.kg(-1).day(-1). After peritonitis and abdominal sepsis, multiple quasi-linear regression models revealed a fish oil dose for minimizing intensive care unit stay of 0.23 g.kg(-1).day(-1) and an inverse linear relationship between dosage and intensive care unit stay in major abdominal surgery. CONCLUSION: Administration of omega-3 fatty acid may reduce mortality, antibiotic use, and length of hospital stay in\u2026", "author" : [ { "dropping-particle" : "", "family" : "Heller", "given" : "Axel R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "R\u00f6ssler", "given" : "Susann", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Litz", "given" : "Rainer J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stehr", "given" : "Sebastian N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heller", "given" : "Susanne C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koch", "given" : "Rainer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koch", "given" : "Thea", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Critical Care Medicine", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2006", "4" ] ] }, "page" : "972-979", "title" : "Omega-3 fatty acids improve the diagnosis-related clinical outcome.", "type" : "article-journal", "volume" : "34" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Heller et al., 2006)", "manualFormatting" : "(Heller, 2006)", "plainTextFormattedCitation" : "(Heller et al., 2006)", "previouslyFormattedCitation" : "(Heller et al., 2006)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Heller, 2006) Mayer and Seeger reviewed the literature in 2008 and concluded that enteral nutrition with ω-3FA improved ventilation time in patients with acute lung injury and study reduced mortality in septic patients. They noted that using a high dose, short-term infusion of fish oil-based lipid emulsion improved immunologic parameters and decreased length of stay in surgical patients by balancing the negative effects of ω-6FA.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "PURPOSE OF REVIEW: The aim of this review is to discuss recent advances in the role of n-3 lipids derived from fish oil in clinical nutrition in an intensive care setting. RECENT FINDINGS: Fish oil supplies n-3 fatty acids which compete with arachidonic acid (n-6) for the conversion to lipid mediators, influence lipid-bound second messenger generation and dependent cellular functions, and are a source for resolvins necessary for the resolution of inflammation. Enteral nutrition with n-3 fatty acids improved ventilation time in patients with acute lung injury and in one study reduced mortality in septic patients. Using a high-dose short-term infusion of fish oil-based lipid emulsion, rapid immunologic changes and effects on the endotoxin-induced stress response may be achieved. Inclusion of n-3 fatty acids in parenteral nutrition improved immunologic parameters and length of stay in surgical patients. SUMMARY: Inclusion of fish oil in nutrition may influence the immune response and clinical outcomes by balancing the negative effects of n-6 fatty acids. Application as a part of enteral immunonutrition in surgical or acute respiratory distress syndrome patients and in lipid emulsions in surgical patients has beneficial effects. In septic patients, data on enteral use are highly controversial. Prospective data from randomized trials, however, are lacking.", "author" : [ { "dropping-particle" : "", "family" : "Mayer", "given" : "Konstantin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seeger", "given" : "Werner", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Opinion in Clinical Nutrition and Metabolic Care", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "121-127", "title" : "Fish oil in critical illness.", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Mayer & Seeger, 2008)", "manualFormatting" : "(Mayer, 2008)", "plainTextFormattedCitation" : "(Mayer & Seeger, 2008)", "previouslyFormattedCitation" : "(Mayer & Seeger, 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Mayer, 2008) More recently, two reviews involving Heller and Mayer provide further evidence that parenteral nutrition with fish oil based emulsions are not only safe and effective in reducing the infection rate and hospital/ICU stay in surgical and ICU patients, but cost effective in Italian, French, German, and UK hospitals.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Pradelli", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eandi", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Povero", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayer", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muscaritoli", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heller", "given" : "AR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fries-Schaffner", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clin Nutr", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "Epub ahead of print", "title" : "Cost-effectiveness of omega-3 fatty acid supplements in parenteral nutrition therapy in hospitals: A discrete event simulation mode", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Pradelli et al., 2013)", "manualFormatting" : "(Pradelli, 2013)", "plainTextFormattedCitation" : "(Pradelli et al., 2013)", "previouslyFormattedCitation" : "(Pradelli et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Pradelli, 2013)Since 2004, European fish oil based lipid parenteral emulsions have been used at Boston Children’s Hospital under investigational new drug status for the treatment of parenteral nutrition-associated liver disease (PNALD) in neonates. The use of parenteral soybean oil is strongly associated with the development of PNALD, cholestasis, and cirrhosis. Without transplant, mortality in this population approaches 100%. Switching infants to a fish oil based emulsion results in resolution of cholestasis, stabilization or improvement of PNALD, and a noticeable impact on decreasing the incidence of morbidity and mortality.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chang", "given" : "MI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puder", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gura", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nutrients", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "1828\u20131850", "title" : "The Use of Fish Oil Lipid Emulsion in the Treatment of Intestinal Failure Associated Liver Disease (IFALD)", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Nandivada", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "MI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Potemkin", "given" : "AK", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carlson", "given" : "SJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cowan", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O\u02bcloughlin", "given" : "AA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mitchell", "given" : "PD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gura", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puder", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of Surgery", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "172-9", "title" : "The natural history of cirrhosis from parenteral nutrition-associated liver disease after resolution of cholestasis with parenteral fish oil therapy", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chang, Puder, & Gura, 2012; Nandivada et al., 2015)", "manualFormatting" : "(Chang, 2012; Nandivada, 2015)", "plainTextFormattedCitation" : "(Chang, Puder, & Gura, 2012; Nandivada et al., 2015)", "previouslyFormattedCitation" : "(Chang, Puder, & Gura, 2012; Nandivada et al., 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chang, 2012; Nandivada, 2015) The Omega Protocol for Brain Health. As noted previously, >80% of TBI are mild not requiring hospitalization and may not even seek medical treatment. These patients are typically capable of swallowing capsules, liquid, or gels on their own. Through several years of clinical experience, the Omega Protocol for Brain Health has been used, recommended, or experienced by thousands of people across the globe including a large number of American university athletic programs following a concussion as well as other brain health issues. The protocol begins with fifteen (15) capsules a day divided into three doses of five (5) capsules (or one teaspoon of liquid concentrate) starting as soon as possible following an injury. This provides approximately 3000mg of combined EPA and DHA per dose or a total of 9000mg daily. It is suggested that patients stay on this dose for one week or until they no longer experience concussion or brain injury symptoms [TABLE 32-1]. In some cases, this is less than a week, in others, greater than a week. A taper is suggested to decrease to two doses a day for a week before going to a single dose per week. [TABLE 32-3] Clinically, many patients see a marked improvement in symptoms within 1-2 days. Every individual is different. This protocol has been developed as a guideline and patients and their healthcare provider may consider adjusting the dosage. For example, if the injury is more severe or happened months or years prior, the patient may find they need to be on the higher doses for a longer period of time.While clinical experience is obviously important, scientific research needs to catch up to the anecdotal reports. There are several human clinical trials underway to evaluate ω-3FA following a concussion or for PCS, but one of the first such studies published was done by Lewis, et al., looking at the use of five weeks of high dose (9000mg of combined EPA and DHA) in seven military veterans having sustained improvised explosive device (IED) blast injury and having a positive symptom history consistent with PCS for greater than six months. The veterans were evaluated pre- and post-therapy with a clinical interview and baseline 19 channel EEG and three lead electrocardiogram. The assessment results incorporated neurocognitive screening, quantitative electroencephalogram (qEEG), event related potentials (ERP), and heart rate variability (HRV) measures. Based on the significant results of ω -3FA on HRV total power and auditory processing ERP, it appears that ω -3FA have a positive impact on both central and autonomic nervous system functions in patients with PCS. Although other measures of HRV, sensory and cognitive ERP, and qEEG amplitude were not found to have a significant change from the intervention, the pilot study only assessed a small number of subjects but all measures were trending towards statistical improvement.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Lewis", "given" : "MD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hagedorn", "given" : "MK", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hagedorn", "given" : "CR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hagedorn", "given" : "NA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hagedorn", "given" : "DW", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Military Medicine", "id" : "ITEM-1", "issue" : "In publication", "issued" : { "date-parts" : [ [ "2015" ] ] }, "title" : "Electrophysiology improvements in veterans with post-concussive symptoms using omega-3 nutritional therapy: a pilot study", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(MD Lewis, Hagedorn, Hagedorn, Hagedorn, & Hagedorn, 2015)", "manualFormatting" : "(Lewis, 2015)", "plainTextFormattedCitation" : "(MD Lewis, Hagedorn, Hagedorn, Hagedorn, & Hagedorn, 2015)", "previouslyFormattedCitation" : "(MD Lewis, Hagedorn, Hagedorn, Hagedorn, & Hagedorn, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lewis, 2015)Potential harmful effects Potential harmful effects of ω-3FA have been described in the literature.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Hasadsri", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "BH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "JV", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erdman", "given" : "JW", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Llano", "given" : "DA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barbey", "given" : "AK", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wszalek", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharrock", "given" : "MF", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "HJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neurotrauma", "id" : "ITEM-1", "issue" : "30(11)", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "897-906", "title" : "Omega-3 fatty acids as a putative treatment for traumatic brain injury", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hasadsri et al., 2013)", "manualFormatting" : "(Hasadsri, 2013)", "plainTextFormattedCitation" : "(Hasadsri et al., 2013)", "previouslyFormattedCitation" : "(Hasadsri et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hasadsri, 2013) By virtue of having several double bonds, ω-3FA have high susceptibility to lipid peroxidation. However, this has never been shown to be an issue clinically. Development of a fatty liver is often cited as a potential issue as well, however, the experience at Boston Children’s Hospital over the past decade demonstrates that ω-3FA have a beneficial effect on liver health. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chang", "given" : "MI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puder", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gura", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nutrients", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "1828\u20131850", "title" : "The Use of Fish Oil Lipid Emulsion in the Treatment of Intestinal Failure Associated Liver Disease (IFALD)", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Nandivada", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "MI", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Potemkin", "given" : "AK", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carlson", "given" : "SJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cowan", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O\u02bcloughlin", "given" : "AA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mitchell", "given" : "PD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gura", "given" : "KM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puder", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of Surgery", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "172-9", "title" : "The natural history of cirrhosis from parenteral nutrition-associated liver disease after resolution of cholestasis with parenteral fish oil therapy", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chang et al., 2012; Nandivada et al., 2015)", "manualFormatting" : "(Chang, 2012; Nandivada, 2015)", "plainTextFormattedCitation" : "(Chang et al., 2012; Nandivada et al., 2015)", "previouslyFormattedCitation" : "(Chang et al., 2012; Nandivada et al., 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chang, 2012; Nandivada, 2015)Due to the established anti-thrombotic action of these compounds, it is commonly believed they may increase the risk of excessive bleeding or even hemorrhagic stroke. Theoretically, the biochemistry of ω-3FAs tells us this should be true. However, that has never been shown to be of clinical concern in any clinical trial reported in the literature. Several surgical studies covered previously using ω-3FAs demonstrate their benefit without any adverse events.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/M.0000206309.83570.45", "ISSN" : "0090-3493", "PMID" : "16484909", "abstract" : "OBJECTIVE: Supplementation of clinical nutrition with omega-3 fatty acid in fish oil exerts immune-modulating and organ-protective effects, even after short-term application. The aim of this study was to evaluate dose-dependent effects of parenteral supplementation of a 10% fish oil emulsion (Omegaven, Fresenius-Kabi, Bad Homburg, Germany) on diagnosis- and organ failure-related outcome. DESIGN: Prospective, open label, multiple-center trial. PATIENTS AND METHODS: A total of 661 patients from 82 German hospitals receiving total parenteral nutrition for > or =3 days were enrolled in this study. The sample included 255 patients after major abdominal surgery, 276 with peritonitis and abdominal sepsis, 16 with nonabdominal sepsis, 59 after multiple trauma, 18 with severe head injury, and 37 with other diagnoses. The primary study end point was survival; secondary end points were length of hospital stay and use of antibiotics with respect to the primary diagnosis and the extent of organ failure. Multiple quasi-linear and logistic regression models were used for calculating diagnosis-related fish oil doses associated with best outcome. RESULTS: The patients enrolled in this survey were (mean sd) 62.8 16.5 yrs old, with a body mass index of 25.1 4.2 and Simplified Acute Physiology Score (SAPS) II score of 32.2 13.6. Length of hospital stay was 29.1 18.7 days (12.5 14.8 days in the intensive care unit). Total parenteral nutrition, including fish oil (mean, 0.11 g.kg(-1).day(-1)), was administered for 8.7 7.5 days and lowered hospital mortality as predicted by Simplified Acute Physiology Score II from 18.9% (95% confidence interval, 17.4-20.4%) to 12.0% (p < .001). The fish oil dose.kg.day did correlate with beneficial outcome (intensive care unit stay, hospital stay, mortality). Fish oil had the most favorable effects on survival, infection rates, and length of stay when administered in doses between 0.1 and 0.2 g.kg(-1).day(-1). Lower antibiotic demand by 26% was observed when doses of 0.15-0.2 g.kg(-1).day(-1) were infused as compared with doses of <0.05 g.kg(-1).day(-1). After peritonitis and abdominal sepsis, multiple quasi-linear regression models revealed a fish oil dose for minimizing intensive care unit stay of 0.23 g.kg(-1).day(-1) and an inverse linear relationship between dosage and intensive care unit stay in major abdominal surgery. CONCLUSION: Administration of omega-3 fatty acid may reduce mortality, antibiotic use, and length of hospital stay in\u2026", "author" : [ { "dropping-particle" : "", "family" : "Heller", "given" : "Axel R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "R\u00f6ssler", "given" : "Susann", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Litz", "given" : "Rainer J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stehr", "given" : "Sebastian N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heller", "given" : "Susanne C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koch", "given" : "Rainer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koch", "given" : "Thea", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Critical Care Medicine", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2006", "4" ] ] }, "page" : "972-979", "title" : "Omega-3 fatty acids improve the diagnosis-related clinical outcome.", "type" : "article-journal", "volume" : "34" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "abstract" : "PURPOSE OF REVIEW: The aim of this review is to discuss recent advances in the role of n-3 lipids derived from fish oil in clinical nutrition in an intensive care setting. RECENT FINDINGS: Fish oil supplies n-3 fatty acids which compete with arachidonic acid (n-6) for the conversion to lipid mediators, influence lipid-bound second messenger generation and dependent cellular functions, and are a source for resolvins necessary for the resolution of inflammation. Enteral nutrition with n-3 fatty acids improved ventilation time in patients with acute lung injury and in one study reduced mortality in septic patients. Using a high-dose short-term infusion of fish oil-based lipid emulsion, rapid immunologic changes and effects on the endotoxin-induced stress response may be achieved. Inclusion of n-3 fatty acids in parenteral nutrition improved immunologic parameters and length of stay in surgical patients. SUMMARY: Inclusion of fish oil in nutrition may influence the immune response and clinical outcomes by balancing the negative effects of n-6 fatty acids. Application as a part of enteral immunonutrition in surgical or acute respiratory distress syndrome patients and in lipid emulsions in surgical patients has beneficial effects. In septic patients, data on enteral use are highly controversial. Prospective data from randomized trials, however, are lacking.", "author" : [ { "dropping-particle" : "", "family" : "Mayer", "given" : "Konstantin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seeger", "given" : "Werner", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Opinion in Clinical Nutrition and Metabolic Care", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "121-127", "title" : "Fish oil in critical illness.", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Pradelli", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mayer", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muscaritoli", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heller", "given" : "AR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Critical Care", "id" : "ITEM-3", "issue" : "5", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "R184", "title" : "n-3 fatty acid-enriched parenteral nutrition regimens in elective surgical and ICU patients: a meta-analysis", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Heller et al., 2006; Mayer & Seeger, 2008; Pradelli, Mayer, Muscaritoli, & Heller, 2012)", "manualFormatting" : "(Heller, 2006; Mayer, 2008; Pradelli, 2012)", "plainTextFormattedCitation" : "(Heller et al., 2006; Mayer & Seeger, 2008; Pradelli, Mayer, Muscaritoli, & Heller, 2012)", "previouslyFormattedCitation" : "(Heller et al., 2006; Mayer & Seeger, 2008; Pradelli, Mayer, Muscaritoli, & Heller, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Heller, 2006; Mayer, 2008; Pradelli, 2012)The anti-thrombotic nature is one of the properties that makes ω-3FA effective in decreasing mortality, particularly cardiovascular mortality where the effect can be more beneficial than statins.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Studer", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "M Briel", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leimenstoll", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glass", "given" : "TR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bucher", "given" : "HC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zuo", "given" : "CS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arch Intern Med", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "725-30", "title" : "Effect of different antilipidemic agents and diets on mortality: a systematic review.", "type" : "article-journal", "volume" : "165" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Studer et al., 2005)", "manualFormatting" : "(Studer, 2005)", "plainTextFormattedCitation" : "(Studer et al., 2005)", "previouslyFormattedCitation" : "(Studer et al., 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Studer, 2005) Multiple clinical trials have shown that high dose fish oil consumption is safe, even in patients receiving other agents that may increase the risk of bleeding, such as aspirin and warfarin.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Hasadsri", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "BH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "JV", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erdman", "given" : "JW", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Llano", "given" : "DA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barbey", "given" : "AK", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wszalek", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharrock", "given" : "MF", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "HJ", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neurotrauma", "id" : "ITEM-1", "issue" : "30(11)", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "897-906", "title" : "Omega-3 fatty acids as a putative treatment for traumatic brain injury", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Hasadsri et al., 2013)", "manualFormatting" : "(Hasadsri, 2013)", "plainTextFormattedCitation" : "(Hasadsri et al., 2013)", "previouslyFormattedCitation" : "(Hasadsri et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hasadsri, 2013) Clinical data suggests that DHA at doses at least up to 6 g/day does not have deleterious effects on platelet aggregation or other clotting parameters, and fish oil does not augment aspirin-induced inhibition of blood clotting. This point is worth examining further. It is standard of care that most critically ill and injured patients are put on subcutaneous heparin, or similar, to prevent deep vein thrombosis while immobile. Recently, Farooqui et al, examined the use of blood thinning pharmaceuticals and concluded they are safe, do not increase the risk of intracranial hemorrhage, and decreases the rate of deep vein thrombosis and pulmonary embolism.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Farooqui", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hiser", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barnes", "given" : "SL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Litofsky", "given" : "NS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neurosurg", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "1576-82", "title" : "Safety and efficacy of early thromboembolism chemoprophylaxis after intracranial hemorrhage from traumatic brain injury", "type" : "article-journal", "volume" : "119" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Farooqui, Hiser, Barnes, & Litofsky, 2013)", "manualFormatting" : "(Farooqui, 2013)", "plainTextFormattedCitation" : "(Farooqui, Hiser, Barnes, & Litofsky, 2013)", "previouslyFormattedCitation" : "(Farooqui, Hiser, Barnes, & Litofsky, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Farooqui, 2013) Potent blood thinners used in this protocol (heparin and Lovenox) completely block the enzymes responsible for allowing the platelets to clot. ω-3FA potentiate the body’s natural anti-clotting abilities rather than blocking enzymatic processes and add the ability to modulate neuroinflammation, decrease apoptosis, and start synaptogenesis. Ironically, most doctors will not use ω-3FA citing that high doses of ω-3FA decrease the ability of blood to clot and increase a patient’s risk of bleeding, yet immediately put their ICU patients on potent pharmaceutical blood thinners that increase the risk far greater than that of ω-3FA.Conclusions and Future Directions TBI, with its diverse heterogeneity and prolonged secondary pathogenesis, remains a clinical challenge to clinician, patients, and their families. Current medical management of TBI patients appropriately focuses on specialized prehospital care, intensive acute clinical care, and long-term rehabilitation, but lacks clinically proven effective management with neuroprotective and neuroregenerative agents.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Xiong", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mahmood", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chopp", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Expert Opin Emerg Drugs", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "67-84", "title" : "Emerging treatments for traumatic brain injury", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Xiong, Mahmood, & Chopp, 2009)", "manualFormatting" : "(Xiong, 2009)", "plainTextFormattedCitation" : "(Xiong, Mahmood, & Chopp, 2009)", "previouslyFormattedCitation" : "(Xiong, Mahmood, & Chopp, 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Xiong, 2009) Clinical studies thus far have failed to identify an effective treatment strategy as they typically have targeted single enzymatic factors in an attempt to identify a pharmacologic target rather than considering multiple mechanisms of injury with a more holistic approach. The concept of a ‘magic bullet’ focused on a single target is not helpful, and instead a combination of targets controlling aspects of neuroprotection, neuroinflammation, and regeneration is needed. ω-3FA offer the advantage of this poly-target approach.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Michael-Titus", "given" : "AT", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Priestley", "given" : "JV", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Trends Neurosci", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "30-38", "title" : "Omega-3 fatty acids and traumatic neurological injury: from neuroprotection to neuroplasticity?", "type" : "article-journal", "volume" : "37" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(A. Michael-Titus & Priestley, 2014)", "manualFormatting" : "(Michael-Titus, 2014)", "plainTextFormattedCitation" : "(A. Michael-Titus & Priestley, 2014)", "previouslyFormattedCitation" : "(A. Michael-Titus & Priestley, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Michael-Titus, 2014) Although further clinical trial research is needed to establish the true advantage of using ω-3FA in severe TBI, mild TBI/concussions, and post-concussion syndrome, there is a growing body of strong preclinical evidence and clinical experience suggests that benefits may be possible from aggressively adding substantial amounts of ω-3FA to optimize the nutritional foundation of severe TBI patients. Recovery from TBI may be hindered by our modern, pro-inflammatory diet. An optimal nutritional regimen to overcome the ω-6FA dominance must be in place if the brain is to be given the best opportunity to repair itself. Administration of substantial and optimal doses of ω-3FA earlier in the course of TBI, even in pre-injury phase of susceptible people such as soldiers and athletes, as well as the pre-hospital or emergency department setting, has the potential to improve outcomes from this potentially devastating public health problem. As the father of one severe TBI survivor says, “Conventional medicine only takes survivors of severe TBI so far, often ending at the nursing home door, or heavily medicated at home, facing long empty hours, and overwhelming family resources. Unconventional therapies are not merely a reasonable option, they are a necessity.”ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Goldstein", "given" : "Joel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "number-of-pages" : "242", "publisher" : "Potomac Books", "publisher-place" : "Dulles, Virginia, USA", "title" : "No Stone Unturned: A Father's Memoir of His Son's Encounter with Traumatic Brain Injury", "type" : "book" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Goldstein, 2012)", "plainTextFormattedCitation" : "(Goldstein, 2012)", "previouslyFormattedCitation" : "(Goldstein, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Goldstein, 2012) With evidence of unsurpassed safety and tolerability, ω-3FA should be considered mainstream, conventional medicine, if conventional medicine can overcome its inherent bias against nutritional, non-pharmacologic therapies.ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY Armonda, R. A., Bell, R. S., Vo, A. H., Ling, G., DeGraba, T. J., Crandall, B., … Campbell, W. W. (2006). Wartime traumatic cerebral vasospasm: recent review of combat casualties. Neurosurgery, 59(6), 1215–1225.Armstead, W. (1998). Brain injury impairs prostaglandin cerebrovasodilation. Journal of Neurotrauma, 15, 721–729.Armstead, W. (1999). Superoxide generation links protein kinase C activation to imparired ATP-sensitive K+ channle function after brain injury. Stroke: A Journal of Cerebral Circulation1, 30, 153–159.Bailes, J. E., & Mills, J. D. (2010). Docosahexaenoic acid reduces traumatic axonal injury in a rodent head injury model. Journal Of Neurotrauma, 27(9), 1617–1624. Belayev, L., Marcheselli, V. L., Khoutorova, L., Rodriguez De Turco, E. B., Busto, R., Ginsberg, M. D., & Bazan, N. G. (2005). Docosahexaenoic acid complexed to albumin elicits high-grade ischemic neuroprotection. Stroke: A Journal of Cerebral Circulation, 36(1), 118–123. Berman, D., Liu, Y., Barks, J., & Mozurkewich, E. (2010). Treatment with docosahexaenoic acid after hypoxia-ischemia improves forepaw placing in a rat model of perinatal hypoxia-ischemia. American Journal of Obstetrics and Gynecology, 203(4), 385.e1–5.Berman, D., Mozurkewich, E., Liu, Y., Shangguan, Y., Barks, J., & Silverstein, F. (2013). Docosahexaenoic acid augments hypothermic neuroprotection in a neonatal rat asphyxia model. Neonatology, 104(1), 71–78.Berman, D. R., Mozurkewich, E., Liu, Y., & Barks, J. (2009). Docosahexaenoic acid pretreatment confers neuroprotection in a rat model of perinatal cerebral hypoxia-ischemia. American Journal of Obstetrics and Gynecology, 200(3), 305.e1–e6. Bradbury, J. (2011). Docosahexaenoic Acid (DHA): An Ancient Nutrient for the Modern Human Brain. Nutrients, 3, 529–554.Chang, M., Puder, M., & Gura, K. (2012). The Use of Fish Oil Lipid Emulsion in the Treatment of Intestinal Failure Associated Liver Disease (IFALD). Nutrients, 4(12), 1828–1850.CY Chang, Kuan, Y., Li, J., Chen, W., Ou, Y., Pan, H., … Chen, C. (2013). Docosahexaenoic acid reduces cellular inflammatory response following permanent focal cerebral ischemia in rats. Journal of Nutritinoal Biochemistry, 24(12), 2127–37.De Souza, M., Conde, C., Lafl?r, C., Sicuro, F., & Bouskela, E. (2015). n-3 PUFA induce microvascular protective changes during ischemia/reperfusion. Lipids, 50(1), 23–37.Desai, A., Kevala, K., & Kim, H. (2014). Depletion of brain docosahexaenoic acid impairs recovery from traumatic brain injury. PLoS One, 27(9), e86472.Diaz-Arrastia, R., Kochanek, P., Bergold, P., Kenney, K., Marx, C., Grimes, J., … Salzer, W. (2014). Pharmacotherapy of Traumatic Brain Injury: State of the Science and the Road Forward Report of the Department of Defense Neurotrauma Pharmacology Workgroup. Journal of Neurotrauma, 31(2):135-158.Eady, T., Khoutorova, L., Anzola, D., Hong, S., Obenaus, A., Mohd-Yusof, A., … Belayev, L. (2013). Acute treatment with docosahexaenoic acid complexed to albumin reduces injury after a permanent focal cerebral ischemia in rats. PLoS One, 8(10), e77237.Eady, T., Khoutorova, L., Atkins, K., Bazan, N., & Belayev, L. (2012). Docosahexaenoic acid complexed to human albumin in experimental stroke: neuroprotective efficacy with a wide therapeutic window. Experimental and Translational Stroke Medicine, 4(1), 19.Eady, T., Khoutorova, L., Obenaus, A., Mohd-Yusof, A., Bazan, N., & Belayev, L. (2014). Docosahexaenoic acid complexed to albumin provides neuroprotection after experimental stroke in aged rats. Neurobiol Dis, 62, 1–7.EFSA. (2012). Scientific Opinion on the Tolerable Upper Intake Level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA Journal, 10(7), 2815. Retrieved from , A., & Loane, D. (2015). Chronic Neurodegeneration After Traumatic Brain Injury: Alzheimer Disease, Chronic Traumatic Encephalopathy, or Persistent Neuroinflammation? Neurotherapeutics, 12(1), 143–50.Farooqui, A., Hiser, B., Barnes, S., & Litofsky, N. (2013). Safety and efficacy of early thromboembolism chemoprophylaxis after intracranial hemorrhage from traumatic brain injury. J Neurosurg, 119(6), 1576–82.Faul, M., Xu, L., Wald, M., & Coronado, V. (2010). Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths 2002-2006. Centers for Disease Control and Prevention. Retrieved from , J. D., Cordero, K., Llán, M. S., & De Leon, M. (2013). Dietary Omega-3 Polyunsaturated Fatty Acids Improve the Neurolipidome and Restore the DHA Status while Promoting Functional Recovery after Experimental Spinal Cord Injury. Journal of Neurotrauma, 16, 1–16. G Rosenberg. (1999). Ischemic Brain Edem. Progress in Cardiovascular Diseases, 42(3), 209–16.Gavett, B., Stern, R., & McKee, A. (2011). Chronic Traumatic Encephalopathy: A Potential Late Effect of Sport-Related Concussive and Subconcussive Head Trauma. Clinical Sports Medicine, 30(1), 179–xi.Goldstein, J. (2012). No Stone Unturned: A Father’s Memoir of His Son's Encounter with Traumatic Brain Injury. Dulles, Virginia, USA: Potomac Books.Gomez-Pinilla, F. (2008). The influences of diet and exercise on mental health through hormesis. Ageing Research Reviews, 7(1), 49–62. H?rtl, R., Gerber, L. M., Ni, Q., & Ghajar, J. (2008). Effect of early nutrition on deaths due to severe traumatic brain injury. Journal Of Neurosurgery, 109(1), 50–56. Hasadsri, L., Wang, B., Lee, J., Erdman, J., Llano, D., Barbey, A., … Wang, H. (2013). Omega-3 fatty acids as a putative treatment for traumatic brain injury. Journal of Neurotrauma, 1(30(11)), 897–906.Heller, A. R., R?ssler, S., Litz, R. J., Stehr, S. N., Heller, S. C., Koch, R., & Koch, T. (2006). Omega-3 fatty acids improve the diagnosis-related clinical outcome. Critical Care Medicine, 34(4), 972–979. Hemphill, M., Dabiri, B., Gabriele, S., Kerscher, L., Franck, C., Goss, J., … Wanunu, M. (2011). A Possible Role for Integrin Signaling in Diffuse Axonal Injury. PLoS ONE, 6(7), e2289.Hong, S., Belayev, L., Khoutorova, L., Obenaus, A., & Bazan, N. (2013). Docosahexaenoic acid confers enduring neuroprotection in experimental stroke. Journal of Neurological Sciences, 15(338(1-2)), 135–41.Hong, S., Khoutorova, L., Bazan, N., & Belayev, L. (2015). Docosahexaenoic acid improves behavior and attenuates blood-brain barrier injury induced by focal cerebral ischemia in rats. Experimental and Translational Stroke Medicine, 7(1), 3–13.Iliff, J., Chen, M., Plog, B., Zeppenfeld, D., Soltero, M., Yang, L., … Nedergaard, M. (2014). Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. Journal of Neuroscience, 34(49), 16180–93.Jotwani, V., & Harmon, H. (2010). Postconcussion syndrome in athletes. Current Sports Medicine Report, 9(1), 21–26.Katz, R. (2011). Investigational New Drug submission. Silver Spring, MD. Retrieved from media/fda.pdf?Kochanek, P., Clark, R., & Jenkins, L. (2007). TBI: Pathology. In N. Zasler, D. Katz, & R. Zafonte (Eds.), Brain injury medicine: principles and practice (pp. 81–92). New York: Demos Medical Publishing, LLC.Lee, B., & Newberg, A. (2005). Neuroimaging in traumatic brain imaging. J American Society for Experimental Neurotherapeutics, 2, 372–383.Lewis, M., Ghassemi, P., & Hibbeln, J. (2013). Therapeutic use of omega-3 fatty acids in severe head trauma. Am J Emerg Med, 31(1), 5–8.Lewis, M., Hagedorn, M., Hagedorn, C., Hagedorn, N., & Hagedorn, D. (2015). Electrophysiology improvements in veterans with post-concussive symptoms using omega-3 nutritional therapy: a pilot study. Military Medicine, (In publication).Ling, G., Bandak, F., Armonda, R., Grant, G., & Ecklund, J. (2009). Explosive blast neurotrauma. Journal Of Neurotrauma, 26(6), 815–825. Ling, G., & Marshall, S. (2008). Management of traumatic brain injury in the intensive care unit. Neurologic Clinics, 26(2), viii.Ling, H., Hardy, J., & Zetterberg, H. (2015). Neurological consequences of traumatic brain injuries in sports. Molecular and Cellular Neuroscience, 66(Pt B), 114–22.Louveau, A., Smirnov, I., Keyes, T., Eccles, J., Rouhani, S., Peske, J., … Kipnis, J. (2015). Structural and functional features of central nervous system lymphatic vessels. Nature, 523(7560), 337–41.Mayer, K., & Seeger, W. (2008). Fish oil in critical illness. Current Opinion in Clinical Nutrition and Metabolic Care, 11(2), 121–127. McClave, S. a, Martindale, R. G., Vanek, V. W., McCarthy, M., Roberts, P., Taylor, B., … Cresci, G. (2009). Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN. Journal of Parenteral and Enteral Nutrition, 33(3), 277–316. Meythaler, J., Peduzzi, J., Eleftheriou, E., & Novack, T. (2001). Current concepts: diffuse axonal injury-associated traumatic brain injury. Archives of Physical Medicine and Rehabilitation, 82(10), 1461–71.Michael-Titus, A., & Priestley, J. (2014). Omega-3 fatty acids and traumatic neurological injury: from neuroprotection to neuroplasticity? Trends in Neuroscience, 37(1), 30–38.Michael-Titus, A. T. (2007). Omega-3 fatty acids and neurological injury. Prostaglandins Leukotrienes and Essential Fatty Acids, 77(5-6), 295–300. Mills, J. D., Bailes, J. E., Sedney, C. L., Hutchins, H., & Sears, B. (2011). Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model. Journal Of Neurosurgery, 114(1), 77–84.Mills, J. D., Hadley, K., & Bailes, J. E. (2011). Dietary supplementation with the omega-3 fatty acid docosahexaenoic acid in traumatic brain injury. Neurosurgery, 68(2), 474–481; discussion 481. Nandivada, P., Carlson, S., Chang, M., Cowan, E., Gura, K., & Puder, M. (2013). Treatment of parenteral nutrition-associated liver disease: the role of lipid emulsions. Advances in Nutrition, 4(6), 711–7.Nandivada, P., Chang, M., Potemkin, A., Carlson, S., Cowan, E., O'loughlin, A., … Puder, M. (2015). The natural history of cirrhosis from parenteral nutrition-associated liver disease after resolution of cholestasis with parenteral fish oil therapy. Annals of Surgery, 26(1), 172–9.Omalu, B., DeKosky, S., Minster, R., Kamboh, M., Hamilton, R., & Wecht, C. (2005). Chronic traumatic encephalopathy in a National Football League playe. Neurosurgery, 57(1), 128–34.Pan, H.-C., Kao, T.-K., Ou, Y.-C., Yang, D.-Y., Yen, Y.-J., Wang, C.-C., … Chen, C.-J. (2009). Protective effect of docosahexaenoic acid against brain injury in ischemic rats. The Journal of Nutritional Biochemistry, 20(9), 715–725. Park, E., Bell, J., & Baker, A. (2008). Traumatic brain injury: Can the consequences be stopped? Canadian Medical Association Journal, 178(9), 1163–70.Paterniti, I., Impellizzeri, D., Di Paola, R., Esposito, E., Gladman, S., Yip, P., … Cuzzocrea, S. (2014). Docosahexaenoic acid attenuates the early inflammatory response following spinal cord injury in mice: in-vivo and in-vitro studies. Journal of Neuroinflammation, 11(6), 1–18.Pradelli, L., Eandi, M., Povero, M., Mayer, K., Muscaritoli, M., Heller, A., & Fries-Schaffner, E. (2014). Cost-effectiveness of omega-3 fatty acid supplements in parenteral nutrition therapy in hospitals: A discrete event simulation mode. Clinical Nutrition , 33(5):785-792.Pradelli, L., Mayer, K., Muscaritoli, M., & Heller, A. (2012). n-3 fatty acid-enriched parenteral nutrition regimens in elective surgical and ICU patients: a meta-analysis. Critical Care, 16(5), R184.U. S. Centers for Disease Control and Prevention (2015). Facts for Physicians About Mild Traumatic Brain Inury (MTBI). Retrieved August 23, 2015, from , G., MacLean, A., & Philipp, M. (2013). Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain. Mediators of Inflammation, (Epub 2013 Aug 12).Reilly, P. (2007). Neurotrauma: New Insights Into Pathology and Treatment. In J. Weber (Ed.), (pp. 5–7). Amsterdam: Academic Press.Roberts, L., Bailes, J., Dedhia, H., Zikos, A., Singh, A., McDowell, D., … Carpenter, J. (2008). Surviving a mine explosion. Journal of the American College of Surgeons, 207(2), 276–83. Rodríguez-Rodríguez, A., Egea-Guerrero, J., Murillo-Cabezas, F., & Carrillo-Vico, A. (2014). Oxidative Stress In Traumatic Brain Injury. Current Medicinal Chemistry. 21(10):1201-11.Russell, K., Berman, N., Gregg, P., & Levant, B. (2014). Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury. Prostaglandins Leukot rienes andEssential Fatty Acids, 90(1), 5–11.Saatman, K., Duhaime, A., Bullock, R., Maas, A., Valadka, A., Manley, G., & Members, W. S. T. and A. P. (2008). Classification of traumatic brain injury for targeted therapies. Jorunal of Neurotrauma, 25(7), 719–38.Schobe, M., Requena, D., Abdullah, O., Casper, T., Beachy, J., Malleske, D., & Pauly, J. (2015). Dietary Docosahexaenoic Acid Improves Cognitive Function, Tissue Sparing, and Magnetic Resonance Imaging Indices of Edema and White Matter Injury in the Immature Rat after Traumatic Brain Injury. Journal Of Neurotrauma, 32(18), Epub ahead of print.Sears, B., Bailes, J., & Asselin, B. (2013). Therapeutic uses of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury. PharmaNutrition, 1, 86–89.Selassie, A., Zaloshnja, E., Langlois, J., Miller, T., Jones, P., & Steiner, C. (2008). Incidence of long-term disability following traumatic brain injury hospitalization, United States, 2003. J Head Trauma Rehabilitation, 23(2), 123–131.Shin, S., & Dixon, C. (2011). Oral fish oil restores striatal dopamine release after traumatic brain injury. Neuroscience Letters, 496(3), 168–171.Smith, D., & Meaney, D. (2000). Axonal damage in traumatic brain injury. Neuroscientist, 6(6), 483–495.Smith, S. (2014). “He”s going to be better than he was before’. Retrieved August 23, 2015, from , D. (2015). Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials. Brain Injury, 14(8), 1–14.Stein, D., Wright, D., & Kellermann, A. (2008). Does progesterone have neuroprotective properties? Annals of Emergency Medicine, 51(2), 164–72.Streit, W., Mrak, R., & Griffin, W. (2004). Microglia and neuroinflammation: a pathological perspective. Journal of Neuroinflammation, 1(1), 14.Studer, M., M Briel, Leimenstoll, B., Glass, T., Bucher, H., & Zuo, C. (2005). Effect of different antilipidemic agents and diets on mortality: a systematic review. Archives of Internal Medicine, 165(7), 725–30.Traumatic brain injury: hope through research. (2002). National Institute of Neurological Disorders and Stroke; National Institutes of Health, NIH Publication No.: 02–158.Turner, R., Lucke-Wold, B., Robson, M., Omalu, B., Petraglia, A., & Bailes, J. (2012). Repetitive Traumatic Brain Injury and Development of Chronic Traumatic Encephalopathy: A Potential Role for Biomarkers in Diagnosis, Prognosis, and Treatment? Frontiers in Neurology, 3(186), 1–11.VG Coronado, McGuire, L., Sarmiento, K., Bell, J., Lionbarger, M., Jones, C., … Xu, L. (2012). Trends in Traumatic Brain Injury in the U.S. and the public health response: 1995-2009. Journal of Safety Research, 43(4), 299–307.Wang, T., Van, K., Gavitt, B., Grayson, J., Lu, Y., Lyeth, B., & Pichakron, K. (2013). Effect of fish oil supplementation in a rat model of multiple mild traumatic brain injuries. Restorative Neurology and Neuroscience, 31(5), 647–659.Wasserman, J., Feldman, J., & Koenigsberg, R. (2012). Diffuse Axonal Injury Imaging. Retrieved from , a, Braga, M., Harsanyi, L., Laviano, a, Ljungqvist, O., Soeters, P., … Vestweber, K. H. (2006). ESPEN Guidelines on Enteral Nutrition: Surgery including organ transplantation. Clinical Nutrition, 25(2), 224–244. Willer, B., & Leddy, J. (2006). Management of concussion and post-concussion syndrome. Curr Treat Options Neurol, 8(5), 415–26.Williams, J. J., Mayurasakorn, K., Vannucci, S. J., Mastropietro, C., Bazan, N. G., Ten, V. S., & Deckelbaum, R. J. (2013). N-3 Fatty Acid rich triglyceride emulsions are neuroprotective after cerebral hypoxic-ischemic injury in neonatal mice. PloS One, 8(2), e56233. Wu, A., Ying, Z., & Gomez-Pinilla, F. (2007). Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury. Journal Of Neurotrauma, 24(10), 1587–1595. Wu, A., Ying, Z., & Gomez-Pinilla, F. (2011). The salutary effects of DHA dietary supplementation on cognition, neuroplasticity, and membrane homeostasis after brain trauma. Journal Of Neurotrauma, 28(10), 2113–22.Wu, A., Ying, Z., & Gomez-Pinilla, F. (2013). Exercise facilitates the action of dietary DHA on functional recovery after brain trauma. Neuroscience, 248, 655–663.X Wang, Dong, Y., Han, X., Qi, X., Huang, C., & Hou, L. (2013). Nutritional Support for Patients Sustaining Traumatic Brain Injury: A Systematic Review and Meta-Analysis of Prospective Studies. PLoS One, 8(3), e58838.Xiong, Y., Mahmood, A., & Chopp, M. (2009). Emerging treatments for traumatic brain injury. Expert Opin Emerg Drugs, 14(1), 67–84.Yealy, D., & Hogan, D. (1991). Imaging after head trauma. Who needs what? Emerg Med Clin North Am, 9, 707–717.Yuh, E., Cooper, S., Mukherjee, P., Yue, J., Lingsma, H., Gordon, W., … INVESTIGATORS, T.-T. (2014). Diffusion tensor imaging for outcome prediction in mild traumatic brain injury: a TRACK-TBI study. J Neurotrauma, 31(17), 1457–77.Zaloshnja, E., Miller, T., Langlois, J., & Selassie, A. (2005). Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States. Journal of Head Trauma Rehabilitation, 23(6), 394–400.[FIGURE 32-1] - Computerized tomographic (CT) in the acute setting.Figure 1. CT scan of the patient approximately two hours after the motor vehicle accident and before neurosurgery. Note the moderate-sized panhemispheric right subdural hematoma, a small right temporal epidural hematoma, subarachnoid hemorrhage, and 3-mm right to left shift of the midline.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Lewis", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghassemi", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibbeln", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Am J Emerg Med", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "5-8", "title" : "Therapeutic use of omega-3 fatty acids in severe head trauma.", "type" : "article-journal", "volume" : "31" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(M Lewis et al., 2013)", "manualFormatting" : "(Lewis, 2013)", "plainTextFormattedCitation" : "(M Lewis et al., 2013)", "previouslyFormattedCitation" : "(M Lewis et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lewis, 2013)[FIGURE 32-2] - Summary of the secondary injury following the initial TBI.Figure 2. The primary injury of TBI is caused by a transfer of mechanical injury to the brain tissue. This is followed by the secondary injury that occurs over minutes to hours to days and even weeks and months. It is characterized by numerous metabolic and biochemical cascades that may cause more damage than the initial tissue insult itself. [FIGURE 32-3] – MRI showing Diffuse Axonal Injury damage ten days after TBI.Figure 3. T2-weighted magnetic resonance imaging (MRI) on hospital day 10. Note the right cerebral convexity subdural hemorrhage, right postcentral gyrus and left temporal lobe parenchymal petechial hemorrhage, and small superior vermian subarachnoid hemorrhage in the image on the right. In addition, multiple zones of abnormal fluid-attenuated inversion recovery signals consistent with diffuse axonal injury (DAI) are present on both images.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Lewis", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghassemi", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hibbeln", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Am J Emerg Med", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "5-8", "title" : "Therapeutic use of omega-3 fatty acids in severe head trauma.", "type" : "article-journal", "volume" : "31" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(M Lewis et al., 2013)", "manualFormatting" : "(Lewis, 2013)", "plainTextFormattedCitation" : "(M Lewis et al., 2013)", "previouslyFormattedCitation" : "(M Lewis et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lewis, 2013)TABLE 32-1 – Signs and Symptoms of a head injury may include:ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "URL" : "", "accessed" : { "date-parts" : [ [ "2015", "8", "23" ] ] }, "author" : [ { "dropping-particle" : "", "family" : "Prevention", "given" : "U.S. Centers for Disease Control and", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Head Up Clinicians", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "title" : "Facts for Physicians About Mild Traumatic Brain Inury (MTBI)", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Prevention, 2015)", "manualFormatting" : "(CDC, 2015)", "plainTextFormattedCitation" : "(Prevention, 2015)", "previouslyFormattedCitation" : "(Prevention, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(CDC, 2015) PhysicalCognitiveEmotionalSleep? Headache ? Nausea ? Vomiting ? Balance problems ? Dizziness ? Visual problems ? Fatigue ? Sensitivity to light ? Sensitivity to noise ? Numbness/Tingling ? Dazed or stunned ? Feeling mentally “foggy” ? Feeling slowed down? Difficulty concentrating ? Difficulty remembering? Forgetful of recent information or conversations? Confused about recent events? Answers questions slowly? Repeats questions? Irritability? Sadness? More emotional? Nervousness? Drowsiness? Sleeping less than usual? Sleeping more than usual? Trouble fallingTABLE 32-2 – Design of a “perfect” TBI drugimpacts all four main mechanisms of the secondary injury phasehas neuroregenerative propertiesbeneficial impact on cardiovascular and mental healtheffective in treating long-term effects of TBI (post-concussive symptoms)well-studied as a substance in the scientific literaturestrong safety profile readily available in oral, enteral, and intravenous formscan be given to a patient pre-hospital, acute phase of injury and can be continued throughout patient’s chronic phase and rehabilitationcan be used prophylactically prior to injury in populations at risk of TBITABLE 32-3 – The Omega Protocol for Brain HealthWeek 1: Take 3,000 mg of combined EPA + DHA three times a day for seven days*Week 2: Take 3,000 mg of combined EPA + DHA two times a day for seven days*Week 3 and beyond: Take 3,000 mg of combined EPA + DHA one time a day**The Omega-3 Protocol for Brain Health has not been approved by the US Food and Drug Administration. The FDA has classified Omega‐3 fatty acids as “generally recognized as safe” (GRAS). The FDA has ruled that up to 3,000 mg of EPA+DHA is safe to be included in the food supply of Americans without fear of adverse events. When using higher amounts of EPA and DHA, it is important for persons considering following this protocol to do so under the supervision of a healthcare provider. ................
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