REVIEW URRENT C OPINION
Do nutrients play a role in delirium? Angela M. Sanford and Joseph H. Flaherty
Purpose of review This study will review the biologic roles of thiamine, niacin, folic acid, cobalamin, antioxidants, lipids, glucose, and water and their implications as contributors or causal agents in the development of delirium, particularly if deficiencies or excesses exist. Recent findings Knowledge on how overall nutritional status and individual nutrients predispose or directly lead to the development of delirium is currently very limited. Most studies in the area of nutrition and cognition still describe mental status changes using the term dementia and do not specifically address nutrition and delirium. However, as the brain pathophysiology that accompanies delirium has been furthered elucidated, it has become clear that nutritional imbalances can lead to these same physiologic changes in neuronal tissue. Summary Delirium, characterized by an acute change in mental status along with diminished awareness and attention and disturbances in memory, language, or perception, confers high rates of morbidity and mortality and can be difficult to both diagnose and treat. Although the cause of delirium is often multifactorial, nutritional status and nutrients may play a role in predisposing or directly causing this acute cognitive dysfunction. Many nutritional deficiencies or excesses (i.e., B vitamins, antioxidants, glucose, water, lipids) have been shown to alter the way one thinks and restoring the balance in many of these nutrients can lead to resolution of delirium. Keywords nutrition and cognition, nutrition and delirium, vitamin deficiencies and delirium
’Delirium constitutes a ubiquitous and thus clinically important sign of cerebral functional decompensation caused by physical illness.’ Zbigniew J. Lipowski, MD, 1980
INTRODUCTION The brain is an organ with high metabolic activity and thus high nutrient turnover and nutritional requirements. Although the science of nutrients as contributors or causes of delirium has not been as well studied as in dementia, understanding the potential role nutrients may play in brain function using delirium as a model of brain ‘dysfunction’ is important because delirium is the sine qua non for understanding the complexity and neuropathophysiology of how we think, how we pay attention, and how we interact with our surroundings. Although dementia is the result of chronic changes in the brain over years, delirium, often known as ‘an acute change in mental status’, usually develops within minutes to hours, but may slowly arise over days or weeks. Although current research into the neuropathophysiology of delirium is focused on
several areas, such as neurotransmitters, cortisol, melatonin and other hormones, oxygenation, cerebral blood flow, and inflammatory mechanisms [1], very little research has been done in the area of nutrients and nutritional status. For the purpose of this study, to advance the science of the role nutrients may play in the development of delirium, it is necessary to understand that the science of delirium is relatively young when compared with the research that has been done in the field of dementia. Furthermore, most studies in the area of nutrition and cognition still describe mental status changes using the term ‘dementia’, even while discussing some of the acute cognitive findings that are more characteristic of ‘delirium’. The most important mental status changes that Department of Internal Medicine, Division of Geriatrics, Saint Louis University School of Medicine, St Louis, Missouri, USA Correspondence to Joseph H. Flaherty, MD, 1402 S. Grand Blvd, Room M238, St Louis, Missouri 63104, USA. Tel: +1 314 977 8462; fax: +1 314 771 8575; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:45–50 DOI:10.1097/MCO.0000000000000022
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Ageing: biology and nutrition
KEY POINTS
events in the brain, culminating in cognitive changes consistent with delirium.
The role of nutrients as contributors or causes of delirium has not been well studied because of errors in terminology and lack of the using the term ‘delirium’ when describing acute cognitive dysfunction.
B VITAMINS
Some of the cognitive changes classically associated with select B vitamins deficiencies (thiamine, niacin, folic acid, and cobalamin) may represent the cognitive changes seen with delirium. Antioxidants have been shown to decrease free radical and oxidative damage to neurons in vitro, but studies have not proven their effectiveness in vivo. Hypertriglyceridemia has been associated with impaired learning and memory, whereas omega-3 polyunsaturated fatty acids may confer an inverse relationship with cognitive decline. Hypoglycemia and hyperglycemia, whether acute or chronic, are both associated with impaired cognition.
patients with delirium exhibit include a disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) or awareness (reduced orientation to the environment). Other acute changes from baseline suggesting delirium include a disturbance in any of the major areas of cognition such as memory, language, visuospatial ability, or perception [2]. Thus, for the purpose of this study, keeping in mind these many characteristics of delirium, let us proceed with the question: do nutrients play a role as contributors or causes of any of these cognitive changes and thus to the state of delirium?
BACKGROUND Most simply defined, nutrients are molecules that are essential for cellular function and metabolism. ‘Nonessential’ nutrients are those that are fully synthesized by humans and thus do not need to be consumed through the diet, whereas ‘essential’ nutrients are not synthesized readily in vivo and must be obtained from food sources. There tends to be a u-shaped curve for the ‘nourished state’, meaning that optimal nutrient function occurs over a large range of nutrient intake levels. However, at either ends of the curve, that is, toxically high levels and severely deficient levels, abnormal physiologic function is likely to occur [3]. The brain is an organ with high metabolic activity and thus high nutrient turnover and nutritional requirements. Thus, it is logical to hypothesize that alterations in nutrient level or balance may ignite a cascade of cellular 46
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Vitamin B1 is also known as thiamine and is used in the biosynthesis of acetylcholine (ACh) and gammaaminobutyric acid (GABA), both of which are neurotransmitters, and when coupled with phosphate (thiamine pyrophosphate), is used in the catabolism of carbohydrate and amino acids. The human body is unable to store large amounts and depletion can occur in as few as 14 days without consumption. Interestingly, the conversion of thiamine to a bioavailable form requires magnesium as a cofactor and thus hypomagnesemia can mimic thiamine deficiency [4]. Deficiency of thiamine can lead to a spectrum of syndromes including Beriberi, Wernicke’s encephalopathy, and Korsakoff’s syndrome. Beriberi is an umbrella term that describes an array of symptoms caused by thiamine deficiency and is divided into dry beriberi (affects central nervous system) and wet beriberi (affects primarily the cardiovascular system). Beriberi may occur simultaneously with Wernicke’s encephalopathy or Korsakoff’s syndrome. Wernicke’s encephalopathy is classically described by the triad of nystagmus/ ophthalmoplegia, mental status changes, and gait ataxia, although this triad is not present in the majority of cases [5 ]. Korsakoff’s syndrome often results from the progression of Wernicke’s encephalopathy and is characterized by severe memory impairment that is typically irreversible, even with the administration of thiamine. Both are clinical diagnoses, as laboratory testing for thiamine lacks sensitivity and specificity. The development of delirium may be seen with thiamine deficiency and its cause is likely to be multifactorial. Thiamine plays a role as a cofactor in the Kreb’s cycle, which generates ATP. In deficient states, decreased ATP production can inhibit the breakdown of the neurotransmitter dopamine, and excess dopamine can trigger hallucinations and delusional thinking. Thiamine is also essential for the production of ACh and GABA and deficiencies of these have been implicated in delirium [6]. Additionally, thiamine is an upstream cofactor in a crucial glutathione-generating pathway, which downstream oxidizes free radicals. Deficiencies in glutathione can lead to neuronal cell injury and death, thus further facilitating delirium [7 ]. Vitamin B3 is also known as niacin, nicotinic acid, or niacinamide. It is an important precursor of the familiar compounds, nicotinamide adenine dinucleotide hydrogen, and nicotinamide adenine &
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Do nutrients play a role in delirium? Sanford and Flaherty
dinucleotide hydrogen phosphate, which are coenzymes needed in many cellular reactions. The human body does not typically store niacin in large amounts and symptoms from a lack of niacin consumption or malabsorption may result within 60 days [8]. However, tryptophan can be converted into niacin, but vitamin B1, B2, and B6 are required for the conversion and typically, those deficient in niacin are deficient in other B vitamins as well. Niacin deficiency causes pellagra, which is classically described by the ‘4 Ds’ of dementia, dermatitis, diarrhea, and death, but as seen with thiamine deficiency, rarely presents with all of the ‘classical’ findings. Although the word ‘dementia’ is usually used when describing the cognitive changes in pellagra, the term ‘delirium’ might be more appropriate in most cases, as the deficits develop rather acutely and usually rapidly improve over a few days with niacin/nicotinamide supplementation [8]. In fact, electroencephalography (EEG) findings in pellagrous encephalopathy show diffuse slowing, especially in the theta range, which is consistent with EEG findings seen in delirium from other causes [8]. Again similar to thiamine deficiency, niacin deficiency is a clinical diagnosis, although there are laboratory tests available, but these are not readily used. Vitamin B9, also called folate or folic acid, plays a crucial role in norepinephrine, serotonin, and dopamine synthesis as well as DNA synthesis and repair. Deficiency is relatively uncommon in Western countries, as many processed grains are fortified with folic acid and takes months with lack of intake to develop. However, there are a disproportional number of elderly individuals with folate deficiency and this is speculated to be secondary to dietary insufficiencies as well as impaired folate absorption. Folate deficiency is characterized by megaloblastic anemia, elevated homocysteine levels (implicated in cardiovascular disease [9] and in dementia [10]), neuronal tube defects in infants of deficient mothers, and glossitis. There is a paucity of research on folate deficiency culminating in delirium, per se, but it has been definitively associated with depression [11,12] and cognitive impairment [13]. The role of folate in neurotransmitter synthesis may be the key in a hypothetical link with delirium, as neurotransmitter dysfunction plays a definitive role in development of delirium [14 ]. Last, but not least of the B vitamins is vitamin B12, which is also called cobalamin and plays a necessary role in the myelination of nerve fibers [15 ]. Worldwide, vitamin B12 deficiency is most commonly caused by a lack of intrinsic factor production by parietal cells in the stomach secondary to the autoimmune destruction of these cells. Intrinsic &
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factor is necessary for B12 absorption and inadequacies produce the condition of ‘pernicious anemia’ [16]. Symptoms seen in B12 deficiency are similar to those seen with folate deficiency (megaloblastic anemia, elevated homocysteine, glossitis), but B12 deficiency tends to cause more neurologic symptoms such as peripheral neuropathy (primarily decreased vibration sense and proprioception) and gait ataxia secondary to neuronal demyelination. Cognitive decline and impairment, as well as psychosis, depression, and personality changes are also known complications of B12 deficiency and may present clinically as a reversible delirium or dementia. Because folate and vitamin B12 metabolism are intertwined by their common link of methionine, folate supplementation can correct many of the signs of B12 deficiency (i.e., megaloblastic anemia) [17]. This is unfortunate, as damage to nerve fibers may continue progressing without other clinical indicators of B12 deficiency and lead to difficulty in diagnosis. There are laboratory assays for the evaluation of serum vitamin B12 levels, but false positives and negatives are frequently seen, and thus serum methylmalonic acid and homocysteine levels should be concurrently measured to improve sensitivity [18,19].
ANTIOXIDANTS Multiple research studies have been done on the role of oxidative stress in predisposing for the development of delirium, particularly in postoperative and ICU settings, as delirium is known to adversely affect outcomes in these settings [20]. A variety of surgeries and infections have been shown to induce systemic inflammatory responses, leading to the release of inflammatory mediators, such as oxygen free radicals and cytokines, which in turn can cause oxidative stress on neural tissue [21 ]. The brain is particularly susceptible to free-radical damage and oxidative stress, as it has a high rate of oxidative metabolism and reduced ability to generate antioxidants [22]. Several micronutrients, such as vitamin E, vitamin C, carotenoids, and flavonoids are considered to have antioxidant properties (i.e., free-radical scavengers) and have been shown to decrease neuronal damage caused by free radicals in vitro [23]. This acute neuronal damage is one proposed mechanism of delirium, albeit the magnitude of its role has not yet been established. If oxidative stress is so cataclysmic, one would surmise that antioxidant supplementation may improve cognitive function and decrease the risk of delirium, but this has not been found to be the case and is often termed the ‘antioxidant paradox’ [24,25 ,26 ].
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LIPIDS Lipids are a diverse group of organic compounds and for the purpose of this review, we will specifically focus on fatty acids, particularly omega-3 polyunsaturated fatty acids (n-3 PUFAs) and triglycerides, as they have been linked to cognitive performance. PUFAs are generally consumed in dietary sources and are found abundantly in many nuts and seeds, plant oils, green leaves, and also in seafood and fish. Standard fish oil supplements contain two major n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and these function to inhibit hepatic triglyceride synthesis and typically lower serum triglyceride levels. Numerous studies have shown inverse relationships with cognitive decline or impairment and intake of n-3 PUFAs either via supplements or food sources in the elderly [27]. Additionally, n-3 PUFAs have many antiinflammatory properties and may act to decrease leukocyte chemotaxis and adhesion and downregulate inflammatory mediators such as prostaglandins, leukotrienes, and cytokines such as tumor necrosis factor and interleukins [28 ]. Triglycerides are composed of three molecules of fatty acids with a glycerol backbone and assist in transporting dietary fat and energy storage. High levels in the bloodstream have been linked with atherosclerotic disease and increased risk of numerous adverse conditions, including heart disease and cerebrovascular disease. Interestingly, elevated serum triglycerides also interfere with memory preservation, leading to mild cognitive deficits and very high triglyceride levels can even induce delirium, which is reversible with lowering of serum levels [29]. It is unclear exactly why hypertriglyceridemia may cause delirium, but one may hypothesize that the degree of inflammation associated with elevated triglycerides likely plays a role, as inflammation has been a key factor implicated in the pathogenesis of delirium [30 ]. &
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HYPER/HYPOGLYCEMIA Glucose is a monosaccharide carbohydrate and is the primary energy source for many cells. Remarkably, the brain, often deemed the ‘control center’ of energy metabolism and homeostasis, accounts for 50% of the body’s glucose consumption at any given time and has reduced ability to utilize energy stored in other modalities (i.e., lipids, fatty acids) [31]. This accounts for its particular sensitivity to serum glucose levels, as it is reliant on a constant, steady supply of glucose. In fact, glucose-sensing neurons are present in several areas of the brain and alter their neuronal firing in response to glucose levels, leading to a cascade of cellular events to either 48
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facilitate anabolism or catabolism in order to maintain blood glucose levels within a narrow physiologic range. Severe hypoglycemia leads to a fall in neuronal intracellular ATP levels, which downstream leads to neuronal hyperpolarization, clinically translating into seizure activity and diminished cognition, both risk factors for delirium. Similarly, hyperglycemia, whether acute or chronic, has been shown to cause oxidative stress and subsequent neuronal damage and declines in cognitive performance [32]. Not only is the acute impact of hyper/hypoglycemia deleterious, individuals with diabetes mellitus are at least one and a half times more likely to develop dementia than individuals without diabetes [31], further emphasizing the role and long-term consequences of alterations in glucose on brain functioning.
WATER Water is the main constituent of cells in most life forms and on average, makes up approximately 60% of body weight in humans. Although water needs vary greatly from person to person, the Institute of Medicine recommends that an average adult male consume 3.7 l of water daily and an adult female consumes at least 2.7 l of water daily [33]. If an individual does not consume the minimal amount of water required to offset his/her daily losses, the potential for dehydration ensues. Some common causes of dehydration include fever, diarrhea, vomiting, excessive sweating, hyperglycemia, inadequate consumption of water, and diuretic use. Chronic mild dehydration can be widespread in the elderly population and is likely the result of habitual low intake of fluid [34]. Unfortunately, dehydration is difficult to measure, particularly in the elderly, as there is no universal, standardized assessment method and clinical signs (e.g., skin turgor) are often difficult to assess in older adults. Plasma osmolality is likely the best laboratory indicator, as blood urea nitrogen and creatinine are frequently dependent on pre-existing renal function [35 ]. Dehydration as a single factor is thought to precipitate delirium and impair cognitive performance, although studies have had difficulty establishing a causal relationship, as there are usually many other confounding factors present (i.e., electrolyte imbalances, infections) [36 ]. It is hypothesized that dehydration results in neuronal mitochondrial dysfunction and subsequent neuronal death, cytokine and nitrous oxide release, and neurotransmitter dysfunction, all of which may be contributors to delirium. Several different studies have noted that losses as small as 2% of total body water weight lead &
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Do nutrients play a role in delirium? Sanford and Flaherty
to impairment in visuospatial processing, shortterm memory attenuation, and performance of attention and psychomotor tasks [36 ]. Additionally, both dehydration and delirium are often seen in patients near end of life and studies in this field have shown that parenteral hydration in cancer patients in terminal stages of life decreases incidence and severity of delirium while having no impact on length of life [37 ]. Although the relationship between dehydration and delirium has not yet been fully elucidated, it is clear that dehydration may be one of many factors that contribute to and culminate into acute cerebral dysfunction. &
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CONCLUSION It is difficult to answer the question, ‘Do nutrients play a role as contributors or causes of delirium?’ because, first and foremost, the role of nutrients in delirium has not been directly well studied. This may be primarily because of incorrect terminology and lack of using the word ‘delirium’ when describing cognitive dysfunction associated with nutritional deficiencies or excess. However, if one considers any of the cognitive changes characteristic of delirium, many of these are classically associated with certain vitamin deficiencies (e.g., B vitamins) and may represent the same cognitive changes seen with delirium, although they are often not labeled as such. In conclusion, research in the area of nutrition and delirium should be expanded, as greater understanding of this complex relationship may confer improved preventive, diagnostic, and treatment measures for delirium. Clinicians should always be vigilant and reflect on the possibility of nutritional deficiencies as causal agents or contributors to delirium and consider testing for and treating underlying nutritional deficiencies (B vitamins, dehydration, hypoglycemia) or excesses (hypertriglyceridemia, hyperglycemia). Acknowledgements Funding source: none. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 2008; 24:789–856; ix.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th Edition Washington, DC: American Psychiatric Association; 2013. 3. Morris MC, Tangney CC. A potential design flaw of randomized trials of vitamin supplements. JAMA 2011; 305:1348–1349. 4. Sechi G, Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 2007; 6:442–455. 5. Wijnia JW, Oudman E. Biomarkers of delirium as a clue to diagnosis and & pathogenesis of Wernicke-Korsakoff syndrome. Eur J Neurol 2013. [Epub ahead of print]. doi: 10.1111/ene.12217. A look at neural tissue biomarkers present in patients with delirium because of thiamine deficiency. 6. Khan BA, Zawahiri M, Campbell NL, Boustani MA. Biomarkers for delirium–a review. J Am Geriatr Soc 2011; 59 (Suppl 2):S256–S261. 7. Osiezagha K, Ali S, Freeman C, et al. Thiamine deficiency and delirium. Innov & Clin Neurosci 2013; 10:26–32. This article focuses specifically on the pathophysiology, predisposing factors, clinical presentation, diagnosis, and treatment of delirium caused by thiamine deficiency. 8. Oldham MA, Ivkovic A. Pellagrous encephalopathy presenting as alcohol withdrawal delirium: a case series and literature review. Addict Sci Clin Pract 2012; 7:12. 9. Galan P, Kesse-Guyot E, Czernichow S, et al. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 2010; 341:c6273. 10. Wald DS, Kasturiratne A, Simmonds M. Serum homocysteine and dementia: meta-analysis of eight cohort studies including 8669 participants. Alzheimers Dement 2011; 7:412–417. 11. Farah A. The role of L-methylfolate in depressive disorders. CNS Spectr 2009; 14 (1 Suppl 2):2–7. 12. Fava M, Mischoulon D. Folate in depression: efficacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry 2009; 70 (Suppl 5):12–17. 13. Hinterberger M, Fischer P. Folate and Alzheimer: when time matters. J Neural Transm 2013; 120:211–224. 14. Hughes CG, Patel MB, Pandharipande PP. Pathophysiology of acute brain & dysfunction: what’s the cause of all this confusion? Curr Opin Crit Care 2012; 18:518–526. This review analyzes many different cerebral pathophysiologic pathways for the development of delirium. 15. Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013; 368:2041– & 2042. This is a recent overview with several helpful graphics on the pathophysiology of vitamin B12 deficiency, clinical manifestations, diagnosis, and treatment. 16. Nielsen MJ, Rasmussen MR, Andersen CB, et al. Vitamin B12 transport from food to the body’s cells–a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol 2012; 9:345–354. 17. Johnson MA. If high folic acid aggravates vitamin B12 deficiency what should be done about it? Nutr Rev 2007; 65:451–458. 18. Carmel R, Agrawal YP. Failures of cobalamin assays in pernicious anemia. N Engl J Med 2012; 367:385–386. 19. Herrmann W, Obeid R. Utility and limitations of biochemical markers of vitamin B12 deficiency. Eur J Clin Invest 2013; 43:231–237. 20. Zhang Z, Pan L, Ni H. Impact of delirium on clinical outcome in critically ill patients: a meta-analysis. Gen Hosp Psychiatry 2013; 35:105–111. 21. Bozza FA, D’Avila JC, Ritter C, et al. Bioenergetics, mitochondrial dysfunction, & and oxidative stress in the pathophysiology of septic encephalopathy. Shock 2013; 39 (Suppl 1):10–16. This article focuses on the changes seen in the brain of the patient with sepsis (septic encephalopathy). 22. Enciu A, Gherghiceanu M, Popescu B. Triggers and effectors of oxidative stress at blood-brain barrier level: relevance for brain ageing and neurodegeneration. Oxid Med Cell Longev 2013; 2013:297512. 23. Feng Y, Wang X. Antioxidant therapies for Alzheimer’s disease. Oxid Med Cell Longev 2012; 2012:472932. 24. Bowman GL. Ascorbic acid, cognitive function, and Alzheimer’s disease: a current review and future direction. Biofactors 2012; 38:114–122. 25. Gillette-Guyonnet S, Secher M, Vellas B. Nutrition and neurodegeneration: & epidemiological evidence and challenges for future research. Br J Clin Pharmacol 2013; 75:738–755. This article discusses the epidemiologic data available on nutritional factors thought to be protective against the development of dementia (i.e., B vitamins, antioxidants, omega-3 fatty acids, vitamin D, among others). 26. Halliwell B. The antioxidant paradox: less paradoxical now? Br J Clin Phar& macol 2013; 75:637–644. This article defines ‘antioxidant paradox’ and presents several hypotheses as to why supplemental antioxidants do not appear to have no preventive or therapeutic effect in humans. 27. Ubeda N, Achon M, Varela-Moreiras G. Omega 3 fatty acids in the elderly. Br J Nutr 2012; 107 (Suppl 2):S137–S151. 28. Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory pro& cesses: nutrition or pharmacology? Br J Clin Pharmacol 2012; 75:645–662. This is a good overview on pathophysiology of inflammation and the anti-inflammatory properties of two omega-3 fatty acids, EPA and DHA. 29. Morley JE. Nutrition and the brain. Clin Geriatr Med 2010; 26:89–98.
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Ageing: biology and nutrition 30. Cerejeira J, Nogueira V, Luis P, et al. The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc 2012; 60:669–675. This is the study looking at several inflammatory mediators and plasma cholinesterase activity before and after surgery and the incidence of postoperative delirium. 31. Scheen AJ. Central nervous system: a conductor orchestrating metabolic regulations harmed by both hyperglycaemia and hypoglycaemia. Diabetes Metab 2010; 36 (Suppl 3):S31–S38. 32. Stadler K. Oxidative stress in diabetes. Adv Exp Med Biol 2012; 771:272–287. 33. Website Institute of Medicine. Dietary reference intakes (DRIs): estimated average requirements 2011. http://www.iom.edu/Activities/Nutrition/Sum maryDRIs//media/Files/Activity%20Files/Nutrition/DRIs/5_Summary%20 Table%20Tables%201-4.pdf [Accessed 1 August 1 2013]. 34. Maughan RJ. Hydration, morbidity, and mortality in vulnerable populations. Nutr Rev 2012; 70 (Suppl 2):S152–S155.
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35. Cheuvront SN, Kenefick RW, Charkoudian N, Sawka MN. Physiologic basis for understanding quantitative dehydration assessment. Am J Clin Nutr 2013; 97:455–462. This article discusses dehydration vs. volume depletion with a focus on improving the clinical assessment of these entities. 36. Adan A. Cognitive performance and dehydration. J Am Coll Nutr 2012; & 31:71–78. This article reviews previous studies looking at the effect dehydration has on memory, psychomotor skills, attention, and task performance. 37. Bruera E, Hui D, Dalal S, et al. Parenteral hydration in patients with advanced & cancer: a multicenter, double-blind, placebo-controlled randomized trial. J Clin Oncol 2012; 31:111–118. This study shows that cancer patients at end of life who receive hydration do not experience improvement in dehydration symptoms, quality of life, or survival. &
Volume 17 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Do nutrients play a role in delirium? Angela M. Sanford and Joseph H. Flaherty
Purpose of review This study will review the biologic roles of thiamine, niacin, folic acid, cobalamin, antioxidants, lipids, glucose, and water and their implications as contributors or causal agents in the development of delirium, particularly if deficiencies or excesses exist. Recent findings Knowledge on how overall nutritional status and individual nutrients predispose or directly lead to the development of delirium is currently very limited. Most studies in the area of nutrition and cognition still describe mental status changes using the term dementia and do not specifically address nutrition and delirium. However, as the brain pathophysiology that accompanies delirium has been furthered elucidated, it has become clear that nutritional imbalances can lead to these same physiologic changes in neuronal tissue. Summary Delirium, characterized by an acute change in mental status along with diminished awareness and attention and disturbances in memory, language, or perception, confers high rates of morbidity and mortality and can be difficult to both diagnose and treat. Although the cause of delirium is often multifactorial, nutritional status and nutrients may play a role in predisposing or directly causing this acute cognitive dysfunction. Many nutritional deficiencies or excesses (i.e., B vitamins, antioxidants, glucose, water, lipids) have been shown to alter the way one thinks and restoring the balance in many of these nutrients can lead to resolution of delirium. Keywords nutrition and cognition, nutrition and delirium, vitamin deficiencies and delirium
’Delirium constitutes a ubiquitous and thus clinically important sign of cerebral functional decompensation caused by physical illness.’ Zbigniew J. Lipowski, MD, 1980
INTRODUCTION The brain is an organ with high metabolic activity and thus high nutrient turnover and nutritional requirements. Although the science of nutrients as contributors or causes of delirium has not been as well studied as in dementia, understanding the potential role nutrients may play in brain function using delirium as a model of brain ‘dysfunction’ is important because delirium is the sine qua non for understanding the complexity and neuropathophysiology of how we think, how we pay attention, and how we interact with our surroundings. Although dementia is the result of chronic changes in the brain over years, delirium, often known as ‘an acute change in mental status’, usually develops within minutes to hours, but may slowly arise over days or weeks. Although current research into the neuropathophysiology of delirium is focused on
several areas, such as neurotransmitters, cortisol, melatonin and other hormones, oxygenation, cerebral blood flow, and inflammatory mechanisms [1], very little research has been done in the area of nutrients and nutritional status. For the purpose of this study, to advance the science of the role nutrients may play in the development of delirium, it is necessary to understand that the science of delirium is relatively young when compared with the research that has been done in the field of dementia. Furthermore, most studies in the area of nutrition and cognition still describe mental status changes using the term ‘dementia’, even while discussing some of the acute cognitive findings that are more characteristic of ‘delirium’. The most important mental status changes that Department of Internal Medicine, Division of Geriatrics, Saint Louis University School of Medicine, St Louis, Missouri, USA Correspondence to Joseph H. Flaherty, MD, 1402 S. Grand Blvd, Room M238, St Louis, Missouri 63104, USA. Tel: +1 314 977 8462; fax: +1 314 771 8575; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:45–50 DOI:10.1097/MCO.0000000000000022
1363-1950 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-clinicalnutrition.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Ageing: biology and nutrition
KEY POINTS
events in the brain, culminating in cognitive changes consistent with delirium.
The role of nutrients as contributors or causes of delirium has not been well studied because of errors in terminology and lack of the using the term ‘delirium’ when describing acute cognitive dysfunction.
B VITAMINS
Some of the cognitive changes classically associated with select B vitamins deficiencies (thiamine, niacin, folic acid, and cobalamin) may represent the cognitive changes seen with delirium. Antioxidants have been shown to decrease free radical and oxidative damage to neurons in vitro, but studies have not proven their effectiveness in vivo. Hypertriglyceridemia has been associated with impaired learning and memory, whereas omega-3 polyunsaturated fatty acids may confer an inverse relationship with cognitive decline. Hypoglycemia and hyperglycemia, whether acute or chronic, are both associated with impaired cognition.
patients with delirium exhibit include a disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) or awareness (reduced orientation to the environment). Other acute changes from baseline suggesting delirium include a disturbance in any of the major areas of cognition such as memory, language, visuospatial ability, or perception [2]. Thus, for the purpose of this study, keeping in mind these many characteristics of delirium, let us proceed with the question: do nutrients play a role as contributors or causes of any of these cognitive changes and thus to the state of delirium?
BACKGROUND Most simply defined, nutrients are molecules that are essential for cellular function and metabolism. ‘Nonessential’ nutrients are those that are fully synthesized by humans and thus do not need to be consumed through the diet, whereas ‘essential’ nutrients are not synthesized readily in vivo and must be obtained from food sources. There tends to be a u-shaped curve for the ‘nourished state’, meaning that optimal nutrient function occurs over a large range of nutrient intake levels. However, at either ends of the curve, that is, toxically high levels and severely deficient levels, abnormal physiologic function is likely to occur [3]. The brain is an organ with high metabolic activity and thus high nutrient turnover and nutritional requirements. Thus, it is logical to hypothesize that alterations in nutrient level or balance may ignite a cascade of cellular 46
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Vitamin B1 is also known as thiamine and is used in the biosynthesis of acetylcholine (ACh) and gammaaminobutyric acid (GABA), both of which are neurotransmitters, and when coupled with phosphate (thiamine pyrophosphate), is used in the catabolism of carbohydrate and amino acids. The human body is unable to store large amounts and depletion can occur in as few as 14 days without consumption. Interestingly, the conversion of thiamine to a bioavailable form requires magnesium as a cofactor and thus hypomagnesemia can mimic thiamine deficiency [4]. Deficiency of thiamine can lead to a spectrum of syndromes including Beriberi, Wernicke’s encephalopathy, and Korsakoff’s syndrome. Beriberi is an umbrella term that describes an array of symptoms caused by thiamine deficiency and is divided into dry beriberi (affects central nervous system) and wet beriberi (affects primarily the cardiovascular system). Beriberi may occur simultaneously with Wernicke’s encephalopathy or Korsakoff’s syndrome. Wernicke’s encephalopathy is classically described by the triad of nystagmus/ ophthalmoplegia, mental status changes, and gait ataxia, although this triad is not present in the majority of cases [5 ]. Korsakoff’s syndrome often results from the progression of Wernicke’s encephalopathy and is characterized by severe memory impairment that is typically irreversible, even with the administration of thiamine. Both are clinical diagnoses, as laboratory testing for thiamine lacks sensitivity and specificity. The development of delirium may be seen with thiamine deficiency and its cause is likely to be multifactorial. Thiamine plays a role as a cofactor in the Kreb’s cycle, which generates ATP. In deficient states, decreased ATP production can inhibit the breakdown of the neurotransmitter dopamine, and excess dopamine can trigger hallucinations and delusional thinking. Thiamine is also essential for the production of ACh and GABA and deficiencies of these have been implicated in delirium [6]. Additionally, thiamine is an upstream cofactor in a crucial glutathione-generating pathway, which downstream oxidizes free radicals. Deficiencies in glutathione can lead to neuronal cell injury and death, thus further facilitating delirium [7 ]. Vitamin B3 is also known as niacin, nicotinic acid, or niacinamide. It is an important precursor of the familiar compounds, nicotinamide adenine dinucleotide hydrogen, and nicotinamide adenine &
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dinucleotide hydrogen phosphate, which are coenzymes needed in many cellular reactions. The human body does not typically store niacin in large amounts and symptoms from a lack of niacin consumption or malabsorption may result within 60 days [8]. However, tryptophan can be converted into niacin, but vitamin B1, B2, and B6 are required for the conversion and typically, those deficient in niacin are deficient in other B vitamins as well. Niacin deficiency causes pellagra, which is classically described by the ‘4 Ds’ of dementia, dermatitis, diarrhea, and death, but as seen with thiamine deficiency, rarely presents with all of the ‘classical’ findings. Although the word ‘dementia’ is usually used when describing the cognitive changes in pellagra, the term ‘delirium’ might be more appropriate in most cases, as the deficits develop rather acutely and usually rapidly improve over a few days with niacin/nicotinamide supplementation [8]. In fact, electroencephalography (EEG) findings in pellagrous encephalopathy show diffuse slowing, especially in the theta range, which is consistent with EEG findings seen in delirium from other causes [8]. Again similar to thiamine deficiency, niacin deficiency is a clinical diagnosis, although there are laboratory tests available, but these are not readily used. Vitamin B9, also called folate or folic acid, plays a crucial role in norepinephrine, serotonin, and dopamine synthesis as well as DNA synthesis and repair. Deficiency is relatively uncommon in Western countries, as many processed grains are fortified with folic acid and takes months with lack of intake to develop. However, there are a disproportional number of elderly individuals with folate deficiency and this is speculated to be secondary to dietary insufficiencies as well as impaired folate absorption. Folate deficiency is characterized by megaloblastic anemia, elevated homocysteine levels (implicated in cardiovascular disease [9] and in dementia [10]), neuronal tube defects in infants of deficient mothers, and glossitis. There is a paucity of research on folate deficiency culminating in delirium, per se, but it has been definitively associated with depression [11,12] and cognitive impairment [13]. The role of folate in neurotransmitter synthesis may be the key in a hypothetical link with delirium, as neurotransmitter dysfunction plays a definitive role in development of delirium [14 ]. Last, but not least of the B vitamins is vitamin B12, which is also called cobalamin and plays a necessary role in the myelination of nerve fibers [15 ]. Worldwide, vitamin B12 deficiency is most commonly caused by a lack of intrinsic factor production by parietal cells in the stomach secondary to the autoimmune destruction of these cells. Intrinsic &
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factor is necessary for B12 absorption and inadequacies produce the condition of ‘pernicious anemia’ [16]. Symptoms seen in B12 deficiency are similar to those seen with folate deficiency (megaloblastic anemia, elevated homocysteine, glossitis), but B12 deficiency tends to cause more neurologic symptoms such as peripheral neuropathy (primarily decreased vibration sense and proprioception) and gait ataxia secondary to neuronal demyelination. Cognitive decline and impairment, as well as psychosis, depression, and personality changes are also known complications of B12 deficiency and may present clinically as a reversible delirium or dementia. Because folate and vitamin B12 metabolism are intertwined by their common link of methionine, folate supplementation can correct many of the signs of B12 deficiency (i.e., megaloblastic anemia) [17]. This is unfortunate, as damage to nerve fibers may continue progressing without other clinical indicators of B12 deficiency and lead to difficulty in diagnosis. There are laboratory assays for the evaluation of serum vitamin B12 levels, but false positives and negatives are frequently seen, and thus serum methylmalonic acid and homocysteine levels should be concurrently measured to improve sensitivity [18,19].
ANTIOXIDANTS Multiple research studies have been done on the role of oxidative stress in predisposing for the development of delirium, particularly in postoperative and ICU settings, as delirium is known to adversely affect outcomes in these settings [20]. A variety of surgeries and infections have been shown to induce systemic inflammatory responses, leading to the release of inflammatory mediators, such as oxygen free radicals and cytokines, which in turn can cause oxidative stress on neural tissue [21 ]. The brain is particularly susceptible to free-radical damage and oxidative stress, as it has a high rate of oxidative metabolism and reduced ability to generate antioxidants [22]. Several micronutrients, such as vitamin E, vitamin C, carotenoids, and flavonoids are considered to have antioxidant properties (i.e., free-radical scavengers) and have been shown to decrease neuronal damage caused by free radicals in vitro [23]. This acute neuronal damage is one proposed mechanism of delirium, albeit the magnitude of its role has not yet been established. If oxidative stress is so cataclysmic, one would surmise that antioxidant supplementation may improve cognitive function and decrease the risk of delirium, but this has not been found to be the case and is often termed the ‘antioxidant paradox’ [24,25 ,26 ].
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LIPIDS Lipids are a diverse group of organic compounds and for the purpose of this review, we will specifically focus on fatty acids, particularly omega-3 polyunsaturated fatty acids (n-3 PUFAs) and triglycerides, as they have been linked to cognitive performance. PUFAs are generally consumed in dietary sources and are found abundantly in many nuts and seeds, plant oils, green leaves, and also in seafood and fish. Standard fish oil supplements contain two major n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and these function to inhibit hepatic triglyceride synthesis and typically lower serum triglyceride levels. Numerous studies have shown inverse relationships with cognitive decline or impairment and intake of n-3 PUFAs either via supplements or food sources in the elderly [27]. Additionally, n-3 PUFAs have many antiinflammatory properties and may act to decrease leukocyte chemotaxis and adhesion and downregulate inflammatory mediators such as prostaglandins, leukotrienes, and cytokines such as tumor necrosis factor and interleukins [28 ]. Triglycerides are composed of three molecules of fatty acids with a glycerol backbone and assist in transporting dietary fat and energy storage. High levels in the bloodstream have been linked with atherosclerotic disease and increased risk of numerous adverse conditions, including heart disease and cerebrovascular disease. Interestingly, elevated serum triglycerides also interfere with memory preservation, leading to mild cognitive deficits and very high triglyceride levels can even induce delirium, which is reversible with lowering of serum levels [29]. It is unclear exactly why hypertriglyceridemia may cause delirium, but one may hypothesize that the degree of inflammation associated with elevated triglycerides likely plays a role, as inflammation has been a key factor implicated in the pathogenesis of delirium [30 ]. &
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HYPER/HYPOGLYCEMIA Glucose is a monosaccharide carbohydrate and is the primary energy source for many cells. Remarkably, the brain, often deemed the ‘control center’ of energy metabolism and homeostasis, accounts for 50% of the body’s glucose consumption at any given time and has reduced ability to utilize energy stored in other modalities (i.e., lipids, fatty acids) [31]. This accounts for its particular sensitivity to serum glucose levels, as it is reliant on a constant, steady supply of glucose. In fact, glucose-sensing neurons are present in several areas of the brain and alter their neuronal firing in response to glucose levels, leading to a cascade of cellular events to either 48
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facilitate anabolism or catabolism in order to maintain blood glucose levels within a narrow physiologic range. Severe hypoglycemia leads to a fall in neuronal intracellular ATP levels, which downstream leads to neuronal hyperpolarization, clinically translating into seizure activity and diminished cognition, both risk factors for delirium. Similarly, hyperglycemia, whether acute or chronic, has been shown to cause oxidative stress and subsequent neuronal damage and declines in cognitive performance [32]. Not only is the acute impact of hyper/hypoglycemia deleterious, individuals with diabetes mellitus are at least one and a half times more likely to develop dementia than individuals without diabetes [31], further emphasizing the role and long-term consequences of alterations in glucose on brain functioning.
WATER Water is the main constituent of cells in most life forms and on average, makes up approximately 60% of body weight in humans. Although water needs vary greatly from person to person, the Institute of Medicine recommends that an average adult male consume 3.7 l of water daily and an adult female consumes at least 2.7 l of water daily [33]. If an individual does not consume the minimal amount of water required to offset his/her daily losses, the potential for dehydration ensues. Some common causes of dehydration include fever, diarrhea, vomiting, excessive sweating, hyperglycemia, inadequate consumption of water, and diuretic use. Chronic mild dehydration can be widespread in the elderly population and is likely the result of habitual low intake of fluid [34]. Unfortunately, dehydration is difficult to measure, particularly in the elderly, as there is no universal, standardized assessment method and clinical signs (e.g., skin turgor) are often difficult to assess in older adults. Plasma osmolality is likely the best laboratory indicator, as blood urea nitrogen and creatinine are frequently dependent on pre-existing renal function [35 ]. Dehydration as a single factor is thought to precipitate delirium and impair cognitive performance, although studies have had difficulty establishing a causal relationship, as there are usually many other confounding factors present (i.e., electrolyte imbalances, infections) [36 ]. It is hypothesized that dehydration results in neuronal mitochondrial dysfunction and subsequent neuronal death, cytokine and nitrous oxide release, and neurotransmitter dysfunction, all of which may be contributors to delirium. Several different studies have noted that losses as small as 2% of total body water weight lead &
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to impairment in visuospatial processing, shortterm memory attenuation, and performance of attention and psychomotor tasks [36 ]. Additionally, both dehydration and delirium are often seen in patients near end of life and studies in this field have shown that parenteral hydration in cancer patients in terminal stages of life decreases incidence and severity of delirium while having no impact on length of life [37 ]. Although the relationship between dehydration and delirium has not yet been fully elucidated, it is clear that dehydration may be one of many factors that contribute to and culminate into acute cerebral dysfunction. &
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CONCLUSION It is difficult to answer the question, ‘Do nutrients play a role as contributors or causes of delirium?’ because, first and foremost, the role of nutrients in delirium has not been directly well studied. This may be primarily because of incorrect terminology and lack of using the word ‘delirium’ when describing cognitive dysfunction associated with nutritional deficiencies or excess. However, if one considers any of the cognitive changes characteristic of delirium, many of these are classically associated with certain vitamin deficiencies (e.g., B vitamins) and may represent the same cognitive changes seen with delirium, although they are often not labeled as such. In conclusion, research in the area of nutrition and delirium should be expanded, as greater understanding of this complex relationship may confer improved preventive, diagnostic, and treatment measures for delirium. Clinicians should always be vigilant and reflect on the possibility of nutritional deficiencies as causal agents or contributors to delirium and consider testing for and treating underlying nutritional deficiencies (B vitamins, dehydration, hypoglycemia) or excesses (hypertriglyceridemia, hyperglycemia). Acknowledgements Funding source: none. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 2008; 24:789–856; ix.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th Edition Washington, DC: American Psychiatric Association; 2013. 3. Morris MC, Tangney CC. A potential design flaw of randomized trials of vitamin supplements. JAMA 2011; 305:1348–1349. 4. Sechi G, Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 2007; 6:442–455. 5. Wijnia JW, Oudman E. Biomarkers of delirium as a clue to diagnosis and & pathogenesis of Wernicke-Korsakoff syndrome. Eur J Neurol 2013. [Epub ahead of print]. doi: 10.1111/ene.12217. A look at neural tissue biomarkers present in patients with delirium because of thiamine deficiency. 6. Khan BA, Zawahiri M, Campbell NL, Boustani MA. Biomarkers for delirium–a review. J Am Geriatr Soc 2011; 59 (Suppl 2):S256–S261. 7. Osiezagha K, Ali S, Freeman C, et al. Thiamine deficiency and delirium. Innov & Clin Neurosci 2013; 10:26–32. This article focuses specifically on the pathophysiology, predisposing factors, clinical presentation, diagnosis, and treatment of delirium caused by thiamine deficiency. 8. Oldham MA, Ivkovic A. Pellagrous encephalopathy presenting as alcohol withdrawal delirium: a case series and literature review. Addict Sci Clin Pract 2012; 7:12. 9. Galan P, Kesse-Guyot E, Czernichow S, et al. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 2010; 341:c6273. 10. Wald DS, Kasturiratne A, Simmonds M. Serum homocysteine and dementia: meta-analysis of eight cohort studies including 8669 participants. Alzheimers Dement 2011; 7:412–417. 11. Farah A. The role of L-methylfolate in depressive disorders. CNS Spectr 2009; 14 (1 Suppl 2):2–7. 12. Fava M, Mischoulon D. Folate in depression: efficacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry 2009; 70 (Suppl 5):12–17. 13. Hinterberger M, Fischer P. Folate and Alzheimer: when time matters. J Neural Transm 2013; 120:211–224. 14. Hughes CG, Patel MB, Pandharipande PP. Pathophysiology of acute brain & dysfunction: what’s the cause of all this confusion? Curr Opin Crit Care 2012; 18:518–526. This review analyzes many different cerebral pathophysiologic pathways for the development of delirium. 15. Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013; 368:2041– & 2042. This is a recent overview with several helpful graphics on the pathophysiology of vitamin B12 deficiency, clinical manifestations, diagnosis, and treatment. 16. Nielsen MJ, Rasmussen MR, Andersen CB, et al. Vitamin B12 transport from food to the body’s cells–a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol 2012; 9:345–354. 17. Johnson MA. If high folic acid aggravates vitamin B12 deficiency what should be done about it? Nutr Rev 2007; 65:451–458. 18. Carmel R, Agrawal YP. Failures of cobalamin assays in pernicious anemia. N Engl J Med 2012; 367:385–386. 19. Herrmann W, Obeid R. Utility and limitations of biochemical markers of vitamin B12 deficiency. Eur J Clin Invest 2013; 43:231–237. 20. Zhang Z, Pan L, Ni H. Impact of delirium on clinical outcome in critically ill patients: a meta-analysis. Gen Hosp Psychiatry 2013; 35:105–111. 21. Bozza FA, D’Avila JC, Ritter C, et al. Bioenergetics, mitochondrial dysfunction, & and oxidative stress in the pathophysiology of septic encephalopathy. Shock 2013; 39 (Suppl 1):10–16. This article focuses on the changes seen in the brain of the patient with sepsis (septic encephalopathy). 22. Enciu A, Gherghiceanu M, Popescu B. Triggers and effectors of oxidative stress at blood-brain barrier level: relevance for brain ageing and neurodegeneration. Oxid Med Cell Longev 2013; 2013:297512. 23. Feng Y, Wang X. Antioxidant therapies for Alzheimer’s disease. Oxid Med Cell Longev 2012; 2012:472932. 24. Bowman GL. Ascorbic acid, cognitive function, and Alzheimer’s disease: a current review and future direction. Biofactors 2012; 38:114–122. 25. Gillette-Guyonnet S, Secher M, Vellas B. Nutrition and neurodegeneration: & epidemiological evidence and challenges for future research. Br J Clin Pharmacol 2013; 75:738–755. This article discusses the epidemiologic data available on nutritional factors thought to be protective against the development of dementia (i.e., B vitamins, antioxidants, omega-3 fatty acids, vitamin D, among others). 26. Halliwell B. The antioxidant paradox: less paradoxical now? Br J Clin Phar& macol 2013; 75:637–644. This article defines ‘antioxidant paradox’ and presents several hypotheses as to why supplemental antioxidants do not appear to have no preventive or therapeutic effect in humans. 27. Ubeda N, Achon M, Varela-Moreiras G. Omega 3 fatty acids in the elderly. Br J Nutr 2012; 107 (Suppl 2):S137–S151. 28. Calder PC. 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Ageing: biology and nutrition 30. Cerejeira J, Nogueira V, Luis P, et al. The cholinergic system and inflammation: common pathways in delirium pathophysiology. J Am Geriatr Soc 2012; 60:669–675. This is the study looking at several inflammatory mediators and plasma cholinesterase activity before and after surgery and the incidence of postoperative delirium. 31. Scheen AJ. Central nervous system: a conductor orchestrating metabolic regulations harmed by both hyperglycaemia and hypoglycaemia. Diabetes Metab 2010; 36 (Suppl 3):S31–S38. 32. Stadler K. Oxidative stress in diabetes. Adv Exp Med Biol 2012; 771:272–287. 33. Website Institute of Medicine. Dietary reference intakes (DRIs): estimated average requirements 2011. http://www.iom.edu/Activities/Nutrition/Sum maryDRIs//media/Files/Activity%20Files/Nutrition/DRIs/5_Summary%20 Table%20Tables%201-4.pdf [Accessed 1 August 1 2013]. 34. Maughan RJ. Hydration, morbidity, and mortality in vulnerable populations. Nutr Rev 2012; 70 (Suppl 2):S152–S155.
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35. Cheuvront SN, Kenefick RW, Charkoudian N, Sawka MN. Physiologic basis for understanding quantitative dehydration assessment. Am J Clin Nutr 2013; 97:455–462. This article discusses dehydration vs. volume depletion with a focus on improving the clinical assessment of these entities. 36. Adan A. Cognitive performance and dehydration. J Am Coll Nutr 2012; & 31:71–78. This article reviews previous studies looking at the effect dehydration has on memory, psychomotor skills, attention, and task performance. 37. Bruera E, Hui D, Dalal S, et al. Parenteral hydration in patients with advanced & cancer: a multicenter, double-blind, placebo-controlled randomized trial. J Clin Oncol 2012; 31:111–118. This study shows that cancer patients at end of life who receive hydration do not experience improvement in dehydration symptoms, quality of life, or survival. &
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