17
Summary of Recommendations

Traumatic brain injury (TBI) is the beginning of an ongoing process that affects multiple organs and systems and may cause or accelerate other diseases and disorders that can reduce life quality and expectancy. As the physiological mechanisms associated with TBI, such as oxidation and inflammation, are elucidated, it becomes clear that nutrition may play a role in ameliorating primary and secondary (i.e., acute, or within minutes; and subacute, or within 24 hours) as well as long-term effects of TBI. The ability of any intervention to improve the outcomes of TBI will largely depend on its ability to inhibit disease progression either by solo action, or by acting synergistically with other interventions or endogenous recovery factors. Specific approaches need to be targeted to the pathophysiology of the disease, and will differ depending on the mechanisms involved in the disease progression. Broadly speaking, different processes—such as hypoxia, excitotoxicity, or proteinopathies—will respond to different interventions. Some interventions also may be most beneficial when administered over an extended period of time, while others may provide optimal benefit with one-time administration. The timing of administration is also critical, as there may be a time window of efficacy for some nutrients; that is, some interventions might be beneficial within minutes, while others will be effective later. For these reasons, it is important to identify promising interventions of two different kinds: those that will target primary and secondary effects early after injury, and those that will target long-term effects of TBI.

In addition to the evidence indicating that nutrition can affect the disease pathophysiology, there is increasing information indicating that nutrition affects brain function and that nutritional strategies may improve resilience or support treatment of brain disorders. With this in mind, an IOM expert committee reviewed the evidence supporting the potential role for nutrition in the acute and subacute phases of TBI. Based on the evidence reviewed, the committee concluded that nutritional interventions could be important both to augment mechanisms that defend against the effects of TBI, and to serve as an integral component of multidisciplinary postinjury treatment to lessen the primary and secondary effects of TBI. With the exception of a recommendation to follow a specific energy- and protein-feeding regimen early after injury for patients with severe TBI, the committee concluded there is a



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17 Summary of Recommendations Traumatic brain injury (TBI) is the beginning of an ongoing process that affects mul- tiple organs and systems and may cause or accelerate other diseases and disorders that can reduce life quality and expectancy. As the physiological mechanisms associated with TBI, such as oxidation and inflammation, are elucidated, it becomes clear that nutrition may play a role in ameliorating primary and secondary (i.e., acute, or within minutes; and subacute, or within 24 hours) as well as long-term effects of TBI. The ability of any intervention to improve the outcomes of TBI will largely depend on its ability to inhibit disease progression either by solo action, or by acting synergistically with other interventions or endogenous re- covery factors. Specific approaches need to be targeted to the pathophysiology of the disease, and will differ depending on the mechanisms involved in the disease progression. Broadly speaking, different processes—such as hypoxia, excitotoxicity, or proteinopathies—will respond to different interventions. Some interventions also may be most beneficial when administered over an extended period of time, while others may provide optimal benefit with one-time administration. The timing of administration is also critical, as there may be a time window of efficacy for some nutrients; that is, some interventions might be beneficial within minutes, while others will be effective later. For these reasons, it is important to identify promising interventions of two different kinds: those that will target primary and secondary effects early after injury, and those that will target long-term effects of TBI. In addition to the evidence indicating that nutrition can affect the disease pathophysiol- ogy, there is increasing information indicating that nutrition affects brain function and that nutritional strategies may improve resilience or support treatment of brain disorders. With this in mind, an IOM expert committee reviewed the evidence supporting the potential role for nutrition in the acute and subacute phases of TBI. Based on the evidence reviewed, the committee concluded that nutritional interventions could be important both to augment mechanisms that defend against the effects of TBI, and to serve as an integral component of multidisciplinary postinjury treatment to lessen the primary and secondary effects of TBI. With the exception of a recommendation to follow a specific energy- and protein-feeding regimen early after injury for patients with severe TBI, the committee concluded there is a 249

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250 NUTRITION AND TRAUMATIC BRAIN INJURY need to either refine study protocols or confirm the effectiveness of nutritional approaches in lessening the health outcomes of TBI. Because of the paucity of data about the efficacy of most of the nutrition approaches reviewed, the committee thought it premature to direct DoD to adopt any of them at this time. For some approaches for which enough preclinical and, in some cases, clinical data exist the committee sees the potential benefits and reached consensus about research needed in some promising areas. The research recommended will serve to confirm published results and to refine the protocols (i.e., optimal route of admin- istration, timing, and dose). There is even less data being generated about the effectiveness of nutritional interventions in combination, either with one another or with other forms of treatment. Investigating the synergistic or antagonistic effects of nutrients is an important area of research for the future. However, there are more pressing areas to investigate that are highlighted below. It is important to note that, as requested in the statement of task, this report has re- viewed nutritional interventions only for primary (i.e., acute) and secondary (i.e., subacute) effects. The effects of TBI are conceptually categorized as primary, secondary, and long-term effects, based on the amount of time elapsed since the injury; but in reality, the boundaries of these definitions are ambiguous. For example, the impact of some of the early pathogenic events related to cell death may linger in the more chronically injured brain, into the time when there is upregulation of growth factors linked to plasticity and ongoing angiogenesis. Moreover, events such as angiogenesis, typically associated with wound healing, are initi- ated within the more acutely injured brain. Because of these challenges, this report includes, in addition to acute effects, some studies that also evaluate outcomes that are seemingly long-term but that might be initiated in the acute phase of the disease. This report does not address other outcomes such as neurodegenerative (e.g., Alzheimer’s disease, Parkinson’s disease), neuroendocrine, psychiatric, and other nonneurological disorders that appear later in life and for which a causal relationship with the original injury has not been clearly established. The report is limited in that it did not evaluate the role of nutritional therapies in the rehabilitation phase and did not address the long-term effects of TBI, despite evidence in- dicating that nutritional therapies may be beneficial. Based on the literature searches the committee concluded that conducting a review of the nutrition approaches to improve long-term effects of TBI, which was part of the initial task and later excluded because of financial constraints, would also be important. Specifically, it would be important to review the alterations in metabolism associated with TBI, together with the nutritional interventions that could enhance or impair recovery from those long-term health disorders in the areas of motor dysfunction and cognitive, neuropsychiatric, and neurodegenerative states, should be reviewed (see also workshop papers by Metzger, Gomez-Pinilla, and Sands in Appendix C). RECOMMENDATIONS The committee concluded that there is already sufficient evidence to indicate that nu- trition should be added to the toolbox of interventions for TBI treatment and recovery. A summary of the committee’s recommendations follows. Only one recommendation calls for updating evidence-based guidelines for severe TBI, to provide patients with energy and protein (Box 17-1). The remaining recommendations identify additional research needs in study methodologies (Box 17-2), nutritional assessments (Box 17-3), and specific recom- mendations for research on nutritional interventions that have been prioritized into the most promising (Box 17-4) and other research (Box 17-5). Finally, the committee includes a general recommendation to develop evidence-based clinical nutritional guidelines, and to continue to update them as more evidence becomes available (Box 17-6).

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251 SUMMARY OF RECOMMENDATIONS BOX 17-1 Standardize the Provision of Energy and Protein to Patients with Severe TBI RECOMMENDATION 6-1. The committee recommends that evidence-based guidelines include the provision of early (within 24 hours after injury) nutrition (more than 50 percent of total energy expen- diture and 1–1.5 g/kg protein) for the first two weeks after injury. This intervention is critical to limit the intensity of the inflammatory response due to TBI, and to improve outcome. BOX 17-2 Continue Improving Animal Models and Identifying Biomarkers RECOMMENDATION 3-1. The committee recommends that the Department of Defense (DoD), in cooperation with others, refine existing animal models to investigate the potential benefits of nutrition throughout the spectrum of TBI injuries, that is, concussion/mild, moderate, severe, and penetrating, as well as repetitive and blast injuries. Development of animal models is particularly urgent for concus- sion/mild TBI and brain injuries due to blast as well as for repetitive injuries. These models also will aid in understanding the pathobiology of TBI, which is particularly needed for concussion/mild TBI, blast, and repetitive injuries. RECOMMENDATION 3-2. The committee recommends that DoD, in cooperation with others, continue to develop better clinical biomarkers of TBI (i.e., concussion/mild, moderate, severe, penetrating, repetitive, and blast injuries) for the purposes of diagnosis, treatment, and outcome assessment. In addition, the committee recommends the identification of biomarkers specifically related to proposed mechanisms of action for individual nutritional interventions. BOX 17-3 Assessing Nutrition Status RECOMMENDATION 5-1. DoD should conduct dietary intake assessments in different military set- tings (e.g., when eating in military dining facilities or when subsisting on a predominantly ration-based diet) both predeployment and during deployment to determine the nutritional status of soldiers as a basis for recommending increases in intake of specific nutrients that may provide resilience to TBI. RECOMMENDATION 5-2. Routine dietary intake assessments of TBI patients in medical treatment facilities should be undertaken as soon after hospitalization as possible to estimate preinjury nutri- tion status as well as to provide optimal nutritional intake throughout the various stages of treatment. RECOMMENDATION 5-3. In individuals with TBI, DoD should estimate preinjury and postinjury di- etary intake or status for those nutrients, dietary supplements, and diets that might show a relationship to TBI outcome. For example, based on the current evidence, the committee recommends collecting those estimates for creatine, n-3 fatty acids, choline, and vitamin D. The data could be used to in- vestigate potential relationships between preinjury nutritional intake or status and recovery progress. Such data also would show possible synergistic effects between nutrients and dietary supplements. Energy and Protein to Patients with Severe TBI The committee made one urgent recommendation to standardize the feeding regimen for TBI patients early after a severe injury. This important recommendation focuses on including specific energy and protein provisions for patients with severe TBI in the current evidence-

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252 NUTRITION AND TRAUMATIC BRAIN INJURY BOX 17-4 Most Promising Research Recommendations on Nutritional Interventions RECOMMENDATION 6-2. DoD should conduct human trials to determine appropriate levels of blood glucose following TBI to minimize morbidity and mortality. These should be clinical trials of early feed- ing using intense insulin therapy to maintain blood glucose concentrations at less than 150–160 mg/ dL versus current usual care of acute TBI in intensive care unit (ICU) settings for the first two weeks. RECOMMENDATION 6-3. DoD should conduct clinical trials of the benefits of insulin therapy for care of acute TBI in inpatient settings with total parenteral nutrition (TPN) alone (or plus enteral feeding) versus enteral feeding alone. The goals for blood glucose in the TPN group should be lower (e.g., less than 120 mg/dL) than in the enteral group (e.g., less than 150–160 mg/dL). Variables to measure include clinical outcomes and incidence of hypoglycemia. RECOMMENDATION 6-4. DoD should conduct studies to determine the optimal goals for nutrition (e.g., when to begin meeting total energy expenditure for optimal lean tissue maintenance or repletion) after the first two weeks following severe injury. RECOMMENDATION 8-1. DoD should continue to monitor the literature on the effects of nutrients, dietary supplements, and diets on TBI, particularly those reviewed in this report but also others that may emerge as potentially effective in the future. For example, although the evidence was not suf- ficiently compelling to recommend that research be conducted on branched-chain amino acides, DoD should monitor the scientific literature for relevant research. RECOMMENDATION 9-1. DoD should monitor the results of the Citicoline Brain Injury Treatment (COBRIT) trial, a human experimental trial examining the effect of CDP-choline and genomic factors on cognition and functional measures in severe, moderate, and complicated mild TBI. If the results of that trial are positive, DoD should conduct animal studies to define the optimal clinical dose and duration of treatment for choline (CDP-choline) following TBI, as well as to explore choline’s potential to promote resilience to TBI when used as a preinjury supplement. RECOMMENDATION 10-1. Based on the evidence supporting the effects of creatine on brain func- tion and behavior after brain injury in children and adolescents, DoD should initiate studies in adults to assess the value of creatine for treating TBI patients. RECOMMENDATION 13-1. DoD should conduct animal studies that examine the effectiveness of preinjury and postinjury oral administration of current commercial preparations of purified n-3 fatty acids on TBI outcomes. RECOMMENDATION 13-2. Based on the evidence that fish oil decreases inflammation within hours of continuous administration, human clinical trials that investigate fish oil or purified n-3 fatty acids as a treatment for TBI are recommended. For acute cases of TBI, it should be noted that there are intravenous fish oil formulations available in Europe, but these are not approved by the Food and Drug Administration (FDA). Continuous enteral feeding with a feeding formula containing fish oil should provide equivalent effects for this purpose in the early phase of severe TBI when enteral access becomes available. RECOMMENDATION 16-1. Based on a report showing efficacy in humans, the committee recom- mends that animal studies be conducted to determine the best practices for zinc administration after concussion/mild, moderate, and severe TBI, such as determining the therapeutic window for zinc ad- ministration, the length of treatment time for greatest efficacy, and the optimal level of zinc to improve outcomes. These t also rials should evaluate the safety of zinc, based on concerns about toxicity and overload. Results from these studies should be used to design human clinical trials using zinc as a treatment for TBI.

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253 SUMMARY OF RECOMMENDATIONS BOX 17-5 Other Research Recommendations RECOMMENDATION 7-1. Based on the literature from animal and human trials concerning stroke and epilepsy, DoD should consider a clinical trial with TBI patients using an array of antioxidants in combination (e.g., vitamins E and C, selenium, beta-carotene). RECOMMENDATION 11-1. DoD should conduct animal studies to examine the specific effects of ke- togenic diets, other modified diets (e.g., structured lipids, low-glycemic-index carbohydrates, fructose), or precursors of ketone bodies that affect energetics and have potential value against TBI. These animal studies should specifically consider dose, time, and clinical correlates with injury as variables. Results from these studies should be used to design human studies with these various diets to deter- mine if they improve outcome against severe TBI. These studies should include time as a variable to determine whether there is an optimal initiation point and length of use. RECOMMENDATION 11-2. If these studies show benefits, then DoD should further investigate whether the potential beneficial effect of such ketogenic or modified diets or precursors to ketone bodies applies to concussion/mild and moderate TBI. Before conducting these studies, DoD should consider the feasibility (i.e., how to ensure compliance with a modified diet) of using diets that affect the metabolic energy available, such as ketogenic diets, for the treatment of TBI. RECOMMENDATION 14-1. Based on positive outcomes in small-animal models of TBI with curcumin and resveratrol, DoD should consider conducting human trials. In addition, other flavonoids (e.g., isoflavones, flavanols, epicatechin, theanine) should be evaluated in animal models of TBI. RECOMMENDATION 15-1. The committee recommends more animal studies be conducted to de- termine if vitamin D enhances the beneficial actions of progesterone in the treatment of TBI. If this synergistic effect is confirmed in animals, then studies in humans should be conducted to evaluate the extent to which vitamin D supplementation might improve the efficacy of progesterone treatment. RECOMMENDATION 15-2. Based on animal studies showing a requirement of vitamin D for the ef- ficacy of progesterone therapy, future animal studies are recommended to test the efficacy of using vitamin D supplements to improve resilience to TBI. Should the data from animal studies support use of this steroid hormone, human trials should be implemented to test the efficacy of vitamin D in populations at high risk for TBI. RECOMMENDATION 16-2. Future work is needed in both humans and animal models to determine the extent to which chronic preinjury zinc supplementation can improve resilience in the event of a TBI. BOX 17-6 Future Update of Evidence-Based Guidelines RECOMMENDATION 2-1. Evidence-based nutrition guidelines specific for severe TBI should be updated. These guidelines should address unique nutritional concerns of severe TBI when different from generic critical illness nutrition guidelines (e.g., meeting energy needs and benefits of specific nutrients, food components, or diets). In addition, current guidelines to manage mild and moderate TBI should include recommendations for nutritional interventions. The guidelines should be developed in a collaborative manner with the various key stakeholders (e.g., American Dietetic Association, Depart- ment of Veterans Affairs, DoD).

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254 NUTRITION AND TRAUMATIC BRAIN INJURY based guidelines. Such nutritional intervention should be implemented immediately, and will achieve significant positive outcomes by reducing the inflammatory response, which is likely to be at its height during the first two weeks after injury. Research Needs The rest of the recommendations concern research questions about the potential ben- efits and adverse effects of nutritional interventions for TBI. The committee made research recommendations for animal studies as well as for both observational and randomized controlled trials in humans. Despite the expressed need for more research in the TBI patient population, the committee recognizes that clinical TBI is extremely complex and that the understanding of the differences in pathophysiology between mild and severe injuries is continuously evolving. Furthermore, the translation of experimental models to clinical care is limited by a number of factors, such as differences between animal species and variations in the mechanisms of injury producing the various types of TBIs. In addition, patients with TBI often suffer from polytrauma, which adds another level of complexity to an already multifaceted injury. Given the diverse nature of the injury, randomized clinical trials in a population with TBI are difficult to carry out, and long-term prospective studies among high-risk populations are costly, from both a financial and human resources perspective. Still, the committee emphasizes the need to follow best practices when designing such studies. Instead of providing specifics about the design of the research studies that might be challenging to meet, the committee offers the following list of considerations for future investigators in this discipline: • A note of caution is offered on extrapolating findings from animal models to humans; although there are good animal models for severe injuries, there is a need for better animal models for other types of TBI, especially concussion/mild TBI and blast TBI (see recommendation 3-1). • There are limitations, such as poor sensitivity and specificity, on the use of biomarkers as indicators of injury and recovery. Better predictability might be attained by using several biomarkers in conjunction with clinical data (see recommendation 3-2). • Unless specified in the recommendations, research should be conducted on the full spectrum of TBI, from mild/concussion to severe injuries. • Although not specifically mentioned in the research recommendations, adverse effects from any studies should be recorded, taking into consideration that TBI patients may experience more frequent adverse effects than a healthy population exposed to the same intervention. The reader is also referred to the 2008 Institute of Medicine (IOM) report Use of Dietary Supplements by Military Personnel, in which a framework to review the safety of dietary supplements in military settings was developed. • In general, and based on results from previous studies, the committee advises that gender and age differences be considered in the study design. • The committee emphasizes that commercial food components and nutrient supple- ments vary in their purity, and this variation will likely have an effect in the results of a study. Therefore, investigators should pay particular attention to the quality (i.e., purity) of these compounds. • The chemistry (and source) of each compound of interest affects its bioavailability, metabolism, and ability to reach the target area, which in turn influence the effective- ness of a nutritional intervention.

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255 SUMMARY OF RECOMMENDATIONS • Before any definitive conclusions can be made about efficacy, the route and timing of administration and dosage are key considerations that investigators need to optimize in study designs. • Investigators should consider synergistic and antagonistic effects with nutrients, dietary supplements, food components, or other substances in the diets of military personnel. Although not related to nutrition specifically, the committee thought it important to mention the significance of appropriate methodologies. There are still substantial deficiencies in the biomarkers and animal models currently used. On that point, the committee made two general recommendations: first, to continue to develop better animal models, and second, to identify biomarkers of both injury and improved brain function. There also is a need to assess the nutritional status of military personnel to determine whether there are nutrients that need to be added to the diets of military personnel to main- tain optimal readiness and mission performance goals. The committee found there are not enough nutritional assessments of military personal conducted in various settings, specifi- cally during deployments. In addition to providing protein and energy after severe injury, there are other nutri- tional interventions that are promising but for which many questions persist about exact protocols (e.g., dosage, time, and route of administration), and more research is critically needed in order to provide optimal treatment to military members with TBI. For example, based on recent reports that mortality and morbidity of TBI patients are affected by early feeding, the committee strongly supports elucidation of the best practices during the early postinjury period. Fundamental questions remain, however, about the appropriate serum levels of glucose and insulin to be achieved within the first 24 hours after severe TBI. More information is also needed on the best nutrition goals for the two weeks following that period. In addition to these urgent questions about protein and energy needs shortly after injury, research gaps also were identified in other promising areas. Based on the existing evidence from animal and human research studies, the nutritional interventions selected for review by the committee were energy and protein provision, antioxidants (e.g., vitamins E and C), polyphenols (e.g., flavonoids, resveratrol, and curcumin), branched-chain amino acids, choline, creatine, ketogenic and similar modified diets, magnesium, n-3 fatty acids, vitamin D, and zinc. Chapter 4 describes how these nutrition interventions were selected. For some of the selected nutrients, such as resveratrol, studies have demonstrated benefits of the nutrient in animal models of TBI or brain injury. However, there are as yet no clinical trials that confirm similar beneficial effects in humans. For other nutrients, such as creatine, there are human trials with promising results that could be extended to military personnel. In other cases, such as magnesium, choline, and n-3 fatty acids, human trials are under way, and the military should review those studies as the results are made public. The committee recognizes the need for the Department of Defense (DoD) to prioritize the research recommendations. Although there will undoubtedly be other criteria that will be used to guide such ranking, the committee offers here its reflections on the prioritization of research based on its opinions about the likelihood of positive results for lessening the effects of TBI. Research on interventions for which human trials to explore efficacy in improving the outcomes of TBI already exist or are ongoing have been presented as “most promising research” (Box 17-4). Research on interventions for which animal studies in TBI or human studies in associated conditions have shown improvements in outcomes is presented as “other research” (Box 17-5). Although the research recommendations are directed to DoD as the sponsor of this study, the committee recognizes that this research agenda would entail

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256 NUTRITION AND TRAUMATIC BRAIN INJURY a tremendous effort. Because the problem of TBI is not unique to military personnel but is also a concern for the civilian population, the research questions would likely be of inter- est to other organizations. DoD is encouraged to conduct research internally, to support extramural research, or to collaborate with others in order to obtain answers in the most effective manner. Ultimately, any potential interventions must be applied to clinical care situations to benefit TBI patients. The committee found that, except for guidance on energy intake, the majority of clinical guidelines for critical care and TBI patients do not include specific recommendations for adequate nutrition either early after injury or in the long term. In ad- dition, discussions with critical care and rehabilitation clinicians indicate there is diversity in clinical practices, and that the small number of current nutrition guidelines is followed by few practitioners. This picture is even more worrisome when considering the lack of specific, evidence-based guidelines for the use of dietary supplements or food components for TBI, and the frequent use of dietary supplements by military personnel discussed in the 2008 IOM report Use of Dietary Supplements by Military Personnel (IOM, 2008). The committee therefore also reflected on the application of the research recommended in this report to improve the clinical guidelines. The findings of the research gaps outlined above would present an opportunity to update the existing clinical guidelines with evidence-based nutritional interventions. To that effect, a table (see Appendix B) was developed with questions for which the evidence does not currently exist, but that will benefit clinicians as they create evidence-based guidelines in the future. These questions are outlined in the PICO (Population/Participant, Intervention, Comparator, Outcomes) format, which is used to present questions for the purpose of creating evidence-based guidelines. Topics include designation of biomarkers, optimal feeding regimens (e.g., sources of energy, percentage of energy needs to be met, route of administration), and novel nutrition therapies. The com- mittee hopes that in addition to creating a research agenda to answer questions about TBI, these recommendations will serve to update clinical guidelines.