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Micronutrient Supplementation in Adult Nutrition Therapy: Practical Considerations Krishnan Sriram and Vassyl A. Lonchyna JPEN J Parenter Enteral Nutr 2009 33: 548 originally published online 19 May 2009 DOI: 10.1177/0148607108328470

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Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 Review Journal of Parenteral and Enteral Nutrition Volume 33 Number 5 September/October 2009 548-562 Supplementation in © 2009 American Society for Parenteral and Enteral Nutrition 10.1177/0148607108328470 Adult Nutrition Therapy: http://jpen.sagepub.com hosted at Practical Considerations http://online.sagepub.com

Krishnan Sriram, MD, FRCS(C) FACS1; and Vassyl A. Lonchyna, MD, FACS2 Financial disclosure: none declared.

Preexisting micronutrient ( and trace elements) defi- for (Se) and (Zn). In practice, a ciencies are often present in hospitalized patients. Deficiencies preparation and a multiple trace element admixture (containing occur due to inadequate or inappropriate administration, Zn, Se, , , and ) are added to par- increased or altered requirements, and increased losses, affect- enteral nutrition formulations. Most enteral nutrition prepara- ing various biochemical processes and resulting in organ dys- tions also contain adequate amounts of vitamins and trace function, poor wound healing, and altered immune status with elements, although may be an issue. Detailed deleterious sequelae. Guidelines for the 13 essential vitamins information about individual micronutrient use specifically in and 10 essential trace elements have been established. These hospitalized adult patients receiving nutrition therapy will be recommendations, however, are applicable to healthy adults and discussed, emphasizing the practical and clinical aspects. not to critically ill patients, in whom decreased serum levels Clinicians are encouraged to think of not as may indicate actual deficiencies or a deficiency due to redistri- nutritional supplements alone but also as therapeutic agents bution. Benefits of supplementation over and above the daily and . (JPEN J Parenter Enteral Nutr. 2009;33: requirements, which may not result in increased serum levels, 548-562) are also unclear and may, in fact, be detrimental. requirements are increased in states, but a similar rec- ommendation for trace elements has not been initiated except Keywords: micronutrients; trace elements; vitamins

he purpose of this review is to highlight practical Preexisting micronutrient deficiencies, especially zinc considerations in the use of micronutrient supple- (Zn), (Fe), selenium (Se), and vitamins A, B, and C, T mentation as part of short-term nutrition therapy are often present in critically ill patients.1 In addition, defi- in adults. The term micronutrient includes vitamins and ciencies may occur due to the inadequate or inappropriate trace elements. Vitamins are organic substances not syn- administration of micronutrients during nutrition therapy thesized by the body and necessary for normal metabo- or because of increased requirements or increased bodily lism. They are divided into soluble or soluble losses.2,3 These deficiencies can be expected to deleteri- and those with or without coenzyme function. Trace ele- ously affect various biochemical processes and ments are present in very minute quantities in the functions, leading to organ dysfunction, muscle , body; they are essential for normal metabolic functions poor wound healing, and altered immune status. and are cofactors of or form an integral part of The U.S. and Nutrition Board first prepared the the structure of specific enzymes. daily requirements more than a half century ago and established the Recommended Dietary Allowance (RDA). The RDA has since been modified numerous times and now includes the 13 essential vitamins (4 fat From the 1Division of Surgical Critical Care, Department of soluble and 9 water soluble)4 and the following trace ele- Surgery, John H. Stroger Jr. Hospital of Cook County, and ments: copper (Cu), chromium (Cr), (Co), Fe, flu- 2Department of General Surgery, Rush University Medical Center, Chicago, Illinois. oride (Fl), (I), (Mo), manganese (Mn), Se, and Zn.5 These recommendations, supported by Received for publication February 25, 2008; accepted for pub- lication July 9, 2008. publications from several organizations, are typically applicable to the general healthy population. Address correspondence to: Krishnan Sriram, MD, FRCS(C), FACS, Stroger Hospital of Cook County, Surgical Critical Over the past decade, the Institute of Medicine has Care/Dept of Surgery, Chicago, IL 60612; e-mail: ksri- developed a new set of dietary requirements known as [email protected]. the (DRI).6 Table 1, based on

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Table 1. Dietary Reference Intakes6

EAR RDA AI UL

Fat-soluble vitamins A 300-625 μg RAE 700-900 μg RAE 3000 μg RAE D 5-10 μg 50 μg E 12 mg 15 mg 1000 mg K 90-120 μg Water-soluble vitamins C (ascorbic acid) 60-75 mg 75-90 mg 2000 mg B () 320 μga 400 μg 1000 μg 11-12 mgb 14-16 mg 35 mg

B2 () 0.9-1.1 mg 1.1-1.3 mg

B1 () 0.9-1.0 mg 1.1-1.2 mg

B6 () 1.1-1.4 mg 1.3-1.7 mg 100 mg μ μ B12 (cobalamin) 2.0 g 2.4 g 5 mg 30 μg Trace elements Zinc 6.8-9.4 mg 8-11 mg 40 mg Selenium 45 μg 55 μg 400 μg Copper 700 μg 900 μg 10 000 μg Chromium 20-35 μg Manganese 1.8-2.3 mg

Cells are left blank where no data are available. EAR, Estimated Average Requirement (the nutrient needs of 50% of the population [age and gender specific]); RDA, Recommended Dietary Allowance (the nutrient needs of 98% of the population; RDA = EAR + 2 standard deviations); AI, Adequate Intake (the recommended daily nutrient intake); UL, tolerable Upper Limit (the highest average daily nutrient intake level above which side effects occur); RAE, activity equivalent (1 μg RAE = 1 μg retinol, 12 μg β-, or 24 μg α-carotene). 1 IU of = 0. 344 μg. aAs dietary folate equivalent (DFE). 1 DFE = 1 μg food folate = 0.6 μg of folic acid. bAs niacin equivalent (NE). 1 g of niacin + 60 mg of .

information obtained from this 2006 publication, provides mandated by the USFDA. The American Society for the DRI for the micronutrients discussed in this review. Parenteral and Enteral Nutrition (A.S.P.E.N.) has estab- DRIs are further categorized as Estimated Average lished guidelines for the administration of parenteral Requirement (EAR), RDA, Adequate Intake (AI), and tol- trace element additives.11 Tables 2 and 3 summarize erable Upper Limit (UL) and are explained in the caption the current recommendations for administration of vita- to Table 1. These figures serve to provide us with reference mins and trace elements to patients requiring nutrition ranges but are applicable only to enteral intake and to sta- support. ble patients. In practice, a multivitamin preparation (including vita- Micronutrient requirements in critically ill patients min K) and a multiple trace element admixture (containing are unknown.7 Decreased serum levels may not indicate Zn, Se, Cu, Cr, and Mn) are added to actual deficiencies but just redistribution. The decrease (PN) formulations. Most standard commercially available in serum levels may actually be a beneficial and adaptive enteral nutrition (EN) preparations already contain the RDA response,8 as some vitamins at high doses function as of vitamins. Table 4 lists the recommendations for vitamins pro-oxidants. Benefits of supplementation, which may and trace elements of interest in critical care practice.12 not result in increased serum levels, are also unclear.9 However, the composition of commercially available However, the United States Food and Drug Admini- trace element preparations in the United States is far from stration (FDA), as early as 1984, recognizing that par- ideal, especially for long-term use, as shown in a recent study enteral vitamins are a requirement for the maintenance of on autopsy specimens obtained from patients with short the body’s reparative and defensive processes, wrote into bowel on long-term PN.13 levels of Cu, Mn, and Cr law the content and dosage of a parenteral multivitamin were elevated, suggesting that better trace element admix- supplement. In 2000, the doses of vitamins B1, B6, C, and tures, available in several other countries, should be approved folic acid were increased, and was added to the and made available in the United States. This study also formulations (for a of 13 vitamins).10 However, a recommended that the daily Mn dose should be decreased to similar recommendation for trace elements has not been 30-60 μg and that the daily Cr dose should be decreased to

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Table 2. Suggested Composition of Parenteral Table 3. Suggested Composition of Parenteral Trace Multivitamin Products for Adults10,11 Element Products for Adults10,11,122

Amount Per Ingredient Amount Per Unit Dose Ingredient Unit Dose Zinc 2.5-5.0 mg Fat-soluble vitamins Selenium 20-60 μg A (retinol) 1 mg Copper 0.3-0.5 mg D ( or ) 5 μga Chromium 10-15 μg E (α-) 10 mg Manganese 60-100 μg K (phylloquinone) 150 μg Water-soluble vitamins C (ascorbic acid) 200 mg Folic acid 600 μg Niacin 40 mg

B2 (riboflavin) 3.6 mg B1 (thiamine) 6.0 mg Absorption and Interactions B6 (pyridoxine) 6.0 mg μ B12 () 5 g Most water-soluble vitamins are absorbed easily from the prox- Pantothenic acid 15 mg imal gastrointestinal (GI) tract. Fat-soluble vitamins are μ Biotin 60 g absorbed in the mid- and distal as of fat by aEquivalent to 200 IU. and pancreatic lipase is required. In conditions where fat can occur, such as pancreatic insufficiency and bile loss, deficiency of fat-soluble vitamins is common. Deficiencies may occur with losses that occur with high- output GI or with excessive , as seen in patients with inflammatory bowel disease. Reinstillation of 5-10 μg. A higher dose of Se (60-100 μg), especially in indi- upper GI secretions into the , either via a nasojejunal viduals younger than age 40 years, was also suggested.14 tube or ,21 will facilitate absorption of fat-soluble In this review, we summarize the currently available vitamins that require bile and pancreatic secretions for optimal information on the use of vitamins and trace elements as absorption; in addition, loss of trace elements is avoided. an important component of nutrition therapy, especially Food needs to be digested first before trace elements in the critically ill adult patient, emphasizing practical become bioavailable. Absorption of trace elements is dif- and clinical aspects. Publications on nutrition support ficult to study, and the information available is limited. Zn often emphasize macronutrient administration with an and Se are absorbed mainly in the duodenum and emphasis on , , and . We expect jejunum. Fe is absorbed in the duodenum and proximal that this review will help the clinician to appreciate the jejunum, whereas Cr and Cu are absorbed in the ileum. important role of micronutrients in the metabolic support Interactions between various vitamins are very com- of patients. Information about the risks and clinical man- plex.22 For example, vitamins E and C are synergistic. ifestations of deficiency, recommended dosages, and pos- recycles ; thus, vitamin C deficiency sible adverse effects for each micronutrient is presented. decreases function of the latter. Vitamin A function is The use of PN has become easier in many parts of the antagonized by an excess of vitamin E. Requirements for world with the ready availability of multicompartment niacin are increased in pyridoxine () and bags, often marketed as “total nutrient admixtures.” riboflavin (vitamin B2) deficiencies. However, if improperly administered without micronutri- Numerous interactions exist between the different ents, serious consequences may occur.15 trace elements affecting absorption via the GI tract. The role of micronutrients in the general population, Factors affecting bioavailability of trace elements include in epidemiologic studies, and in specific disease states will the actual chemical form of the nutrient (eg, organic form not be presented and can be obtained from other of Cr is better absorbed than the ionic form), antagonis- reviews.16,17 Reviews on the use of micronutrient supple- tic ligands (eg, Zn absorption is decreased by phytate and mentation in critical illness18 and human immunodefi- fiber; Fe absorption is decreased by fiber), facilitatory lig- ciency virus (HIV) infections19 provide more detailed ands (eg, Zn absorption is aided by citric acid), and com- information. We will also not discuss in detail the individ- petitive interactions (eg, Fe depresses the absorption of ual and combined roles for several micronutri- Cu and Zn; Zn depresses Cu absorption and vice versa). ents, as these have also been reviewed recently.20 The main Administration of ferrous sulfate with EN can result in focus will be nutrition therapy of the hospitalized patients, .23 usually short-term rather than long-term home support. Vitamins and most trace elements are stored in the .

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Table 4. Recommendations for Micronutrients in Critical Illness10,11,22,56,82

Standard Dose

Micronutrient Recommended PN EN Additional Enhanced Recommendations Daily Allowance Formula Formula Supplementation EN

Vitamin A 1 mg 1 mg 0.9-1.0 mg/L PN: 3.5 mg/d; 1.5-4 mg/L EN: 8.6 mg/d Vitamin C 75-90 mg 200 mg 125-250 mg/L 500-3000 mg/d 80-844 mg/L Vitamin E 15 mg 10 mg 25-50 mg/L PN: 400 mg/d; 40-212 mg/L (α-tocopherol) EN: 40-1000 mg/d Vitamin K 150 μg 150 μg 40-135 μg/L Zinc 15 mg 2.5-5 mg 11-19 mg/L 10-30 mg/d 15-24 mg/L Selenium 50-100 μg 20-60 μg 20-70 μg/L 100-400 μg/d 77-100 μg/L Iron 10-15 mg 0 12-20 mg/L

EN, enteral nutrition; PN, parenteral nutrition; 1 IU of vitamin A = 0.344 μg. Standard PN dose is per day.

Effect of Inflammatory Response on of individual vitamins, where clinically relevant, Micronutrient Status and dosage recommendations are discussed later. When used at recommended doses, toxicity due to Serum levels of various vitamins decrease with the inflam- trace elements is unlikely. Zn and Se toxicity as a result of matory response, although the clinical significance of this nutrition support has not been reported. Up to 30 mg/d of is unclear.24 For example, in postoperative patients, levels Zn may be administered parenterally over 24 hours and is 29 μ of vitamins A, C, and E are decreased.25,26 Septic patients considered safe. Up to 400 g/d of parenteral Se is safe, have high vitamin A excretion in the .27 Levels of vita- although higher amounts have been administered with no apparent short-term adverse effects. mins B1, B2, B12, and folate are not affected by inflamma- tion, and decreased levels may therefore represent a true It is not necessary to routinely obtain serum levels of deficiency. However, there is no conclusive proof to indi- micronutrients. Serum levels of vitamins D 25-OH, B12, cate that additional supplementation is needed when the and folate are the only ones easily available, at least in serum level of a specific vitamin declines. North America, and of use in clinical practice. Other lev- Serum levels of various trace elements also decrease els that are not commonly requested but may be obtained in critical illness.28 Serum levels of Se, Cu, Fe, and Zn are from specialized reference laboratories include vitamins 30 decreased due to sequestration, possibly in the liver and A, B1, B6, and E. Obtaining serum levels of trace ele- reticuloendothelial system. This may also be due to ments is even more difficult. Meticulous collection and increased urinary or other losses and increased handling techniques, using special trace element–free . The decrease in serum levels of trace ele- tubes and collection devices, are needed. Previous bal- ments may actually be beneficial. For example, lower Fe ance studies have demonstrated the unreliability of serum 13 levels protect the individual against bacterial infections. trace element levels. Serum levels may indicate recently administered trace elements and not tissue levels. Despite these limitations, serum levels are the only tests available Toxicity of Micronutrients for clinical use. Functional endpoints, such as using enzyme assays (alkaline phosphatase for Zn; plasma glu- Toxicity from water-soluble vitamins is unlikely, and up to tathione peroxidase [GPx] for Se) are also not reliable or 100 times the RDA can be safely administered. Fat-soluble practical. vitamin toxicity can occur, and it is generally recom- mended that a safe limit is 10 times the RDA. Serum Factors Affecting Vitamin and Trace levels of vitamins are not routinely measured in critical Element Requirements care. Several forms of vitamins, pro-vitamins, active forms, and metabolites can be measured. The clinical sig- The vitamin status at the time of admission is commonly nificance of low levels is unclear, and supplementation altered in patients with a history of excessive intake may not increase the serum levels. Adverse reactions and of (deficiency of most water-soluble vitamins,

Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 552 Journal of Parenteral and Enteral Nutrition / Vol. 33, No. 5, September/October 2009 especially thiamine, folate, and zinc). Elderly patients, syndrome, which occurs in severely malnourished indi- especially those in long-term care facilities, and the indi- viduals placed on PN or EN therapy without adequate gent are often vitamin and trace element deficient.31 micronutrient supplementation. Disease processes alter vitamin status. For example, in renal failure, deficiencies of pyridoxine, folic acid, and vita- Detailed Information on Individual Vitamins min C occur.32 Patients on often have sub- 33 clinical ; they are also deficient in Table 5 provides information on the more important vita- 34 trace elements (Se, Zn) and vitamins (vitamins C and E), mins with references.45-79 With regard to other vitamins, 35 as well as folic acid and pyridoxal , possibly due there is insufficient information to make firm recommen- to loss in dialysate or adsorption by the filters. Patients on dations to provide extra dosages of biotin, pantothenic peritoneal are often Zn and Se deficient, but this is acid, and riboflavin (vitamin B ), although these are con- 36 2 not because of loss in the dialysate. Patients with alco- sidered essential. There are no recent publications on holic frequently manifest deficiencies of their additional roles in nutrition support. Individual par- 37 folate, thiamine, pyridoxine, and vitamin A. enteral forms of these vitamins are not generally avail- GI (eg, fistulas, diarrhea) deficiencies result in loss of able, although they are present in multivitamin additives. all vitamins and multiple trace elements, especially Zn Biotin is important for carboxylase enzymes involved and Se. Loss of bile results in fat malabsorption and even- with and fat . Symptoms of defi- tually loss of fat-soluble vitamins. Pancreatic enzymes are ciency are nonspecific, and deficiencies as such are rare. needed for optimal absorption, and therefore Symptoms include , , alopecia, deficiency may occur with . , and and may be seen in long- Chylous leaks and fistulas, conditions for which PN term PN patients without biotin. Increased requirements is often required, result in micronutrient losses, due to are seen in hemodialysis and peritoneal dialysis. the large volumes of protein-rich fluid (up to 3 L) lost Pantothenic acid and its biologically active form, each day. Se deficiency secondary to chylous loss has , are essential for many acetylation reactions, 38 been reported, and it is highly likely that other trace ele- especially the tricarboxylic (TCA) acid cycle. Deficiencies ments are also lost. are rare in humans. Treatment modalities also alter vitamin and trace ele- Riboflavin (vitamin B2) is a member of natural com- ment status. or terminal ileum resection may pounds collectively called flavins, with numerous roles as lead to Fe and . admin- coenzymes in critical oxidation reduction reactions. istration during anesthesia is known to cause acute folic Deficiency is more common than often suspected, due to 39 acid and vitamin B12 deficiencies. Various drug-nutrient the nonspecific nature of , including interactions can occur, for example, due of the oral mucosa, , , sebor- to trimethorprim/sulfamethoxazole. Vitamin K deficiency rheic dermatitis, and normocytic-normochromic . occurs due to administration of antimicrobials that alter Riboflavin’s role in the treatment of patients with HIV has intestinal flora, responsible for the synthesis of vitamin K. been recently recognized. Treatment of AIDS with nucle- A recent issue has been the detection of micronutri- oside reverse transcriptase inhibitors (NRTIs) may result ent deficiencies after bariatric surgery for weight reduc- in . This is attributed to the mitochondrial tion. Despite oral supplements, deficiencies of both toxicity of these agents.80 NRTIs inhibit HIV viral replica- fat-soluble vitamins (A, D, E, and K) and water-soluble tion by binding to viral DNA polymerase. However, they vitamins (especially B1, B6, and B12), as well as trace elements bind to other DNA polymerases too, such as those found such as Fe and Zn, have been reported after Roux-en-Y gas- in mitochondria, and thereby disrupt oxidative phospho- 40-42 tric bypass and gastric banding procedures. rylation with resultant lactic acidosis. Symptoms are non- Critically ill patients are especially susceptible to specific and include nausea, , abdominal , developing despite what is per- , and , delaying recognition. When sus- ceived to be adequate replacement. The vitamin content pected and confirmed with hyperlactatemia, these effects present in the best designed commercially available of NRTIs have been shown to be easily reversed by enteral formulas does not meet the needs of patients with riboflavin,81 supposedly through its beneficial effect on 43 inflammatory bowel disease. Low levels of vitamin C in mitochondrial function. critically ill patients are not explained by age, intake, or treatment differences and are not prevented by the use of PN containing vitamin C.9 patients are especially Detailed Information on susceptible to micronutrient deficiencies even when Individual Trace Elements provided twice the recommended parenteral vitamin dosages.44 It is also important to keep micronutrient Updated DRIs for various trace elements has recently deficiencies in mind as a component of the refeeding been published.82 Table 6 provides information on Zn, Se,

Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 61 58 μ g 59 52 (continued) Toxicity Increased 51 50 and contribute Enhanced Effects 57 60 ≈ 7.5 g/d are toler- reported in long-term enteral feeding. to platelet dysfunction. with long-term intake of high doses. limit of intake is 50 (2000 IU) per day. occurs only Toxicity when intakes are in the range of 1000 μ g/d (40,000 IU/d). A. High doses vitamin adversely affect wound healing Upregulates proinflam- matory cytokines. Doses as high 3 g/d show no deleterious effects. enteral formulas provid- ing ated. Doses of 600-1000 mg/d are generally safe. levels in renal failure; if modified MV preparation is not available, use stan- dard doses. Hepatic dysfunction occurs Hypercalcemia. Upper Excess doses antagonize 2 56 7 d). in × 49 μ g. EN 0.344 = μ g/d. 1 g of calciferol 40 IU. In renal or Recommendations doses of 10,000-15,000 IU/d (3-5 mg/d 3000 IU). 1 IU of vita- min A formulas contain 2600- 5200 IU/L (0.9-1.0 mg/L). Enhanced formu- las contain 4200-12,000 IU/L (1.5–4.0 mg/L). Reverses inhibitory effect of corticosteroids on wound healing, form instead of calciferol, as the latter cannot be adequately hydroxylated. preparations contain 10 mg/dose. EN formulas have variable amounts (25-50 mg/L). In criti- cally ill patients, higher IV doses of 50-60 mg/d are recommended. forms of vitamin Various E have different levels of (Parenteral activity. forms of vitamin E are not available in the United States). present in about 1 L of EN formulas. PN dose is 5 = hepatic insufficiency, give active 1,25 (OH) RDA is 1 mg ( ≈ 900 RAE or RDA is 15 mg. PN MV RDA RDA is 5 μ g (200 IU), RDA 54 11 ; cardiomy- 53 27.5 nmol/L), 48 Manifestations opathy. Serum level of opathy. 25-OH < ng/mL ( < suggestive of deficiency. xerophthalmia, mucosal and changes, diarrhea. mucosa does not regen- thereby erate adequately, facilitating bacterial translocation. porosis; immune dysfunction and erythro- myopathy, cyte fragility Vitamins Poor wound healing, Poor A–deficient Vitamin and osteo- neuropathy, Peripheral 47 Table 5. Table ; urinary losses (may represent 46 States 55 Deficiency Toxicity/Adverse Deficiency Toxicity/Adverse 3 times RDA in pneu- 3 times RDA × monia and individuals, especially with sedentary lifestyles. B light from sunlight stimulates cuta- neous synthesis (UVA light from tanning equip- ment does not). Hepatic and renal insufficiency; obesity. individuals. May occur in fat malabsorption. Levels decrease with stress. Decrease seen in septic occurs in parallel with peroxi- dation increased free activity). High-volume GI losses; Lack of sunlight, elderly None identified in healthy form. ; maintenance 2 45 Role Receptors are found in several tissues, with unknown functions. Stored in adipose tissues. membrane fluidity and (Lipid emul- integrity. sions contain large amounts of vitamin E to ensure stability by protection from peroxidation.) of mucosal integrity Actually a prohor- lism. mone; hydroxylated in liver and kidneys to the biologically active 1,25(OH) and growth; neutrophil function Antioxidant, important for and metabo- Vision, immune function, Vision, , , and retinyl ) Vitamin A (includes retinol, Vitamin D Vitamin E Vitamin

553 Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 (continued) Effects may result in . diminished ability to subsequently anti- coagulate patients with . can cause sensory neu- ropathy and convulsions. Rapid IV administration Excessive doses result in None known high doses of > 2 g/d Very 64 65 μ g/L). Do not coadmin- 63 Recommendations ister with warfarin. IV lipid emulsions are a “hidden” source, preparations reformu- lated to provide 150 μ g/d. with variable amounts (0-290 mum GI absorption is 5 mg. Excess doses are excreted in the urine. Doses of 100 mg/d for patients at risk for defi- especially EtOH ciency, abuse, hemo- and peri- toneal dialysis; malabsorption and . RDA is 150 μ g. IV MV RDA is only 3 mg; maxi- RDA is 1.5 mg/d. RDA ; 68 Serum lev- 69 62 Manifestations els reflect recent intake; not indicative of total body pool. and mucosal changes, mental changes (depres- sion, ) “GI beri-beri” (syndrome of nausea, vomiting, and abdominal pain with lac- tic acidosis). time (may not detect subclinical deficiency states that become pro- nounced after surgery or ). decrease in bone . (beri-beri); mental changes (, confusion, seen in encephalopa- Wernicke’s thy and Korsakoff’s psy- chosis); congestive , heart failure Microcytic anemia, skin Increased prothrombin Deficiency results in neuropathy Peripheral (continued) 66,67 Table 5. Table States ; preclampsia, Deficiency Toxicity/Adverse Deficiency Toxicity/Adverse 35 and bacterial syn- thesis (altered with use). Not stored; deficiencies may occur rapidly. component of ; iatrogenic (when PN or EN is administered without adequate thiamine). In critically ill patients with a high CHO intake. Loop . continuous venovenous renal replacement ther- apy ; use of oral contraceptives, INH. Normal sources are from Alcohol (EtOH) abuse; a Excessive EtOH intake; 62 ketoacids, α Role plasma prothombin [fac- tor II] and factors VII, Also regulates IX, and X). involved in bone formation. lism and in the oxidation of pyruvate, and branched-chain amino acids of amino acids and fatty acids; synthesis of and . Absorbed throughout the entire length of ileum and transported to liver. Excess stores are also found in the muscle. (production of in CHO metabo- Coenzyme in metabolism (thiamine) (pyridoxine) 1 6 Vitamin K Vitamin B Vitamin Vitamin B Vitamin

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Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 (continued) Increased Fe 71 Effects deficiency, leading deficiency, 12 absorption and free Fe, promoting bacterial pro- liferation. Exacerbates symptoms of hemochro- matosis. Increased intakes produce hyper- aoxaluria with renal cal- culi formation. Large doses ( > 3 g/d) may cause diarrhea and GI distur- bances, although gener- ally tolerated during short-term consumption. the diagnosis of vitamin B oxidant. to neurological complications. Excessive doses can mask May function as a pro- , 12 signifi- 6 74 μ g/d, usually Recommendations cantly decreases the incidence of major adverse events following percutaneous coronary interventions. (although 35 mg satu- rates enzyme systems). Standard PN dose is 20 mg/d. EN solutions con- tain 125-250 mg/L. Supplementation recom- mendations are 500- 3000 mg/d. Enhanced formulas contain 80-850 and mg/L. Trauma patients are given increased doses of vita- min C, up to 1000 mg/d. present in standard EN and PN. Doses of 1000 μ g/d are needed in all suspected deficiency states. - lowering therapy using folic acid, vitamin B and vitamin B RDA is 75-90 mg/d RDA RDA is 400 RDA Manifestations and keratosis; ecchymo- sis; poor wound healing; gingivitis, glossitis; ane- mia and fatigue fatigue; ; atrophic glossitis, skin ; increase in serum homocysteine levels Peri-follicular petechiae Peri-follicular Macrocytic anemia, (continued) 73 70 35 Table 5. Table renal replace- 72 States Deficiency Toxicity/Adverse Deficiency Toxicity/Adverse . Previous high scurvy. intake with abrupt cessa- tion of intake may cause rebound scurvy. Requirements are increase in critical ill- ness, especially trauma and . exposure, antiepileptic drugs ment therapy, Classic deficiency state is EtOH abuse; nitrous oxide Role function in syn- thesis, wound healing, and synthesis of neuro- transmitters; required for the synthesis of (important for the metabolism of long- chain triglycerides). Unlike most other mam- mals, vitamin C is not synthesized by humans. of nucleic and amino acids; prevents mega- loblastic anemia; involved with homocys- teine metabolism (of interest in hypercoagula- is tion states). Folate absorbed mainly in the jejunum. Nonenzymatic antioxidant; Coenzyme in metabolism Vitamin C (ascorbic acid) Vitamin acid Folic

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Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 Effects doses are given orally, only a small amount is absorbed from the GI tract. hyperlipidemia) may cuta- cause liver toxicity, neous flushing, nausea, and vomiting, especially in preexisting liver dis- ease, mellitus, and inflammatory bowel disease. None known. When high Excess dose (treatment of 79 g/d) g/wk) or μ g. Correct 77 g) is as μ g may suf- first before 12 nal units; IV, intravenous; MV, multivitamin; intravenous; MV, nal units; IV, g every 1-3 months Recommendations giving folic acid to avoid neurologic deterioration. parenteral Typical replacement dose is 1000 μ (preferred in patients with terminal ileal resec- tion or malabsorption); after serum levels are normalized with higher or more frequent injec- tions, 100 μ fice. Oral Cbl (1000-2000 effective as parenteral administration. Intranasal (200 sublingual (2000 μ administration possible. 40 mg/d. Infused trypto- phan gets partly con- verted to niacin. No specific recommenda- tions for critically ill patients. May present acutely in GI . vitamin B RDA is 12 μ g. PN dose RDA RDA is only 2.4 μ RDA Manifestations ropathy (gait distur- bance, numbness, tingling in extremities), and neuropsychiatric manifestations (loss of , dis- , orientation). Serum homocysteine and methylmalonic acid are decreased in Cbl deficiency. lem, manifested as pella- gra, or dry skin, with a bright red tongue; the classic 3 “Ds” are diar- rhea, dermatitis, and dementia. Macrocytic anemia, neu- Presents as a chronic prob- (continued) 75 ; 75 Table 5. Table States Deficiency Toxicity/Adverse Deficiency Toxicity/Adverse develop a deficiency state. Occurs in elderly patients (due to atrophic gastritis with lack of intrinsic factor) syndrome; hemo- or peritoneal dialysis; INH and 6-mercapto- patients on long-term gastric acid suppression; diseases and resections of terminal ileum (eg, in disease); expo- Crohn’s sure to nitrous oxide. It takes several months to EtOH abuse; carcinoid ) Role + of methyl folate to tetrahydrofolate, thus affecting DNA synthesis. Serves as a coenzyme in conversion of homocys- teine to . Absorbed in terminal ileum. role in antioxidation through dinuleotide (NAD Needed for the conversion Indirect though important ) 12 ) 3 acid, nicotinamide, vitamin B (vitamin B Niacin (nicotinic Cobalamin (Cbl) PN, parenteral nutrition; RAE, retinol activity equivalents; RDA, Recommended Daily Allowance; UVA Ultraviolet A. Ultraviolet Allowance; UVA Recommended Daily PN, parenteral nutrition; RAE, retinol activity equivalents; RDA, CHO, carbohydrate; EN, enteral nutrition; EtOH, alcohol; GI, gastrointestinal; INH, isonicotinic acid ; IU, internatio

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Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 104 (continued) Effects emesis, pain, and diar- rhea) may be seen in doses of 50-150 At recom- mg/day. mended doses, toxicity does not occur. (selenosis) due to EN or PN. Symptoms include brittleness of hair and nails; irritabil- fatigue; peripheral ity, neuropathy; skin rash; and GI symptoms (nausea and emesis). GI symptoms (nausea, No report of toxicity μ g/d. g. RDA is 55 μ g. RDA dose is 2.5-4 mg/d, although higher amounts may be needed as the (enteral) RDA is 8-11 mg/d. Additional 2 mg/d is given in acute catabolism. Short bowel patients lose 3.6 mg Zn/kg of fluid lost, whereas patients with intact small bowel and diar- rhea lose 15.2 mg Zn/kg of enteric fluid. GI losses should preferably be measured and not estimated. intake is 20-100 μ g/d; usual dose is 60 μ g. IV Se is adsorbed by filters and thus not fully available. Ensure that MTE addi- tives containing Se are used. is Enteral RDA 50-100 Monitor plasma levels in renal insufficiency. Recommended PN Recommended PN Tests Recommendations range 70-150 μ g/dL). Levels increase in starva- tion and decrease in infections. Low serum alkaline phosphatase can be used as indirect evidence of Zn deficiency. monly used to determine Se sta- tus) do not accu- rately reflect intakes but acute fluxes between compartments. Erythrocyte GPx levels reflect long- term Se status. Serum level (normal Plasma levels (com- 100 91 ; 89 90 Manifestations Trace Elements Trace worsening hepatic dysfunction. hyperpigmented lesions involving elbows and knees, also called acro- dermatitis entero- pathica), characteristic rash around ala nasi; intoler- ance; poor wound healing; abnormal hemostasis; immune dysfunc- tion; ; altered per- ception (dysgeu- sia), altered smell perception; diar- rhea; decrease in work capacity of muscles with detrimental effects on respiratory function manifesting as congestive heart failure and . (Suspect Se defi- ciency in unex- plained cardiac failure.) Peripheral muscles involve- ment: presents as myositis, with weakness and muscle . Skin changes (dry- ness with Skin rash (scaly, Cardiomyopathy, ; or or 97 87 98 34 36 Table 6. Table GI fistu- 88 99 Not lost via 38 Se loss and States 86 35 Deficiency Laboratory Toxicity/Adverse peritoneal dialy- sis. dialysis (peritoneal), negative Se bal- ance occur with venovenous hemodialysis, (protracted diar- rhea, emesis, high- output fistulas), malabsorption; short bowel syn- drome; trauma, burns; ; pancreatic and renal diseases; high-dose steroids; HIV infection, malignancies; coadministration of ferrous with EN. hemodialysis, free PN or EN trauma, continuous renal replacement therapy. EtOH abuse; HIV infection; resection of duodenum and jejunum. Not lost in intermittent hemodialysis las, and chylous leaks. Excessive GI losses Administration of Se- Absorbed 84,85 GI excretion 95 Metabolism Zn is bound to albu- min; 95% is intracel- Excreted (90%) lular. in feces via bile and pancreatic secretions. Normal urinary Zn loss is low and increased in burns, trauma, and sepsis. acids form the main source; 90% of Se- Met is absorbed in the duodenum and proximal jejunum. Inorganic Se absorp- tion is less efficient. in Transported bound to proteins; 75% of dietary Se is excreted in urine and the rest via GI tract. duodenum and jejunum. offers some protection Dietary seleno amino Good absorption from 83 Role the following major categories: formation of metalloenzymes, RNA conformation, membrane stabiliza- tion, and . Metalloenzymes include carbonic anhydrase, alkaline phosphatase, , and superoxide dismu- tase. Role in carbo- hydrate metabolism, , and wound healing. Present in 2 forms: selenomethionine (Se-Met) and seleno- (Se-Cys). Se-Met can substi- tute for methionine in several tissues and cannot be synthe- sized. Converted to biologically active Se-Cys, present in selenoproteins such as perox- idase (GPx) family Functions fall under Antioxidant function. Zinc Selenium

557 Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 > 2 times nor- delete or Effects 13 13,108 (rise of liver-associated enzymes mal), decrease in PN. delete or decrease in PN. In hepatic insufficiency In hepatic insufficiency, 103 102 μ g. immune-deficient patients benefit from supplemen- tation. In critical illness, high phar- macologic doses (Na-selenite [1000 μ g/d IV]) decrease mortality. Suppresses HIV viral load, although not recommended routinely to all HIV/AIDS patients. whereas daily PN dose is 300-500 whereas daily PN dose is 60-100 μ g. Critically ill and is 900 μ g, RDA AI is 1.8-2.3 mg, Tests Recommendations plasmin level. Circulating levels do not reflect hepatic stores. Serum levels, cerulo- Serum levels 107 30 ; neuro- 106 101 (continued) changes (thinning, light coloration) occur in more severe deficiency states. (including micro- cytic hypochromic anemia) produce defects in carbohydrate and . logic manifesta- tions include ataxia, peripheral and neuropathy, myelopathy. Manifestations erythema) and hair Deficiency known to 105 104 Table 6. Table States Deficiency Laboratory Toxicity/Adverse short-term nutri- tion support but seen in patients receiving long-term PN and EN. Burn patients may develop acute defi- ciencies due to exudative losses. or EN has not been reported. Deficiency is rare in Mn deficiency in PN 96 Metabolism Se loss is positively correlated with urea and creatinine excretion. GI tract, excreted in bile. Low daily requirements. tion is unclear. against toxicity. Renal against toxicity. absorption from Poor Mechanism for absorp- 92 B 93 B) Role that remove ). pro- duction via iodo-thy- ronine . Inhibits nuclear tran- scription factor κ healing and antioxi- dant defense. Cofactor for - loenzymes involved with connective tis- sue cross-linking, noradrenalin synthe- sis. Important role in hematopoiesis. metalloenzymes, including superoxide dismutase. Important for and pyruvate metabolism. (NF- κ expression. (“scavenger” enzymes Important for wound Component of several Copper Manganese AI, Average Intake; EN, enteral nutrition; EtOH, alcohol; GI, gastrointestinal; GPx, ; HIV, human immunodeficiency virus; IV, intravenous; PN, parenteral; virus; IV, human immunodeficiency Intake; EN, enteral nutrition; EtOH, alcohol; GI, gastrointestinal; GPx, glutathione peroxidase; HIV, Average AI, Allowance; RNA, ribonucleic acid; SC, selenium Recommended Daily MTE, multiple trace elements; RDA,

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Cu, and Mn with references.83-108 A brief discussion about needs of the body. Clinical trials that have used the enteral FE, CR, and I is presented below. route for micronutrient supplementation have been con- Fe is an oxygen carrier with its well-known role as a ducted in trauma.119 Although nutrient absorption with major component of . Fe is considered to be hypocaloric enteral feeding seems to be unaffected even in essential for bacterial growth . Anemia and low hemodynamically compromised patients,120 it is generally serum Fe seen in chronic illness are considered to be pro- believed that in critical illness, the quantity of tective mechanisms.109 Free Fe interferes with reticuloen- absorbed by the GI tract is unpredictable due to bowel dothelial system activity, decreases macrophage activity, , edema, or . and promotes growth of , especially gram- There is no need to routinely monitor serum levels of negative bacilli. However, the original concerns were micronutrients as discussed in the earlier section on tox- based on studies done on patients with chronic renal fail- icity. Serum levels must be obtained only if higher ure who have other reasons for increased susceptibility to amounts are administered, to avoid toxicity, especially in infections.110 More recent information suggests that hepatic and renal insufficiency; in specific disease states intravenous Fe does not increase the infection rate fol- such as burns, renal replacement therapy, and GI fistulas; lowing cardiac surgery and may be used safely in the post- and in long-term support.11,13 operative period.111,112 When depleted patients are fed without proper sup- Supplemental enteral Fe (ie, in addition to what is plementation, the refeeding syndrome may occur as a contained in the enteral formula) is not recommended ; this involves not only the well-known during acute illness but may be used during the recovery decreases in serum levels of , , and phase, with or without . We recommend not but also several micronutrients.121 using parenteral Fe in acute illness, especially in cases of Dosage recommendations made in this review have suspected or established infections and sepsis. When Fe been carefully obtained from various sources. However, needs to be added to PN, the formulation appears as commercial formulations may have variable amounts to be safe and is devoid of lipid peroxide formation and is of the active vitamin compound or the elemental form of the preferred form of addition rather than using free Fe.113 trace elements, the clinician is advised to study the pack- Cr is important for attachment of to periph- age insert for detailed information. Until modified trace eral receptor sites and for glucose oxidation, , element additives are available, it may be necessary in , and transport. It is biologically some patients to order each trace element separately, active only in an organic form. Cr should be deleted or although this is more expensive, labor intensive, and decreased in renal insufficiency.114 brings an increased possibility of compounding errors.13 Iodine (I) is not routinely added in PN supplements in the United States, although it is standard in at a dose of 1 μmol/d. The use of I-containing Conclusion results in saturation of the thyroid gland with I. In this review, we provide general guidelines for the use of vitamins and trace elements in nutrition therapy. This General Recommendations should help the clinician to understand the important role of micronutrients as a crucial component of enteral and Micronutrients should be included whenever nutrition parenteral nutrition care, without which nutrition repletion therapy is instituted. Whether a patient has depleted by providing macronutrients alone may be suboptimal. stores due to , suffers severe losses such as the result of a burn, or simply has a critical illness that will sap his or her reserves over the coming days, the micronu- Acknowledgments trient levels must be restored and any remaining reserves preserved. It has been stated that a patient who develops We acknowledge with gratitude the assistance of Mr a micronutrient deficiency while being cared for in a crit- Shyam Sriram, MA, in preparation of the manuscript, and ical care unit has not received good care.115 Micronutrient of Ms Tissy Cyriac, RN, CNSN, in obtaining updated and supplementation should begin on the first day of nutrition accurate reference materials. therapy and continue daily. In burns, early administration of micronutrients has been shown to be beneficial.116-118 Additional supplementation is needed when there is an References identifiable deficiency. The most reliable of micronutri- 1. Berger MM. Can oxidative damage be treated nutritionally? Clin Nutr. 2005;24:172-183. ents is intravenous, as we can be more confident of the levels 2. Vrees MD, Albina JE. Metabolic response to illness and its achieved. The gut is the ideal way of administering vitamins mediators. In: Rombeau JL, Rolandelli RH, eds. : and minerals as it can regulate absorption according to the Parenteral Nutrition. Philadelphia, PA: WB Saunders; 2000:21.

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3. Sriram K, Cue J. Micronutrients in critical care. In: Cresci G, ed. 25. Louw JA, Werbeck A, Louw MEJ. Blood vitamin concentrations Nutrition Support in the Critically Ill. Boca Raton, FL: Taylor & during the acute phase response. Crit Care Med. 1992;20:934-941. Francis, CRC Press; 2005:109-123. 26. Agarwal N, Norkus E, Garcia C. Effect of surgery on serum antiox- 4. Nutrition Advisory Group. Multivitamin preparations for idant vitamins. JPEN J Parenter Enteral Nutr. 1996;20(suppl):32S. parenteral use. JPEN J Parenter Enteral Nutr. 1975;3:258-262. 27. Stephenson D, Alvarez JO, Kohatsu J. Vitamin A is excreted in the 5. American Medical Association, Department of and urine during acute infection. Am J Clin Nutr. 1994;60:388-392. Nutrition. Guidelines for essential trace element preparations for 28. Berger MM, Chiolero RL. Key vitamins and trace elements in the parenteral use: a statement by an expert panel. JAMA. 1979; critically ill. In: Cynober L, Moore FA, eds. Nutrition and Critical 241:2051-2054. Care: Nestle Nutrition Workshop Series Clinical & Performance 6. Otten JJ, Hellwig JP, Meyers LD, eds. Dietary Reference Intakes: Program. Vol. 8. Basel, Switzerland: Nestec, Ltd; 2003:99-117. The Essential Guide to Nutrient Requirements. Washington, DC: 29. Clark SF. Vitamins and minerals. In: Gottschlich MM, ed. The National Academies Press; 2006. ASPEN Nutrition Support Core Curriculum. Spring, MD: 7. Elia M. Changing concepts of nutrient requirements in disease: American Society for Parenteral and Enteral Nutrition; 2007:148. implications for artificial nutritional support. Lancet. 1995;5: 30. Tan JC, Burns DL, Jones HR. Severe ataxia, myelopathy and 1279-1284. due to acquired . JPEN J 8. Solomons NW, Ruz M. Trace element requirements in humans: an Parenter Enteral Nutr. 2006;30:446-450. update. J Trace Elem Exp Med. 1998;11:177-195. 31. Johnson KA, Bernard MA, Funderburg K. Vitamin nutrition in 9. Schorah CJ, Downing C, Piripitsi A. Total vitamin C, ascorbic acid, older adults. Clin Geriatr Med. 2002;18:773-799. and concentrations in plasma of critically ill 32. Kopple JD. Renal disorders and nutrition. In: Shils ME, Olson JA, patients. Am J Clin Nutr. 1996;63:760-765. Shike M, Ross AC, eds. Modern Nutrition in and Disease. 10. Food and Drug Administration (FDA) Parenteral multivitamin 9th ed. Baltimore, MD: Williams & Wilkins; 1999:1439. products; drugs for human use; drug efficacy study implementa- 33. Pilkey RM, Morton A, Noordhof MB. Subclincial vitamin K defi- tion; amendment. Federal Register. 2000;65:21200-21201. ciency in hemodialysis patients. Am J Dis. 2007;49:432-439. 11. A.S.P.E.N. Board of Directors and the Clinical Guidelines Task 34. Story DA, Ronco C, Bellomo R. Trace element and vitamin con- Force: Guidelines for the use of parenteral and enteral nutrition in centrations and losses in critically ill patients treated with continu- adult and pediatric patients. JPEN J Parenter Enteral Nutr. ous venovenous hemofiltration. Crit Care Med. 1999;27:220-223. 2002;26(suppl):22SA-24SA. Errata 2002;26(2):144. 35. Fortin M-C, Amyot S-L, Geadah D, Leblanc M. Serum concentra- 12. Fuhrman PM, Herrmann VM. Micronutrients in critical illness. In: tions and clearances of folic acid and pyridoxal-5′-phosphate dur- Shikora SA, Martindale RG, Schwaitzberg SD, eds. Nutritional ing venovenous continuous renal replacement therapy. Intens Care Considerations in . Silver Spring, MD: American Med. 1999;25:594-598. Society for Parenteral and Enteral Nutrition; 2002:51-60. 36. Sriram K, Abraham G. Zinc and selenium loss does not occur with 13. Howard L, Ashley C, Lyon D, Shenkin A. Autopsy tissue trace ele- peritoneal dialysis. Nutrition. 2000;16:1047-1051. ments in 8 long-term parenteral nutrition patients who received 37. Halsted CH. Nutrition and . Semin Liver Dis. the current U.S. Food and Drug Administration formulation. JPEN 2004;24:289-304. J Parenter Enteral Nutr. 2007;31:388-396. 38. de Berranger E, Colinet S, Michaud L, et al. Severe selenium defi- 14. Lyon TDB, Fell GS, Hall SDJ, Clark J, McKenna F. Determination ciency secondary to chylous loss. JPEN J Parenter Enteral Nutr. of nine inorganic elements in human autopsy tissue. J Trace Elem 2006;30:173-174. Electrolytes Health Dis. 1989;31:109-118. 39. Schilling RF. Is nitrous oxide a dangerous anesthetic for vitamin

15. Francini-Pesenti F, Brocadello F, Famengo S, Nardi M, Caregaro B12-deficient subjects? JAMA. 1986;255:1605-1606. L. Wernicke’s during parenteral nutrition. JPEN J 40. Ponsky TA, Brody F, Pucci E. Alterations in gastrointestinal Parenter Enteral Nutr. 2007;31:69-71. after Roux-en-Y gastric bypass. J Am Coll Surg. 2005;201: 125-131. 16. Prelack K, Sheridan RL. Micronutrient supplementation in the 41. Abell TL, Minocha A. Gastrointestinal complications of bariatric critically ill patient: strategies for clinical practice. J Trauma. surgery: diagnosis and therapy. Am J Med Sci. 2006;331:214-218. 2001;51:601-620. 42. Kushner R. Managing the obese patient after bariatric surgery: a 17. Clark SF. Vitamins and minerals. In: Gottschlich MM, ed. The case report of severe malnutrition and review of the literature. ASPEN Nutrition Support Core Curriculum. Silver Spring, MD: JPEN J Parenter Enteral Nutr. 2000;24:126-132. American Society for Parenteral and Enteral Nutrition; 2007:130-162. 43. Abad-Lacruz A, Fernandez-Banares F, Cabre E, et al. The effect of 18. Berger MM, Shenkin A. Update on clinical micronutrient supple- total enteral tube feeding on the vitamin status of malnourished mentation studies in the critically ill. Curr Opin Clin Nutr Metab patients with inflammatory bowel disease. Int J Vit Nutr Res. Care. 2006;9:711-716. 1988;58:428-435. 19. Tang AM, Lanzillot J, Hendricks K, Gerrior J, Ghosh M, Woods M. 44. Inculet RI, Nortan JA, Nichoalds FE, Maher MM, White DE, Micronutrients: current issues for HIV care providers. AIDS. Brennan MF. Water-soluble vitamins in cancer patients on par- 2005;19:847-861. enteral nutrition: a prospective study. JPEN J Parenter Enteral 20. Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant Nutr. 1987;11:243-249. nutrients: a systematic review of trace elements and vitamins in the 45. Stephensen CB. Vitamin A, infection and immune function. Annu critically ill patient. Intens Care Med. 2005;31:327-337. Rev Nutr. 2001;21:167-192. 21. Sriram K, Sridhar R. Gastroduodenal decompression and simulta- 46. Hunt TK. Vitamin A and wound healing. J Am Acad Dermatol. neous nasoenteral nutrition: “extracorporeal gastrojejunostomy.” 1986;15:817-821. Nutrition. 1996;12:440-441. 47. Stephenson D, Alvarez JO, Kohatsu J. Vitamin A is excreted in the 22. Demling RH, De Biasse MA. Micronutrients in critical illness. Crit urine during acute infection. Am J Clin Nutr. 1994;60:388-392. Care Clin. 1995;11:651-673. 48. Gottschlich MM, Warden GD, Michel P, et al. Diarrhea in tube- 23. Kenny F, Sriram K, Hammond J. Clinical zinc deficiency during fed patients: incidence, etiology, nutritional impact and preven- adequate enteral nutrition. J Am Coll Nutr. 1989;8:83-85. tion. JPEN J Parenter Enteral Nutr. 1988;12:338-345. 24. Galloway P, McMillan DC, Sattar N. Effect of the inflammatory 49. Hunt TK, Ehrlich HP, Garcia JA, Dunphy JE. Effect of vitamin A response on trace element and vitamin status. Ann Clin Biochem. on reversing the inhibitory effect of cortisone on healing of open 2000;37:289-297. wounds in animals and man. Ann Surg. 1969;170:633-641.

Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 Micronutrients in Adults / Sriram, Lonchyna 561

50. Miksad R, deLedinghen V, McDoughall C, Fiel I, Rosenberg H. 75. Andres E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) defi- Hepatic hydrothorax associated with vitamin A toxicity. J Clin ciency in elderly patients. CMAJ. 2004;171:251-259. Gastroenterol. 2002;34:275-379. 76. Kinsella LJ, Green R. “Anesthesia paresthetica”: nitrous oxide- 51. Gleghorn EE, Eisenberg LD, Hack S. Observations of vitamin A induced cobalamin deficiency. . 1995;45:1608-1610. toxicity in three patients with renal failure receiving parenteral ali- 77. Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin

mentation. Am J Clin Nutr. 1986;44:107-112. B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. 52. Bhalla K, Ennis DM, Ennis ED. Hypercalcemia caused by iatro- Cochrane Database Syst Rev. 2005;(3):CD004655.

genic A. J Am Diet Assoc. 2005;105:119-121. 78. Dharmarajan TS, Adiga GU, Norkus EP. Vitamin B12 deficiency: 53. Holick MF. : what a pain it is. Mayo Clin recognizing subtle symptoms in older adults. . 2003;58: Proc. 2003;78:1457-1459. 30-38. 54. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D con- 79. Sriram K, Jayanthi V, Suchitra D. Acute niacin deficiency. centrations, and safety. Am J Clin Nutr. 1999;69:842-856. Nutrition. 1996;2:355-357. 55. Goode HF, Cowley HC, Walker BE, Howdle PD, Webster NR. 80. Chattha G, Arieff AI, Cummings C, Tierney LM Jr. Lactic acidosis Decreased antioxidant status and increased lipid peroxidation in complicating the acquired immunodeficiency syndrome. Ann patients with and secondary organ dysfunction. Crit Intern Med. 1993;118:37-39. Care Med. 1995;23:646-651. 81. Fouty F, Frerman F, Reves R. Riboflavin to treat nucleoside ana- 56. Grant JP. Nutritional support in critically ill patients. Ann Surg. logue-induced lactic acidosis. Lancet. 1998;352:291. 1994;220:610-616. 82. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, 57. Greenwald DP, Scharzer LA, Padawer J, Levenson SM, Seifter E. Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, , Zone II flexor tendon repair: effects of vitamins A, E and beta- Silicon, Vanadium and Zinc. Vol. 12. Washington, DC: National carotene. J Surg Res. 1990;49:98-102. Academies Press; 2002:442-501. 58. Jandak J, Steiner M, Richardson PD. Alpha-tocopherol, an 83. Cousins RJ. Zinc. In: Ziegler EE, Filer LJ, eds. Present Knowledge effective inhibitor of platelet adhesion. Blood. 1989;73:141-149. of Nutrition. 7th ed. Washington, DC: International Life Sciences 59. Herbert V. Destroying immune in normal adults with Institute, North America; 1996:293-306. antioxidant supplements. Am J Clin Nutr. 1997;65:1901-1903. 84. Griffin IJ. Zinc physiology and therapeutics: recent insights. US 60. Seeger W, Ziegler A, Wolf HR. Serum alpha-tocopherol levels after Dept of Agriculture/Agricultural Research Services. http://www. high-dose enteral vitamin E administration in patients with acute cyberounds.com/conf/nutrition/2007-09-11. Accessed March 10, respiratory failure. Intens Care Med. 1987;13:395-400. 2008. 61. Meyers DG, Maloley PA, Weeks D. Safety of . Arch 85. Solomons NW. Biological availability of zinc in humans. Am J Clin Intern Med. 1996;156:925-935. Nutr. 1982;35:1048-1075. 62. Bolton-Smith C, McMurdo ME, Paterson CR, et al. Two-year ran- 86. Kenny F, Sriram K, Hammond JB. Clinical zinc deficiency during

domized controlled trial of vitamin K1 (phylloquinone) and vitamin adequate enteral nutrition. J Am Coll Nutr. 1989;8:83-85.

D3 plus calcium on bone health of older women. J Bone Miner Res. 87. Mansouri K, Halsted JA, Gombos EA. Zinc, copper and calcium in 2007;22:509-519. dialysed and nondialysed uremic patients. Arch Intern Med. 63. Helphingstine CJ, Bistrian BB. New food and drug administration 1970;125:88-93. requirements for inclusion of vitamin K in adult parenteral multi- 88. Klein CJ, Moser-Veillon PB, Schweitzer A, et al. Magnesium, cal- vitamins. JPEN J Parenter Enteral Nutr. 2003;27:220-224. cium, zinc and loss in trauma patients during continuous 64. Lennon C, Davidson KW, Sadowski JA. The vitamin K content of renal replacement therapy. JPEN J Parenter Enteral Nutr. intravenous lipid emulsions. JPEN J Parenter Enteral Nutr. 2002;26:77-92. 1993;17:142-144. 89. Kumar S, Sehgal VN, Sharma RC. Acrodermatitis enteropathica. J

65. Chambrier C, Leclercq M, Saudin F, et al. Is vitamin K1 supple- Dermatol. 1997;24:135-136. mentation necessary in long-term parenteral nutrition? JPEN J 90. Van Loan MD, Sutherland B, Lowe NM. The effects of zinc deple- Parenter Enteral Nutr. 1998;22:87-90. tion on peak force and total work of knee and shoulder extensor 66. Cruickshank AM, Telfer AB, Shenkin A. in and flexor muscles. Int J Sport Nutr. 1999;9:125-135. the critically ill. Intens Care Med. 1988;14:384-387. 91. Leverve XM, Piquet M-A. Liver function alteration and insuffi- 67. Kim CYP, Han MS, Jang HJ, Kim JS, Kim YH, Lee SG. Severe lac- ciency. In: Pichard C, Kudks KA, eds. From Nutrition Support to tic acidosis and thiamine deficiency during total parenteral nutri- Pharmacologic Nutrition in the ICU: Update in Intensive Care tion: case report. Hepatogastroenterology. 2004;51:253-255. Medicine. New York, NY: Springer; 2002:288-302. 68. Brady JA, Rock CL, Horneffer MR. Thiamin status, med- 92. Berger MM, Reymond MJ, Shenkin A, et al. Influence of sele- ications, and the management of congestive heart failure. J Am nium supplements on the post-traumatic alterations of the thy- Diet Assn. 1995;95:541-544. roid axis: a -controlled trial. Intens Care Med. 2001;27: 69. Donnino M. Gastrointestinal beriberi: a previously unrecognized 91-100. syndrome. Ann Int Med. 2004;41:898-899. 93. Flohe L, Brigelius-Flohe R, Saliou C, Traber MG, Packer L. 70. Omaye ST, Skala JH, Jacob RA. with ascorbic acid regulation of NF-kappa B activation. Free Radic Biol Med. in adult males. Am J Clin Nutr. 1988;48:379-381. 1997;22:1115-1126. 71. Halliwell B. , nutrition and health: experimental 94. Moosmann B, Behl C. Selenoprotein synthesis and side effects of strategies for optimization of nutritional antioxidant intake in . Lancet. 2004;363:892-894. humans. Free Radic Res. 1996;25:57-74. 95. Yoneyama S, Miura K, Itai K, et al. Dietary intake and urinary 72. Chanarin I. The effects of nitrous oxide on cobalamins, , excretion of selenium in the Japanese adult population: the and on related events. Crit Rev Toxicol. 1982;10:179-213. INTERMAP Study Japan. Eur J Clin Nutr. 2007. http://www 73. Goldman WJ. Epileptogenic activity of folic acid (comment). Eur J .nature.com/ejcn/journal/vaop/ncurrent/abs/1602842a.html. Obset Gynecol Reprod Biol. 2000;82:217-219. Accessed April 22, 2008. 74. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of 96. Oster O, Prellwitz W. The renal excretion of selenium. Biol Trace

homocysteine-lowering therapy with folic acid, vitamin B12 and Elem Res. 1990;24:119-146.

vitamin B6 on clinical outcome after percutaneous coronary inter- 97. Yagi M, Tani T, Hashimoto T, et al. Four cases of selenium defi- vention: the Swiss heart study: a randomized controlled trial. ciency in postoperative long-term enteral nutrition. Nutrition. JAMA. 2002;288:973-979. 1996;12:40-43.

Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 562 Journal of Parenteral and Enteral Nutrition / Vol. 33, No. 5, September/October 2009

98. Berger MM, Shenkin A, Revelly J-P, et al. Copper, selenium, zinc 111. Torres S, Kuo Y-K, Morris K, Neibart R, Holtz JB, Davis JM. and thiamine balances during continuous venovenous hemodiafil- Intravenous iron following cardiac surgery does not increase the tration in critically ill patients. Am J Clin Nutr. 2004;80:410-416. infection rate. Surg Infect. 2006;7:361-366. 99. Berger MM, Cavadini C, Chiolero R, Dirren H. Copper, selenium 112. Swoboda SM, Lipsett PA. Intravenous iron as a risk factor for bac- and zinc status and balances after major trauma. J Trauma. teremia in the surgical intensive care unit patient. Surg Infect. 1996;40:103-109. 2005;6:158. 100. Johnson RA, Baker SS, Fallon JT, et al. An occidental case of car- 113. Lavoie JC, Chessex P. Bound iron admixture prevents the sponta- diomyopathy and . N Engl J Med. 1981;304: neous generation of peroxides in total parenteral nutrition solu- 1210-1212. tions. J Pediatr Gastroenterol Nutr. 1997;25:307-311. 101. Kanekura T, Yotsumoto S, Maeno N, et al. Selenium deficiency: 114. Moukarzel AA, Song MK, Buchman AL, et al. Excessive chromium report of a case. Clin Exp. 2005;30:346-348. intake in children receiving total parenteral nutrition. Lancet. 102. Angstwurm MWA, Engelmann L, Zimmermann T, et al. Selenium 1992;339:335-388. in intensive care: results of a prospective randomized, placebo-con- 115. Berger MM, Shenkin A. Vitamins and trace elements: practical trolled, multiple-center study in patients with severe systemic aspects of supplementation. Nutrition. 2006;22:952-955. inflammatory response syndrome, sepsis and septic shock. Crit 116. Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Care Med. 2007;35:118-126. Shimazaki S. Reduction of resuscitation fluid volumes in severely 103. Hurwitz BE, Klaus JR, Llabre MM, et al. Suppression of human burned patients using ascorbic acid administration. Arch Surg. immunodeficiency virus type I viral load with selenium supple- 2000;135:326-331. mentation. Ann Intern Med. 2007;167:148-154. 117. Angswrum MWA, Schottdorf J, Schopohl J, Gaertner R. Selenium 104. Levander OA, Burk RF. Selenium. In: Ziegler EE, Filer LJ, eds. replacement in patients with severe systemic inflammatory Present Knowledge of Nutrition. 7th ed. Washington, DC: response syndrome improves clinical outcome. Crit Care Med. International Life Sciences Institute, North America; 1996:320-328. 1999;27:1807-1813. 105. Oliver A, Allen KR, Taylor J. Trace element concentrations in 118. Berger MM, Spertini F, Shenkin A, et al. Trace element supple- patients on home enteral feeding: two cases of severe copper defi- mentation modulates pulmonary infection rates after major burns: ciency. Ann Clin Biochem. 2005;42:136-140. a double-blind placebo-controlled trial. Am J Clin Nutr. 106. Berger MM, Cavadini C, Bart A. Cutaneous zinc and copper losses 1998;68:365-371. in burns. Burns. 1992;18:373-380. 119. Porter JM, Ivatury RR, Azimuddin K. Antioxidant therapy in the 107. Buchman AL. Manganese. In: Shils ME, Shike M, Ross AC, prevention of organ dysfunction syndrome and infectious compli- Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. cations after trauma: early results of a prospective randomized 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:326-331. study. Am Surg. 1999;65:478-483. 108. Dickerson RN. Manganese toxicity and parenteral nutrition. 120. Berger MM, Berger-Gryllaki M, Wiesel PH. Gastrointestinal Nutrition. 2001;17:689-693. absorption after cardiac surgery. Crit Care Med. 2000;28: 109. Williams P, Griffiths E. Bacterial receptors: structure, 2217-2223. function and contribution to virulence. Med Microbiol Immunol. 121. Crook MA, Hally V, Panteli JV. The importance of the refeeding 1992;181:301-322. syndrome. Nutrition. 2001;17:632-637. 110. Hoen B, Kessler M, Hestin D, Mayeux X. Risk factors for bacter- 122. Mirtallo J. Parenteral formulas. In: Rombeau JL, Rolandelli RH, ial infections in chronic hemodialysis adult patients: a multicenter eds. Parenteral Nutrition. 3rd ed. Philadelphia, PA: WB Saunders; prospective survey. Nephrol Dial Transplant. 1995;10:337-381. 2001:124.

Downloaded from pen.sagepub.com by Karrie Derenski on April 1, 2013 Support Line Volume 33 No. 3 7 Developing a Plan of Care for Fluid and Electrolyte Management Kristen M. Rhoda, MS, RD, LD, CNSD Mary Jo Porter, RD, LD, CNSC

Abstract Fluid and electrolyte management requires Table 1. Electrolyte Content of Intravenous Fluid Solutions in mEq/L (5) assessment of hydration, renal function, and Source Na Cl K+ Lactate Dextrose mOsm acid-base balance as well as an understanding NS 154 154 00 0 280 to 300 of the relationship between electrolytes and their movement within total body water. D5W 00 00 50 250 This article discusses the assessment of fluid D5, 0.45NS 77 77 00 50 400 andelectrolytesandprovidesrecommendations D5, 0.9NS 154 154 00 50 560 to promote the prevention and treatment of electrolyte abnormalities. LR 130 109 4 28 0 270 D5, LR 130 109 4 28 50 525 Cl=chloride, D5=5% dextrose solution, D5W=5% dextrose solution in water, K+=potassium, Introduction LR=lactated Ringer solution, Na=, NS=normal Electrolyte management is challenging for clinicians because of the complexity of the required assessment to provide treatment to as hypovolemia. Volume depletion may significant role in transporting molecules recommendations. Hydration status, renal result from ; insufficient intake; across membranes (5). Sodium imbalances function,,metabolicsyndromes, “third spacing”; or with any abnormal losses result from fluctuations in hydration and and acid-base balance all affect electrolyte from the skin, kidneys, or gastrointestinal renal function or abnormal losses through balance and must be considered during the (GI) tract. Symptoms include dry oral urine, sweat, and GI secretions. The assessment process. mucosa, poor skin turgor, tachycardia, and assessment of sodium balance must include hypotension. Elevated blood urea nitrogen an evaluation of hydration status, urine Fluid Balance (BUN), creatinine, BUN-to-creatinine ratio, concentration, and intake/output records. Total body water (TBW) comprises about and are seen in hypovolemia, but Calculations of factors such as serum 50% of body weight in women and about these laboratory parameters are neither osmolality, sodium deficit, and TBW can 60% of body weight in men (1). About two- sensitive nor specific markers (4). Treatment assist in understanding the cause of the thirds of TBW is within the intracellular fluid of volume depletion involves replacement imbalance (Table 2). (ICF) and one-third of TBW is contained of ECF losses (2), which requires an isotonic within extracellular fluid (ECF), which is solution such as normal saline (NS) or lactated is the most common comprised of intravascular, interstitial, and Ringer (LR) to replace losses (Table 1). In electrolyte abnormality in hospitalized transcellular fluid. The movement of water contrast, treatment for dehydration without patients, with symptoms developing at between compartments is driven, in part, concomitant volume depletion is the provision concentrations less than 120 mEq/L (Table by the osmolality of body fluids, which is of free water such as a 5% dextrose solution, 3) (4). Treatment for hyponatremia starts the ratio of solutes to water in milliosmoles which expands both fluid compartments, with determining the current fluid balance. per . Isotonic solutions share the predominantly into the ICF (2). Hypervolemic hyponatremia usually same osmolality as body fluids (280 to 300 requires fluid restriction or administration mOsm/kg), and any imbalance between Volume overload involves water retention of a diuretic because the total body sodium TBW and solute concentration may result in with a decrease in body sodium concentrations is normal or slightly elevated. Hypovolemic fluid shifts and electrolyte imbalances (2). (2). It is characterized by weight gain, edema, hyponatremia results from a deficit in TBW ascites, elevated blood pressure, and and sodium that responds to volume Volume depletion refers to the loss of sodium pulmonary edema (4). Treatment includes replacement of NS or LR. In either case, the and water from the extracellular space; limitation of sodium and fluid intake and sodium concentration must be corrected dehydration results from loss of intracellular correction of the underlying cause. In some slowly at a rate of 0.5 mEq/L/hr for chronic water, which raises plasma sodium cases, diuretic therapy may be required. hyponatremia (developed over 2 to 3 days) concentrations and serum osmolality (1,3). and up to 1 to 2 mEq/L/hr for acute In most cases, patients who are dehydrated Sodium hyponatremia (developed <48 hours) (7). have concomitant volume depletion, but it is Sodium, the most abundant extracellular Correcting hyponatremia too quickly may important to be aware that volume depletion cation, is a key determinant in regulating induce neurologic complications (7). Half of and dehydration are often collectively referred fluid and acid-base balance, and has a (Continued on next page) 8 Support Line June 2011

1 1 the estimated sodium deficit should be Treatment for also starts water, ⁄2 NS, or ⁄4 NS (Table 4). No more than replaced during the first 24 hours and the with determining the current fluid balance. half the calculated water deficit should be remainder over the next 24 to 72 hours. Use Hypovolemic hypernatremia is a result of replaced over the first 24 hours, with of a 3% sodium chloride solution should be both sodium and TBW loss that responds complete correction occurring over the reserved for severe, symptomatic to NS until euvolemia is restored. Further next 48 to 96 hours (Table 2). Hypervolemic hyponatremia (Table 4). correction of hypernatremia can be achieved hypernatremia is typically iatrogenic and through administration of 5% dextrose in may require restrictions in both fluid and sodium. Patients experiencing symptomatic hypernatremia should have serum sodium Table 2. Equations Used to Assess Electrolyte Abnormalities (2,6,7) monitored every 2 to 4 hours, and Electrolyte Normal Range Equations should continue every 4 to 8 hours once symptoms have resolved and the serum Corrected 1.7 to 2.5 mg/dL Serum Mg2+ x 0.005(40 – serum sodium concentration has normalized (7). magnesium (Mg2+) albumin mg/dL) Corrected calcium 8.0 to 11.0 mg/dL ([4 – serum albumin (g/dL)] x 0.8) + Chloride and Acetate measured calcium (mg/dL) Chloride and acetate are anions found Total body water (TBW) n/a (men) = 0.6 L/kg x weight in kg primarily in the ECF that are essential to (women) = 0.5 L/kg x weight in kg maintaining osmotic pressure and acid- base balance (2). Imbalances in chloride and Sodium deficit (mEq) n/a TBW x (140 – measured serum sodium acetate may result from hypovolemia or an concentration mEq/L) acid-base imbalance. Assessment of these Water deficit (in L) n/a TBW x ([serum sodium concentration anions includes evaluation of hydration mEq/L/140] – 1) status, serum trends, and ventilator settings, Serum osmolality (sOsm) 280 to 300 mOsm/L (2 x serum sodium in mEq/L) + (serum when indicated. Chloride and acetate have glucose in mg/dL/18) + (BUN in an inverse relationship; as one increases, mg/dL/2.8) the other decreases. Adjustments to acetate are based on fluctuations in serum HCO3- deficit (mmol) n/a 0.5 x ([HCO3-] normal – [HCO3-] (HCO -) concentrations, which measured) 3 are reported in the laboratory results as BUN=blood urea nitrogen, HCO3-=bicarbonate, n/a=not available - dioxide (CO2). Because HCO3 is not compatible with parenteral nutrition (PN), due to precipitation of calcium and Table 3. Commonly Observed Symptoms During (2-4) magnesium in the solution, acetate is Electrolyte Elevation Depletion provided in PN, which is converted to HCO - (1:1) in the liver (Table 2) (1,11). Calcium Present in concentrations Hyperactive reflexes, muscle cramps, 3 >11 mg/dL; lethargy, , numbness with tingling of fingers, Patients receiving intravenous fluids (IVFs) nausea, vomiting, , tetany, convulsions or PN should respond to an adjustment in confusion, coma the chloride and acetate provision in the Phosphorus Anorexia, nausea, vomiting, Confusion, , coma, chest pain, - solution. Oral and IV sodium HCO3 may be hyperactive reflexes, tetany, difficulty speaking or breathing, administered as needed for correction of tachycardia, muscle weakness weakness, joint stiffness acid base imbalances (2). Magnesium Nausea, vomiting, diaphoresis, Weakness, lethargy, muscle cramps, altered mental status, coma, mood changes, confusion, vomiting Potassium muscle weakness Potassium is the primary intracellular Sodium Increased thirst, fatigue, Nausea, vomiting, , muscle cation, with about 98% of total body restlessness, muscle irritability, cramps, disorientation, weakness, potassium found in cells (2). It is essential seizures, coma and lethargy, confusion, dizziness, , for cellular metabolism, neuromuscular coma and death function, and protein/ synthesis. It is primarily regulated by the kidneys and Potassium Muscle cramping, weakness, Constipation, lethargy, weakness, is lost through urine, the GI tract, and skin, electrocardiographic changes, leg cramps resulting in a variety of symptoms (Table 3). The balance of potassium between Support Line Volume 33 No. 3 9

Table 4. Considerations for Treatment of Electrolyte Abnormalities (2,4,8-10) Electrolyte Elevation Depletion Calcium Oral Oral • Low-calcium diet • 1,000 to 1,500 mg/day IV IV (tetany present) • Increased infusion of NS • 10 to 20 mL of 10% over ≥4 hrs Phosphorus Oral Oral • Low-phosphorus diet • Increased dietary intake • Phosphate binders • Oral supplementation (i.e., Na3PO4) IV IV (Moderate) • Assess the need for volume repletion • 0.32 to 0.64 mmol/kg (maximum, 30 mmol) Na3PO4 slowly over 6 hrs IV (Severe) • 1 mmol/kg (maximum, 80 mmol) Na3PO4 slowly over 8 to 12 hrs Magnesium Oral Oral • Remove magnesium-containing medications • Increased dietary intake • Consider starting diuretics • Oral supplementation (i.e., magnesium lactate) IV IV (Mild-to-moderate) • Start 10 mL of a 10% calcium gluconate solution • 8 to 32 mEq daily (maximum, 1.0mEq/kg) slowly, with in severe cases each 8 mEq given over 1 to 2 hrs IV (Severe) • 32 to 64 mEq daily (maximum, 1.5 mEq/kg) slowly, with each 8 mEq given over 1 to 2 hrs Sodium Oral Oral • Low-sodium diet • Consider free water restriction • Increase oral fluid intake IV (Mild-to-moderate) IV • Consider free water restriction 1 • Decrease or discontinue administration of • Provision of ⁄2 NS or NS (correct at a rate of sodium, with replacement of water deficit 1 to 2 mEq/L/hr) IV (Severe) • 3% sodium chloride Potassium Oral Oral • Low-potassium diet • Increased dietary intake • Remove potassium-sparing medications • Oral supplementation (40 to 100 mEq daily) • Start diuretics IV (Mild-to-moderate) IV (Asymptomatic) • 20 to 40 mEq* • Sodium bicarbonate (50 to 100 mEq) IV (Severe) • Dextrose infusion (25 to 100 g with • 40 to 80 mEq* 5 to 10 units insulin) IV (Symptomatic): • Calcium gluconate (1 to 2 g)

IV=intravenous, NS=normal saline, Na3PO4=sodium phosphate *Not to exceed 20 mEq/hr without electrocardiographic monitoring intracellular and extracellular compartments move extracellularly when acidemia is Potassium can be replaced with either is controlled by the sodium-potassium- being corrected (2). Thus, these two chloride, acetate, or phosphate. Potassium pump (2). have an inverse relationship. chloride is best used with a volume deficit, Hypomagnesemia must be corrected to potassium acetate may be administered to facilitate the correction of Asymptomatic or mild hypokalemia correct acid-base imbalances, and potassium because magnesium plays a vital role in the (3.0 to 3.5 mEq/L) can be treated orally; phosphate should be administered to functioning of the pump. Correction of symptomatic or severe hypokalemia patients at high risk for refeeding syndrome acid-base imbalances results in potassium (<2.5 mEq/L) requires intravenous (IV) (Table 4) (2). may require - and HCO3 shifts because potassium tends replacement (7). Replacing a potassium dietary restriction, volume repletion, a drug- - to move intracellularly and HCO3 tends to deficit may take up to several days. (Continued on next page) 10 Support Line June 2011 reducing agent such as a or supplementation. with cases of severe and sodium polystyrene sulfonate, or the concomitant hypomagnesemia requires hypercalcemia because a product greater provision of IV calcium for patients replacement of magnesium before starting than 70 can lead to precipitation, experiencing electrocardiographic changes calcium repletion. For asymptomatic causing calcium deposits in soft tissues (2). (Table 4) (7). In asymptomatic patients, patients who have hypocalcemia, oral In these cases, dialysis may be required. - sodium HCO3 or dextrose supplementation supplementation should be increased to may help drive the potassium intracellularly 1,000 to 1,500 mg/day (Table 4) (2). Magnesium (5). Before treating hyperkalemia, it is Magnesium is an intracellular cation vital for important to ascertain that the blood sample Hypercalcemia can often be corrected with regulation of macronutrient metabolism is not hemolyzed, and for patients receiving improved hydration and ambulation. For and the sodium-potassium-adenosine PN or IV potassium, the clinician must ensure severe cases, rapidly infused NS to increase triphosphate pump that also significantly that blood has not been contaminated at renal excretion of calcium, followed by contributes to the maintenance bone blood draw by the PN or IV potassium. initiation of diuretics to reduce serum structure and muscle contraction (2,5). calcium concentrations, is needed (5). Magnesium imbalances are typically a result Calcium Dietary restriction should be used in the of decreased GI function, increased urinary Calcium is an extracellular cation found setting of chronic hypercalcemia; dialysis is losses, and renal failure, resulting in a primarily in and teeth that is essential reserved for patients who are refractory to variety of symptoms (Table 3). Renal for many physiologic functions, including treatment or who are at risk for calcium function and hydration status must be bone metabolism and muscle contraction (2). phosphate salt precipitation. assessed with serum magnesium values. Calcium imbalances result from altered Total serum magnesium is not a good intestinal absorption or urinary excretion, Phosphorus indicator of intra- and extracellular abnormal magnesium and phosphorus Phosphorus is the primary intracellular magnesium status because values are concentrations, and altered parathyroid anion and has many essential functions, affected by protein status (2). Serum function, which can create a variety of including macronutrient metabolism, magnesium values can be used once symptoms (Table 3). Because calcium neuromuscular function, and aiding in corrected for hypoalbuminemia (Table 2) balance is regulated by (parathyroid building bones and teeth (2). Phosphate or ionized magnesium can be used as a hormone and calcitonin) and vitamin/mineral imbalances result from abnormal renal more reliable indicator of both intra- status (e.g., vitamin D, phosphorus), these function, altered intestinal absorption, or and extracellular magnesium status (2). parameters must be evaluated (2). redistribution across cellular membranes, Hypokalemia and hypocalcemia are often leading to a variety of symptoms (Table 3) reported in the presence of hypomagnesemia Total plasma calcium concentrations are that should be assessed during the and require magnesium repletion before affected by protein status because evaluation of a phosphorus imbalance (6). supplementing potassium and calcium (5). approximately 50% of calcium is protein- Unfortunately, assessing physical signs of bound (2). Assessment of ionized calcium is Asymptomatic, mild-to-moderate magnesium imbalance is extremely difficult the preferred method for determining calcium (1 to 2.5 mg/dL) can because symptoms tend not to develop status. If ionized calcium measurement is be treated with oral supplementation and unless serum values are less than 1 mg/dL unavailable, total plasma calcium values can increased dietary intake, except in cases of or greater than 4 mg/dL (2). be used once corrected for hypoalbuminemia intestinal failure, when IV supplementation (Table 2). Because calcium balance is is needed (2). Symptomatic patients who Patients who have normal renal function and affected by the status of other electrolytes, have hypophosphatemia or moderate-to- are receiving IV treatment for hypomagnesemia such as phosphorus and magnesium, severe (<1 mg/dL) depletion should receive may require several grams of magnesium understanding their interrelationships can IV treatment (Table 4). IV phosphate sulfate until serum concentrations are enhance the clinician’s understanding of infusions must be administered slowly to repleted because healthy kidneys retain less electrolyte abnormalities. Phosphorus and prevent rapid correction and rebound than half the delivered dose (2). Each gram of calcium have an inverse relationship, with an hypocalcemia and tetany. When serum magnesium sulfate should be infused slowly increase in one associated with a decrease in potassium concentrations exceed 4 mEq/L, over 1 to 2 hours to maximize retention the other (2,5). In contrast, hypomagnesemia IV phosphorus should be administered with (Table 4) (7,12). A healthy GI tract absorbs contributes greatly to hypocalcemia and sodium instead of potassium (6). approximately 30% to 40% of dietary should be corrected before calcium magnesium, necessitating large doses of oral concentrations normalize (2,5). Hyperphosphatemia may require dietary magnesium, which are not usually tolerated restriction, volume repletion, and phosphate due to increased diarrhea. For this reason, IV Symptomatic patients with corrected calcium binders (Table 4). The serum calcium- supplementation is the common route of values of less than 7.5 mg/dL (2) require IV phosphorus product must be calculated in repletion. Support Line Volume 33 No. 3 11

Dietary restriction or diuretics can assist in correcting the imbalance in mild cases Table 5. Laboratory Assessment of Acid-base Imbalances (5,9,10,13) of (5). Severe Arterial Serum hypermagnesemia requires IV calcium Acid Base Imbalance pH Carbon Dioxide Bicarbonate infusion or dialysis for patients who have Metabolic acidosis Stable to renal insufficiency (Table 4). ↓ ↓ ↓ ↑ Stable to ↑↑ Acid-base Balance Respiratory acidosis ↓↑ Stable to ↑ The hydrogen (H+) concentration of a Respiratory alkalosis Stable to solution is referred to as pH. A balance of ↑↓ ↓ - CO2 maintained by the and HCO3 maintained by the kidneys regulates the Respiratory alkalosis is characterized by hyperkalemia that develops in diabetic acid-base balance within the body (2). An hypocapnia (PaCO2 <40 mm Hg) and can be ketoacidosis, renal failure, and lower GI losses interruption in acid-base balance leads to attributed to hypoxic events, pulmonary (i.e., diarrhea) (13). The pathophysiology acidemia (pH <7.35), resulting in decreased embolism, congestive heart failure, and more includes increased production of ketones or cardiac, hepatic, and renal function, or commonly, hyperventilation (9). Management , decreased excretion of H+ ions, - alkalemia (pH >7.45), leading to neurologic is directed at treating the underlying cause, or increased loss of HCO3 . The and respiratory dysfunction (9,13). Fortunately, assessing ventilator settings, and avoiding (AG) can be used for a complex buffer systems, along with the excess acetate infusion. because a positive AG typically represents a lungs and kidneys, efficiently maintain this normochloremic acidosis where the decrease - balance to sustain life. Respiratory acidosis is characterized by in HCO3 is balanced by an increase in hypercapnia (PaCO2 >40 mm Hg) and can unmeasured anions (2,5). A positive AG is - Buffer systems, comprising HCO3 , be seen during central seen with increased production/intake or phosphate, ammonium, and protein, work , respiratory disorders, and decreased elimination of acid (e.g., lactic by binding with acid and/or base to form neuromuscular impairment (13). acidosis, renal failure, abuse). Normal compounds that do not affect the serum Identification and treatment of the AG acidosis is usually hyperchloremic, in - pH (2). They are considered the first line of underlying condition is needed for which the low HCO3 is balanced by an defense and can react to an alteration in pH correction. For patients receiving nutrition increase in chloride. Normal AG acidosis is - within 1 second compared with minutes for support, overfeeding must be avoided seen with large HCO3 losses from the GI the respiratory system and days for the because this contributes to the production tract or the kidneys (e.g., diarrhea, fistulae, kidneys to compensate (2). The lungs aid in of CO2, worsening the acidosis. renal tubular acidosis). Treatment begins maintaining acid-base balance by adjusting with correcting the underlying condition alveolar ventilation to retain or excrete CO2. Metabolic alkalosis is characterized by and maintaining potassium homeostasis The kidneys work to retain and excrete hyperbicarbonatemia (CO2 >28 mEq/L) and by adjusting potassium delivery, as needed, - + HCO3 and H as changes in pH occur. hypochloridemia, commonly seen in the to prevent hyperkalemia. This includes presence of excessive vomiting and the use assessment of the potassium content of the Classification of acid-base imbalances is of loop diuretics (9). The pathophysiology is PN, IVFs, or tube feeding. Adjustment of determined by the organ system that is related to increased loss of H+, the addition chloride salts and an increase in acetate can - - affected by the serum HCO3 concentrations. of HCO3 or its precursors, an increased loss assist in the correction (10). Reduction of - Metabolic imbalances result when the of chloride in relation to the loss of HCO3 , chloride administration may also be needed - serum HCO3 concentrations drive the and severe potassium depletion. Treatment in cases of hyperchloridemia. kidneys to absorb and excrete H+ and of the underlying condition is the first step, - HCO3 ions. Respiratory imbalances result followed by volume repletion with NS or Case Study - 1 when the serum HCO3 concentrations alter ⁄2 NS if needed (5,10). Chloride, acetate, FB is a 67-year-old man who has a complex - ventilation. In complex scenarios, mixed and HCO3 administration should be medical history that includes irritable bowel acid-base imbalances can also occur. adjusted to normalize laboratory values, disease, hypertension, peripheral and discontinuation of the diuretic should disease, atrial fibrillation, and failure to

Assessment of an acid-base imbalance be evaluated. A histamine2-receptor thrive. He has undergone multiple small involves a thorough review of the patient’s antagonist can be used to avoid additional bowel resections, leaving him with a history, laboratory parameters, and arterial loss of gastric acid (5,10). foreshortened length of intestine ending in blood gases, including pH, arterial CO2 an end ileostomy. He relies on a modified - (PaCO2) values, and arterial HCO3 values Metabolic acidosis is characterized by diet to maintain his nutritional status and (Table 5). hypobicarbonatemia (CO2 <24 mEq/L) and (Continued on next page) 12 Support Line June 2011 to prevent intestinal malabsorption. FB is 5 ft 9 in, and his usual body weight is 55 kg. Table 6. Electrolyte Content of Body Fluids in mEq/L (14) - Source Na K HCO3 Cl FB is admitted with dehydration and weight Gastric 60 10 n/a 130 loss. Upon admission, several electrolyte abnormalities are documented, including Pancreatic 140 5 115 75 hyperkalemia (serum potassium of 6.2 mmol/L), Bile 145 5 35 100 hypermagnesemia (serum magnesium of Small Bowel 100 15 25 100 2.9 mg/dL) and hypernatremia (serum sodium of 150 mmol/L). He reports that Diarrhea 60 30 45 45 his stoma output has increased from 1 L of Urine 40 40 n/a 20 stool daily to more than 2 L. The increase is Sweat 50 5 n/a 55 attributed to noncompliance with his modified - diet and an increased intake of hypertonic Cl=chloride, K=potassium, Na=sodium, HCO3 =bicarbonate fluids (ie, juice and sports drinks). Step #2: Determine administration instructions. 5. Langley G. Fluid, electrolytes, and acid-base FB has no electrocardiographic changes 2.3 L/2 (Remember to provide no disorders. In: Gottschlich M, DeLegge MH,

1 Mattox T, eds. The A.S.P.E.N. Nutrition Support or heart arrhythmias, suggesting that fluid more than ⁄2 of the deficit within Core Curriculum: A Case-Based Approach – The resuscitation likely would correct the the first 24 hours) Adult Patient. Silver Spring, MD: American electrolyte imbalances. The clinicians = 1,150 mL/24 hours Society for Parenteral and Enteral Nutrition; decide to start NS at 50 mL/hr to provide = 47.9 mL/hr or 2007:104–128. about half of his calculated fluid ~50 mL/hr daily 6. Geerse D, Bindels A, Kuiper M, et al. Treatment requirements (see calculations). A complete of hypophosphatemia in the intensive care unit: a review. Crit Care. 2010;14:R147. metabolic panel 24 hours later shows a Conclusion 7. Kraft M, Btaiche I, Sacks G, Kudsk K. decrease in serum potassium to 5.1 mmol/L Understanding the electrolyte composition Treatment of electrolyte disorders in adult (normal range, 3.5 to 5.1 mmol/L), normal of IVFs (Table 1), body fluids (Table 6), and patients in the intensive care unit. Am J serum magnesium of 2.0 mg/dL, and medications is essential for a clinician Health-Syst Pharm. 2005;63:1663–1681. normal serum sodium of 147 mg/dL. The NS managing IV electrolytes. In addition, 8. Brown K, Dickerson R, Morgan L, et al. A new is continued at 50 mL/hr for another 24 understanding the relationship between graduated dosing regimen for phosphorus replacement in patients receiving nutrition hours until euvolemia is achieved. electrolytes and their movement within support. JPEN J Parenter Enteral Nutr. 2006; TBW during altered hydration status, 30:209–214. Following fluid resuscitation, the clinicians electrolyte imbalances, or acid-base 9. Adrogué H, Madias N. Management of life- decide to start standard polymeric tube imbalance is key to developing a thorough threatening acid-base disorders. Second of feeding to assist FB in meeting his fluid and nutrition care plan. With this knowledge, two parts. N Engl J Med. 1998;338:107–111. 10. Langley G, Canada T, Day L. Acid base nutritional needs. Within 6 days of admission, electrolyte abnormalities can be prevented disorders and nutrition support treatment. he is transitioned to a nocturnal tube or treated safely. Nutr Clin Pract. 2003;18:259–261. feeding with a modified diet to maintain his 11. Skipper A. Parenteral nutrition. In: Matarese L, nutritional status without the need for Kristen M. Rhoda, MS, RD, LD, CNSD, and Gottschlich M, eds. Contemporary Nutrition supplemental IVFs. FB is discharged home on Mary Jo Porter, RD, LD, CNSC, are intestinal Support Practice. A Clinical Guide. 2nd ed. enteral nutrition and closely followed in the rehabilitation and transplant clinicians at St. Lewis, MO: Saunders; 2003:227–241. 12. Hamilton C, Speerhas R, Steiger E. Metabolic outpatient setting to ensure weight gain the Cleveland Clinic, Cleveland, OH. complications of parenteral nutrition. In: and prevent recurrent dehydration. Parekh N, DeChicco B, eds. Nutrition Support References Handbook. Cleveland, OH: Cleveland Clinic; Step #1: Calculate the total body water 1. Whitmire, S. Nutrition focused evaluation and 2004:93–106. (TBW) and water deficit. management of dysnatremias. Nutr Clin Pract. 13. Adrogué H, Madias N. Management of life- 2008;23:108–121. TBW (men) = 0.6 L/kg x weight in kg threatening acid-base disorders. First of two 2. Heitz U, Horne M, Spahn D. Mosby’s Pocket parts. N Engl J Med. 1998;338:26–34. = 0.6 L/kg x 55 kg Guide to Fluid, Electrolyte, and Acid-Base 14. Whitmire S. Fluid, electrolytes and acid-base = 33 L Balance. 5th ed. St Louis, MO: Elsevier; 2005. balance. In: Matarese L, Gottschilch M, eds. Water Deficit =33 L x ([150 mEq/L/140] – 1) 3. McGee S, Abernethy W, Simel D. Is this patient Contemporary Nutrition Support Practice. A = 2.3 L of free water hypovolemic? JAMA. 1999;281:1022–1029. Clinical Guide. 2nd ed. St. Lewis, MO: Saunders; 4. Verbalis J, Goldsmith S, Greenberg A, Schrier R, 2003:122–144. Sterns R. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120:S1–S21. Nutrition in Clinical Practice http://ncp.sagepub.com/

A.S.P.E.N. Position Paper : Recommendations for Changes in Commercially Available Parenteral Multivitamin and Multi −Trace Element Products Vincent W. Vanek, Peggy Borum, Alan Buchman, Theresa A. Fessler, Lyn Howard, Khursheed Jeejeebhoy, Marty Kochevar, Alan Shenkin, Christina J. Valentine, Novel Nutrient Task Force, Parenteral Multi-Vitamin and Multi −Trace Element Working Group and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors Nutr Clin Pract 2012 27: 440 originally published online 22 June 2012 DOI: 10.1177/0884533612446706

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Position Paper

Nutrition in Clinical Practice Volume 27 Number 4 A.S.P.E.N. Position Paper: Recommendations for Changes August 2012 440-491 © 2012 American Society in Commercially Available Parenteral Multivitamin and for Parenteral and Enteral Nutrition DOI: 10.1177/0884533612446706 Multi–Trace Element Products http://ncp.sagepub.com hosted at http://online.sagepub.com

Vincent W. Vanek, MD, FACS, FASPEN (Chair)1; Peggy Borum, PhD, FASPEN2; Alan Buchman, MD, MSPH, FACP, FACG, FACN, AGAF3; Theresa A. Fessler, MS, RD, CNSC4; Lyn Howard, MB, FRCP5; Khursheed Jeejeebhoy, MBBS, PhD, FRCPC6, Marty Kochevar, MS, RPh, BCNSP7, Alan Shenkin, MB, ChB, PhD, FRCP, FRCPath8; Christina J. Valentine, MD, MS, RD9; Novel Nutrient Task Force, Parenteral Multi-Vitamin and Multi–Trace Element Working Group; and the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors

Abstract The parenteral multivitamin preparations that are commercially available in the United States (U.S.) meet the requirements for most patients who receive parenteral nutrition (PN). However, a separate parenteral vitamin D preparation (cholecalciferol or ergocalciferol) should be made available for treatment of patients with vitamin D deficiency unresponsive to oral vitamin D supplementation. Carnitine is commercially available and should be routinely added to neonatal PN formulations. should also be routinely added to adult and pediatric PN formulations; however, a commercially available parenteral product needs to be developed. The parenteral multi–trace element (TE) preparations that are commercially available in the U.S. require significant modifications. Single-entity trace element products can be used to meet individual patient needs when the multiple-element products are inappropriate (see Summary/A.S.P.E.N. Recommendations section for details of these proposed modifications). (Nutr Clin Pract. 2012;27:440-491) Keywords mineral; trace elements; parenteral nutrition; parenteral nutrition solutions; vitamins

Introduction/Background Adequate Intake (AI) was used. However, it must be noted that the DRIs are for healthy individuals on a usual oral diet, so Vitamins and trace elements (TEs) are required for specific these must be extrapolated with care to patients on nutrition metabolic functions. Vitamins are essential organic substances support with or without concurrent acute disease processes. unable to be synthesized in the . TEs are minerals With the advent of parenteral nutrition (PN) in the 1960s, present at very low concentrations (equal to or less than vitamins and TEs (collectively termed micronutrients) had to 0.005% of body weight) in the human body. Appendix 1 lists be provided intravenously. This represented a unique nutri- each of the vitamins and TEs with their basic functions, and ent delivery system that required a reevaluation of nutrient clinical sequelae of deficiency and toxicity. requirements. While intravenously infused nutrients are In 1941, the U.S. National Academy of Sciences estab- 100% bioavailable, it was unknown whether metabolism lished the Food and Nutrition Board, which was responsible would be affected by the bypass of normal hepatic first-pass for the establishment of recommendations for standard oral daily allowances for each nutrient. The final set of guidelines From 1St. Elizabeth Health Center, Youngstown, Ohio; 2University was referred to as the Recommended Daily Allowances (RDA), 3 which were then revised every 5–10 years. In 1997, the of Florida, Gainesville, Florida; Northwestern University School of Medicine, Chicago, Illinois; 4University of Virginia, Charlottesville, Institute of Medicine (IOM) of the U.S. National Academy of Virginia; 5Albany Medical College, Albany, New York; 6Polyclinic, Sciences developed the Dietary Reference Intakes (DRIs), Toronto, Ontario; 7A.S.P.E.N., Silver Spring, Maryland; 8Royal Liverpool which expanded upon the RDAs. The current terms used for University Hospital, Liverpool, England; and 9University of Cincinnati, recommended oral nutrition intakes are described in Table 1.1 Cincinnati, Ohio. In this position paper, the RDA was used to determine the daily Corresponding Author: Vincent W. Vanek, St. Elizabeth Health Center, oral vitamin and TE requirements; however, an RDA was not 1044 Belmont Ave, PO Box 1790, Youngstown, OH 44501-1790; available for some vitamins and TEs, in which case the e-mail: [email protected].

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Table 1. Current Terms Used to Describe Dietary Reference urinary losses. In addition, difficulties were encountered in the 1 Intakes for Oral Requirements development of safe and effective means for both the prepara- • Estimated Average Requirement (EAR)—the average tion of intravenous (IV) micronutrients, as well as their admin- 2 daily intake expected to meet the needs of 50% of the healthy istration. Subsequently, parenteral multivitamin and multi-TE individuals in a particular life stage or gender group based on products became commercially available. The importance of available scientific literature. vitamins in the PN formulation was demonstrated by reports of • Recommended Dietary Allowance (RDA)—the average significant complications and even related to thiamine daily dietary nutrient intake level that is sufficient to meet (also spelled as thiamin) and other vitamin deficiencies during the nutrient requirements of nearly all (97%–98%) healthy national parenteral vitamin shortages in 1988 and 1996.3-8 individuals in a particular life stage and gender group. The RDA is calculated by adding 2 standard deviations to the EAR Moreover, zinc, copper, selenium, and chromium deficiencies unless the requirement distribution is skewed, in which case have been reported when these TEs have been excluded from 9-12 the RDA is set between 97th and 98th percentile. If there is PN. insufficient evidence to establish an EAR, then no RDA can be In 1972, the U.S. Food and Drug Administration (FDA) calculated. declared parenteral multivitamin preparations as “ineffective • Adequate Intake (AI)—the recommended average daily as currently formulated” because they lacked certain essential intake level based on observed or experimentally determined vitamins and some vitamins were present in too high or too approximations or estimates of nutrient intake by a group or low concentrations.13 In 1975, the Nutrition Advisory Group groups of apparently healthy individuals that are assumed to be adequate. AI is used when an RDA cannot be determined. (NAG) of the Department of Food and Nutrition and the • Tolerable Upper Intake Level (UL)—the highest average American Medical Association (AMA) proposed guidelines daily nutrient intake level that is likely to pose no risk of for 9 water-soluble (ascorbic acid, thiamine, riboflavin, niacin, adverse health effects to almost all individuals in the general pyridoxine, pantothenic acid, folate, cobalamin, and biotin) population. As intake increases above the UL, the potential and 4 fat-soluble vitamins (vitamins A [retinol], D [cholecal- risk of adverse effects may increase. ciferol/ergocalciferol], E [α-tocopherol], K [phylloquinone]) for adult and pediatric age groups.14,15 The FDA accepted the adult formulation in 1979 and the pediatric formulation in Table 2. Historical Changes in Recommendations for Parenteral 1981. In 1985, the FDA and AMA co-sponsored a workshop Trace Elements for Adults on parenteral where increases in doses of ascor- Published Zinc,a Copper,b Manganese,b Chromium, Selenium, bic acid, thiamine, pyridoxine, and folate, as well as the addi- Guidelines mg mg mcg mcg mcg tion of vitamin K to the adult formula, were recommended. However, these changes were not mandated by the agency 1979 NAG- 2.5–4 0.5–1.5 150–800 10–15 — until 2000.16 In 1988, pediatric parenteral vitamin require- AMA18,19 ments were reevaluated by the Committee on Clinical Practice 1984 AMA; 2.5–4 0.3–0.5 400–800 10–20 50–60 Issues of the American Society for Clinical Nutrition and mod- NY Ac Med20 ified according to input from the American Academy of Pediatrics and National Institute of Child Health and 1994 9th ed 2.5–4 0.3–0.5 60–100 10–15 40–80 17 Mod Nutr Development. 18,19 H-D21 In 1979, the NAG and AMA recommended that 4 TEs, 1998 2.5–5 0.3–0.5 60–100 10–15 20–60 zinc, copper, manganese, and chromium, be provided in adult A.S.P.E.N.22 PN formulas; daily dose ranges were provided (Table 2). In and 2004 1984, recommendations were made to add selenium, decrease 23 A.S.P.E.N. the dose range for copper, and increase the dose ranges for both manganese and chromium.20 In 1994, the recommended AMA, American Medical Association; A.S.P.E.N., American Society for Parenteral and Enteral Nutrition; Mod Nutr H-D, Modern Nutrition in dose range for selenium was increased and those for manga- Health & Disease; NAG-AMA, Nutrition Advisory Group of the American nese and chromium were decreased.21 These recommendations Medical Association; NY Ac Med, New York Academy of Medicine. were reviewed by the American Society for Parenteral and Adapted from Buchman AL, Howard LJ, Guenter P, Nishikawa RA, Com- 22 23 pher CW, Tappenden KA. Micronutrients in parenteral nutrition: too little Enteral Nutrition (A.S.P.E.N.) in 1998 and 2004, and a fur- or too much? The past, present, and recommendations for the future. Gas- ther recommendation was made to modestly decrease the dose troenterology. 2009;137(5)(suppl):S1-S6 with permission from Elsevier. range for selenium. a Increase with abnormal intestinal loss. In February 2009, the annual A.S.P.E.N. Research Workshop bDecrease or omit with increasing . focused on “Micronutrients in Parenteral Nutrition: Too Little or Too Much?”24 At this workshop, a group of international metabolism. Therefore, it was unclear whether nutrient require- experts reviewed the parenteral requirements of many of ments would be reduced because of their increased bioavail- the vitamins and TEs as well as two related nutrients, carnitine ability or increased due to altered metabolism and increased and choline. The panel concluded that changes were needed in

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Table 3. Review of the Literature for Vitamins and Trace available in the U.S. The task force was divided into working Elements Provision in Parenteral Nutrition groups for each of these nutrients, one of which was the Micronutrient Source of Literature Review Parenteral Vitamin and TE Working Group. Vitamin A Working Group—see Appendix 2 Vitamin D 2009 A.S.P.E.N. Research Issue/Problem Definition 25 Workshop—DeLuca Recommendations for adult and pediatric patients are included Vitamin E 2009 A.S.P.E.N. Research in this position paper, and the pediatric patients are referred to Workshop—Biesalski26 as either neonates or pediatric (pediatric patients excluding Vitamin K 2009 A.S.P.E.N. Research 27 neonates). The Working Group determined the procedure for Workshop—Shearer development, review, and approval of this position paper Vitamin B (thiamine) Working Group—see Appendix 3 1 (Figure 1). The literature review was primarily based on the Vitamin B (riboflavin) Working Group—see Appendix 4 2 review articles published from the 2009 A.S.P.E.N. Research Vitamin B (niacin) Working Group—see Appendix 4 3 Workshop. However, several vitamins and TEs were not Vitamin B (pantothenic Working Group—see Appendix 5 5 acid) reviewed as a part of the workshop, so Working Group mem- Vitamin B Working Group—see Appendix 6 bers were assigned to complete literature reviews on these 6 Vitamin B Working Group—see Appendix 7 micronutrients (Table 3). Members of the Working Group 12 Vitamin C 2009 A.S.P.E.N. Research with pediatric and neonatal expertise also conducted an addi- Workshop—Berger28 tional literature review regarding recommendations for paren- Folate Working Group—see Appendix 8 teral vitamin and TE supplementation in these patient Biotin Working Group—see Appendix 9 populations. Carnitine 2009 A.S.P.E.N. Research The current adult, pediatric, and neonatal oral and paren- Workshop—Borum29 teral daily recommendations for vitamins and TEs are shown Choline 2009 A.S.P.E.N. Research in Tables 4–7. The commercially available multiple and indi- Workshop—Buchman30 vidual parenteral vitamin and TE products available in the U.S. Copper 2009 A.S.P.E.N. Research and in Europe are shown in Tables 8–13. Workshop—Shike9 Chromium 2009 A.S.P.E.N. Research Workshop—Moukarzel10 Recommendations for Parenteral Vitamins Fluoride, boron, and 2009 A.S.P.E.N. Research Based on the recommended doses for the current parenteral silicone Workshop—Nielsen31 multivitamin products, the daily dose of the fat-soluble vita- Iodine 2009 A.S.P.E.N. Research 32 mins is approximately the same as the oral RDA or AI for Workshop—Zimmermann these vitamins, even though the bioavailability should be Iron 2009 A.S.P.E.N. Research Workshop—Forbes33 much greater when these vitamins are administered intrave- Manganese 2009 A.S.P.E.N. Research nously. The rationale for providing a higher effective dose Workshop—Hardy34 when given as part of PN therapy was that these patients Molybdenum Working Group—see Appendix 10 had higher vitamin requirements due to malnutrition, base- Selenium 2009 A.S.P.E.N. Research line vitamin deficiencies, and metabolic changes secondary Workshop—Shenkin11 to acute and chronic illness.41 The currently administered Zinc 2009 A.S.P.E.N. Research water-soluble vitamin daily parenteral doses are 2–5.5 times Workshop—Jeejeebhoy12 greater than the oral RDA or AI. The rationale for giving even higher relative doses for these vitamins was that in addition A.S.P.E.N., American Society for Parenteral and Enteral Nutrition. to the increased requirements, as discussed above, there is increased urinary excretion of water-soluble vitamins when the recommendations for the daily requirements for these administered intravenously.41 These relatively high doses of micronutrients in PN, which would require significant changes vitamins have been used in PN therapy for over 30 years, and in current commercially available products. no toxicity has been described. Therefore, A.S.P.E.N. does not In May 2009, the A.S.P.E.N. Board of Directors formed the recommend any dose reductions in the parenteral multivitamin Novel Nutrient Task Force with a charge to assess the level of products. scientific evidence for the clinical use of several different par- The recommendations for daily oral intake of vitamin D enteral nutrients and develop position statements for each were increased in 2010.42 The IOM established RDAs for vita- nutrient. The position statements were to address evidence- min D that ranged from 400 International Units at birth to 800 based data on the use of these nutrients in clinical practice and International Units in the elderly (Tables 4 and 5). There is to provide recommendations for changes in the products concern as to whether the daily dose of 200 International Units

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Formation of A.S.P.E.N. Parenteral Vitamin and Trace Element Working Group

Determine the Availability and Content of the Multiple and Individual Parenteral Vitamin and Trace Element formulas within and outside of the U.S.

Review of the Literature Regarding the Current Recommendations for the Daily Oral and Parenteral Intake of Vitamins and Trace Elements and the Scientific Evidence Suggesting Any Changes in these Recommendations

Development of First Draft of Parenteral Vitamin and Trace Element Position Paper

Circulate Position Paper for Review and Comment to · Internal Review  Other members of the A.S.P.E.N. Novel Nutrient Task Force  A.S.P.E.N. Clinical Practice Committee  Members of A.S.P.E.N. Board of Directors (BOD)  Other identified experts in parenteral vitamin and trace elements · External Review  Other identified experts in parenteral vitamins and trace elements

Revision of Parenteral Vitamin and Trace Element Position Paper based on above reviews Approval of Revised Draft of Parenteral Vitamin and Trace Element Position Paper by the Parenteral Vitamin and Trace Element Working Group

Submit Final Draft of Parenteral Vitamin and Trace Element Position Paper to the A.S.P.E.N. BOD for Review and Final Approval

Figure 1. Procedure for the development of the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) position paper on parenteral vitamin and trace elements.

per day of vitamin D in the current parenteral vitamin products 77% of the patients. In a recent study, Thomson and is adequate for most patients that require long-term PN. Duerksen45 reported vitamin D insufficiency in 27% and vita- Compher et al43 measured serum 25-hydroxyl vitamin D min D deficiency in 68% of a group of 22 adult home patients concentrations in 6 stable, intestinal failure patients on long- who used PN for a duration of 1 month to over 14 years. term PN, 2 males and 4 females, and all the patients were Vitamin D insufficiency was defined as 25(OH) vitamin D vitamin D deficient with concentrations ranging from 5–14 >50 nmol/L (20 ng/mL) but <75 nmol/L (30 ng/mL), and ng/mL (reference range, 20–100 ng/mL). Corey et al44 mea- vitamin D deficiency was defined as <50 nmol/L (20 ng/mL). sured serum 25-hydroxyl vitamin D concentrations in 35 Two of the patients in that study were taking oral vitamin D patients that required home PN, all of whom had received supplements; one took 2000 International Units cholecalcif- parenteral multivitamin formulations that contained 200 erol per day and was not deficient, and the other was taking International Units of cholecalciferol (D ) per day. This 50,000 International Units ergocalciferol per week and was 3 group consisted of 26 women and 9 men who used PN for a deficient. In an abstract published in 2009, doses of 40–75 duration of 4 weeks to over 20 years, and all patients con- mcg (1600–3000 International Units) of oral vitamin D per sumed some oral nutrition. Vitamin D deficiency, defined as day failed to improve 25(OH) vitamin D levels in 5 out of a 25(OH) vitamin D concentration <30 ng/mL, occurred in group of 10 home PN patients.46

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Table 4. Current Recommended Adult Daily Oral and Parenteral Micronutrient Requirements

Oral1,a Parenteral23

Fat-Soluble Vitamins Vitamin A M, 900 mcg or 3000 IU; F, 700 mcg or 2333 IUb 990 mcg or 3300 IUb 770 mcg (preg); 1300 mcg (lact) Vitamin D Age 19–70 y: 15 mcg or 600 IUc,35 5 mcg or 200 IUc Age >70 y: 20 mcg or 800 IU35 Vitamin E 15 mg; 19 mg (lact) 10 mg or 10 IUd Vitamin K M, 120 mcg; F, 90 mcg (AI) 150 mcg Water-Soluble Vitamins Vitamin B (thiamine) M, 1.2 mg; F, 1.1 mg 6 mg 1 1.4 mg (preg/lact) Vitamin B (riboflavin) M, 1.3 mg; F, 1.1 mg 3.6 mg 2 1.4 mg (preg); 1.6 mg (lact) Vitamin B (niacin) M, 16 mg; F, 14 mg 40 mg 3 18 mg (preg); 17 mg (lact) Vitamin B (pantothenic acid) 5 mg; 6 mg (preg); 7 mg (lact) 15 mg 5 (AI) Vitamin B (pyridoxine) Age 19–50 y: 1.3 mg 6 mg 6 Age >51 y: M, 1.7 mg; F, 1.5 mg 1.9 mg (preg); 2.0 mg (lact) Vitamin B (cyanocobalamin) 2.4 mcg; 2.6 mcg (preg); 2.8 mcg (lact) 5 mcg 12 Vitamin C (ascorbic acid) M, 90 mg; F, 75 mg 200 mg 85 mg (preg); 120 mg (lact) Folate 400 mcg; 600 mcg (preg); 500 mcg (lact) 600 mcg Biotin 30 mcg; 35 mcg (lact) 60 mcg (AI) Other Nutrients Choline M, 550 mg; F, 425 mg Not available for PN use 450 mg (preg); 550 mg (lact) (AI) Trace Elements Copper 900 mcg 0.3–0.5 mg 1000 mcg (preg); 1300 mcg (lact) Chromium Age 19–50 y: M, 35 mcg; F, 25 mcg 10 – 15 mcg Age >51 y: M, 30 mcg; F, 20 mcg 30 mcg (preg); 45 mcg (lact) (AI) Fluoride M, 4 mg; F, 3 mg Not routinely added in U.S.e (AI) Iodine 150 mcg; 220 mcg (preg); 290 mcg (lact) Not routinely added in U.S.e Iron Age 19–50 y: M, 8 mg; F, 18 mg Not routinely added in U.S.e (given Age >50 y: 8 mg 25–50 mg/monthly as separate IV 27 mg (preg); 9 mg (lact) infusion when indicated) Manganese M, 2.3 mg; F, 1.8 mg 0.06–0.1 mg 2.0 mg (preg); 2.6 mg (lact) (AI) Molybdenum 45 mcg; 50 mcg (preg/lact) Not routinely added in U.S.e Selenium 55 mcg; 60 mcg (preg); 70 mcg (lact) 20–60 mcg Zinc M, 11 mg; F, 8 mg 2.5–5 mg 11 mg (preg); 12 mg (lact)

Ranges include female (lower amounts) and male (higher amounts). This table does not include nutrient needs for or lactation for ages <19 years. AI, Adequate Intake; F, female; IU, ; IV, intravenous; lact, lactation; M, male; PN, parenteral nutrition; preg, pregnancy. aEnteral recommendations are the Recommended Dietary Allowance (RDA) unless one is not established, in which case the AI is listed and so noted in the table. b1 mcg RAE (retinol activity equivalent) = 1 mcg retinol = 12 mcg β-carotene = 24 mcg α-carotene or β-cryptoxanthin. c1 IU of retinol = 0.3 mcg retinol or 0.3 mcg RAE. dTo convert IU α-tocopherol to mg: IU × 0.67 mg RRR-α-tocopherol, natural form (“d-α-tocopherol”) or IU × 0.45 mg all-rac-α-tocopherol, synthetic form (“dl-α-tocopherol”). dl-α-tocopheryl acetate (1 IU = 1 mg = 1 USP unit) is used in IV multivitamin preparation.36 eFluoride (0.57–1.45 mg), iodine (10–130 mcg), iron (1–1.95 mg), molybdenum (10–25 mcg), and cobalt (0–1.47 mcg) are routinely added to PN prod- ucts in Europe.37

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Table 5. Daily Oral or Enteral Recommended Daily Allowances (RDA) for Pediatric Age Groups1

Age Groups

<18 y <18 y 0–6 mo 7–12 mo 1–3 y 4–8 y 9–13 y 14–18 y Pregnant Lactating Fat-Soluble Vitamins Vitamin A, mcga 400b 500b 300 400 600 M, 900; F, 700 750 1200 Vitamin D, mcg/IU35 10/400b 10/400b 15/600 15/600 15/600 15/600 15/600 15/600 Vitamin E, mg 4b 5b 6 7 11 15 15 19 Vitamin K, mcg 2b 2.5b 30b 55b 60b 75b 75b 75b Water-Soluble Vitamins Vitamin B (thiamine), mg 0.2b 0.3b 0.5 0.6 0.9 M, 1.2; F, 1.0 1.4 1.4 1 Vitamin B (riboflavin), mg 0.3b 0.4b 0.5 0.6 0.9 M, 1.3; F, 1.0 1.4 1.6 2 Vitamin B (niacin), mg 2b 4b 6 8 12 M, 16; F, 14 18 17 3 Vitamin B (pantothenic acid), mg 1.7b 1.8b 2b 3b 4b 5b 6b 7b 5 Vitamin B (pyridoxine), mg 0.1b 0.3b 0.5 0.6 1.0 M, 1.3; F, 1.2 1.9 2.0 6 Vitamin B (cyanocobalamin), mcg 0.4b 0.5b 0.9 1.2 1.8 2.4 2.6 2.8 12 Vitamin C (ascorbic acid), mg 40b 50b 15 25 45 M, 753; F, 65 80 115 Folate, mcg 65b 80b 150 200 300 400 600 500 Biotin, mcg 5b 6b 8b 12b 20b 25b 30b 35b Choline, mg 125b 150b 200b 250b 375b M, 550; F, 400b 450b 550b Trace Elements Copper, mcg 200b 220b 340 440 700 890 1000 1300 Chromium, mcg 0.2b 5.5b 11b 15b M, 25; F, 21b M, 35; F, 24b 29b 44b Fluoride, mg 0.01b 0.5b 0.7b 1b 2b 3b 3b 3b Iodine, mcg 110b 130b 90 90 120 150 220 290 Iron, mg 0.27b 11 7 10 8 M, 11; F, 15 27 10 Manganese, mg 0.003b 0.6b 1.2b 1.5b M, 1.9; F, 1.6b M, 2.2; F, 1.6b 2b 2.6b Molybdenum, mcg 2b 3b 17 22 34 43 50 50 Selenium, mcg 15b 20b 20 30 40 55 60 70 Zinc, mg 2b 3 3 5 8 M, 11; F, 9 12 13

F, female; IU, International Unit; M, male. bNo Recommended Daily Allowance (RDA) available; Adequate Intake (AI) is listed. a1 mcg RAE (retinol activity equivalent) = 1 mcg retinol = 12 mcg β-carotene = 24 mcg α-carotene or β-cryptoxanthin; 1 IU of retinol = 0.3 mcg retinol or 0.3 mcg RAE.

Currently, no separate parenteral ergocalciferol or cholecal- The scientific data supporting the current dose recommen- ciferol product is commercially available. A.S.P.E.N. recom- dations for pediatric and neonatal parenteral vitamin adminis- mends a parenteral cholecalciferol or ergocalciferol vitamin D tration are very limited, so there are insufficient data to make product be developed for use in PN-dependent patients that are any recommended changes in the current pediatric and neona- vitamin D deficient and fail to respond to oral vitamin D sup- tal parenteral multivitamin products. plementation.47 There is some evidence to show that cholecal- ciferol may be more effective at increasing vitamin D levels.48 Recommendations for Parenteral Carnitine Vitamin D supplementation in pediatric and neonatal PN patients is important, but there is insufficient evidence to and Choline develop definitive daily recommendations. It appears that the Carnitine and choline are technically not vitamins, but their current parenteral form and dose of vitamin D supports ade- essentiality was considered by the Food and Nutrition Board quate blood levels.49 of the IOM. Both of these nutrients either have been used in A.S.P.E.N. also recommends that parenteral multivitamin PN formulas or have been investigated for inclusion in PN products with and without vitamin K should continue to be formulas. Carnitine is a quaternary ammonium compound available. This permits clinicians the option to withhold vita- biosynthesized from the amino acids and methionine. min K when required, such as in the case of those patients who It is required for the transport of fatty acids from the cytosol require warfarin therapy. into the mitochondria during the breakdown of for the

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Table 6. Current Daily Parenteral Recommendations for Infants and Children38

Infants Children Fat-Soluble Vitamins Vitamin Aa 150–300 mcg/kg/d 150 mcg/d Vitamin D 0.8 mcg/32 IU per kg/d 10 mcg/400 IU per d Vitamin E 2.8–3.5 mg/kg/d 7 mg/d Vitamin K 10 mcg/kg/d 200 mcg/d Water-Soluble Vitamins Vitamin B (thiamine) 0.35–0.5 mg/kg/d 1.2 mg/d 1 Vitamin B (riboflavin) 0.15–0.2 mg/kg/d 1.4 mg/d 2 Vitamin B (niacin) 4.0–6.8 mg/kg/d 17 mg/d 3 Vitamin B (pantothenic acid) 1–2 mg/kg/d 5 mg/d 5 Vitamin B (pyridoxine) 0.15–0.2 mg/kg/d 1 mg/d 6 Vitamin B (cyanocobalamin) 0.3 mcg/kg/d 1 mcg/d 12 Vitamin C (ascorbic acid) 15–25 mg/kg/d 80 mg/d Folate 56 mcg/kg/d 140 mcg/d Biotin 5–8 mcg/kg/d 20 mcg/d Trace Elements Copper 20 mcg/kg/d (no max stated)b 20 mcg/kg/d (500 mcg/d maxc,d) b Chromium 0.2 mcg/kg/d (max 5 mcg/d)e 0.2 mcg/kg/d (max 5 mcg/dc)e Fluoride No recommendations No recommendations Iodine 1 mcg/df 1 mcg/df Iron Premature: 200 mcg/kg/df 50–100 mcg/kg/df Infant: 50–100 mcg/kg/df Manganese 1 mcg/kg/d (max 50 mcg/dc) 1 mcg/kg/d (max 50 mcg/dc) Molybdenum Premature: 1 mcg/kg/d 0.25 mcg/kg/d (max 5 mcg/dc) Infant: 0.25 mcg/kg/d (max 5 mcg/dc) Selenium Premature: 2–3 mcg/kg/d 1–3 mcg/kg/d Infant: 1–3 mcg/kg/d (100 mcg/d maxc,d) (no max stated) Zinc Premature: 450–500 mcg/kg/d 50 mcg/kg/d (max 5000 mcg/dc) Infants <3 mo: 250 mcg/kg/d Infants >3 mo: 50 mcg/kg/d (max 5000 mcg/d)

IU, International Unit; max, maximum; PN, parenteral nutrition. a1 mcg/kg RAE (retinol activity equivalent) = 1 mcg/kg retinol. bAuthors recommend monitoring plasma copper and ceruloplasmin concentrations in long-term PN patients and patients with burns or cholestasis with appropriate adjustment of doses as needed. cRefers to maximum dose for routine supplementation; however, higher doses may be indicated in patients with established deficiency or increased requirements. dMaximum dose was not specified in above reference but is included in this table as the maximum dose based on the recommended adult dose. eAuthors state that chromium contaminates in PN products satisfies requirements; therefore, additional supplementation is unnecessary. fNot currently added to PN in U.S. generation of metabolic energy. It is currently added to neo- Choline is a quaternary endogenously synthesized natal PN and adult PN in selected cases only.29 A.S.P.E.N. from the amino acid methionine and has been listed as a recommends the routine addition of 2 to 5 mg/kg/d to the required dietary nutrient since 1998 by the U.S. IOM Food and PN for neonates29 if no enteral source is provided.50,51 Nutrition Board. In addition, the FDA requires choline supple- Carnitine is currently not provided routinely in either adult mentation of infant enteral formulas.52 It is an essential compo- or pediatric PN formulas, but there is some evidence that nent of all cell membranes and is necessary for DNA repair due supplementation in these patient populations may be ben- to its role as a methyl donor. It also serves as the precursor for eficial. A.S.P.E.N. recommends that further investigation is the . Deficiency states have needed in these patient populations. been reported and include memory deficits,

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Table 7. Current Parenteral and Enteral Vitamin and Trace Element Recommendations for Preterm and Term Neonates

Preterm Neonates Term Neonates

Route of Administration Parenteral38-40 Enteral38,39 Parenteral38 Enteral1 Vitamins Vitamin A 700–1500 IU/kg/d 700–1500 IU/kg/d 2300 IU/d 1333 IU/d 400 mcg/d Vitamin D 40–160 IU/kg/d 150–400 IU/kg/d 400 IU/d 400 IU/d goal 400 IU/d Vitamin E 2.8–3.5 IU/kg/d 6–12 IU/kg/d 7 IU/d 6 IU/d Vitamin K 10 mcg/kg/d in PN 8–10 mcg/kg/d 200 mcg/d 2 mcg/d +500 mcg IM at birth +500 mcg IM at birth Thiamin 200–350 mcg/kg/d 180–240 mcg/kg/d 1.2 mg/d 0.2 mg/d Riboflavin 150–200 mcg/kg/d 250–360 mcg/kg/d 1.4 mg/d 0.3 mg/d Niacin 4–6.8 mg/kg/d 3.6–4.8 mg/kg/d 17 mg/d 2 mg/d Vitamin B 150–200 mcg/kg/d 150–210 mcg/kg/d 1000 mcg/d 14 mcg/kg/d 6 Folate 56 mcg/kg/d 25–50 mcg/kg/d 140 mcg/d 65 mcg/d Vitamin B 0.3 mcg/kg/d 9.3 mcg/kg/d 1 mcg/d 0.4 mcg/d 12 Pantothenic acid 1–2 mg/kg/d 1.2–1.7 mg/kg/d 5 mg/d 1.7 mg/d Biotin 5–8 mcg/kg/d 3.6–6 mcg/kg/d 20 mcg/d 5 mcg/d Vitamin C 15–25 mg/kg/d 18–24 mg/kg/d 80 mg/d 40 mg Trace Elements Iron 100–200 mcg/kg/d 2000–4000 mcg/kg/d 250–670 mcg/kg/d 2000–4000 mcg/kg/d if PN only >2 mo if PN only >2 mo Zinc 400 mcg/kg/d 1000–3000 mcg/kg/d 250 mcg/kg/d 2000 mcg/d Coppera 29 mcg/kg/d 120–150 mcg/kg/d 20 mcg/kg/d 200 mcg/d Selenium 1.5–4.5 mcg/kg/d 1.3–4.5 mcg/kg/d 2 mcg/kg/d 15 mcg/d Chromium 0.05–0.3 mcg/kg/d 0.1–2.25 mcg/kg/d 0.2 mcg/kg/d 0.2 mcg/d Molybdenum 0.25 mcg/kg/d 0.3 mcg/kg/d 0.25 mcg/kg/d 2 mcg/d Manganese 1 mcg/kg/d 0.7–7.5 mcg/kg/d 1 mcg/kg/d 0.3 mcg/d Iodineb 1 mcg/kg/d 10–60 mcg/kg/d 1 mcg/kg/d 110–130 mcg/d

IM, intramuscular; IU, International Unit; PN, parenteral nutrition. aCopper dose may need to be removed or reduced in infants with obstructive jaundice. Check serum copper and ceruloplasmin concentration to deter- mine need for dose change. bInsufficient data at this time to support routine parenteral iodine supplementation in preterm infants. injury, and possible activation of cellular in lympho- •• 9–13 years: 375 mg cytes and hepatocytes. Importantly, choline deficiency may •• >13 years: adult amounts cause or contribute to PN-associated hepatic steatosis; animal models have shown progression to and even Additional data will be required to determine whether development of hepatocellular carcinoma with long-term cho- higher doses (ie, greater than the AI for choline) are optimal. line deficiency. Currently, there is no commercially available parenteral choline product.30 A.S.P.E.N. recommends that a Recommendations for Parenteral TEs commercially available parenteral choline product, either as an individual product or incorporated into a multivitamin product, A.S.P.E.N. has numerous recommendations for changes to should be developed and routinely added to adult PN formulas the currently available parenteral TE products. This stems at a dose of 550 mg/d. The recommended daily choline neona- from several factors. First, and foremost, while the FDA tal and pediatric PN doses are: approved the initial 1979 guidelines for daily parenteral TE doses published by the AMA,18 the agency’s approval has •• 0–6 months: 125 mg not been updated to reflect the changes advised by recent •• 7–12 months: 150 mg TE expert conferences (Table 2). These recommendations •• 1–3 years: 200 mg included greatly reduced daily doses of both copper and •• 4–8 years: 250 mg manganese based on the reports of manganese toxicity and

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Table 8. Parenteral Multivitamin Formulations Available in North America

Content A, D, E, K, B , B , B , B , B , B , C, Biotin, Folic Acid, 1 2 3 5 6 12 Product (Distributor) per mL IU IU IU mcg mg mg mg mg mg mcg mg mcg mcg How Supplied Adult M.V.I.-12 10 mL 3300 200a 10b 0 6 3.6 40c 15d 6 5 200 60 600 Unit vial or (Hospira) bulk packagee M.V.I. Adult 10 mL 3300 200a 10b 150f 6 3.6 40c 15d 6 5 200 60 600 Dual vial, unit vial, (Hospira) or pharmacy bulk packagee Infuvite Adult 10 mL 3300 200g 10b 150f 6 3.6 40c 15d 6 5 200 60 600 Pharmacy bulk (Baxter) packagee Vitamin 1 mL 0 0 0 0 100 2 100c 2d 2 0 0 0 0 30-mL multiple-dose B-Complex 100 vial (Bioniche Pharma) Pediatric M.V.I. Pediatric 5 mLh 2300 400a 7b 200f 1.2 1.4 17c 5d 1 1 80 20 140 Single-dose vial (Hospira) reconstituted to 5 mL Infuvite PEDiatric 5 mLi 2300 400g 7b 200f 1.2 1.4 17c 5d 1 1 80 20 140 Two single-dose vialsi (Baxter)

IU, International Unit. Information based on manufacturer’s labeling information as of February 2010. Manufacturers, products, and product information can frequently change. aErgocalciferol (D ). 2 bdl-α-tocopheryl acetate. cNiacinamide. d15 mg dexpanthenol (d-pantothenyl alcohol). eDual vial is 2 vials labeled vial 1 (5 mL) and vial 2 (5 mL) with both vials to be used for a single 10-mL dose. Unit vial is a 2-chambered single-dose vial that must be mixed just prior to use and will provide one 10-mL dose. Pharmacy bulk package consists of 2 vials labeled vial 1 (50 mL) and vial 2 (50 mL), and 5 mL of each vial provides 10 mL of a single dose. fPhylloquinone (K ). 1 gCholecalciferol (D ). 3 hThe 5 mL is the daily dose for infants and children weighing 3 kg or more up to age 11 years, 3.25 mL (65% of daily dose) for infants weighing 1–3 kg, and 1.5 mL (30% of daily dose) for infants weighing less than 1 kg. iSupplied in 2 single-dose vials, vial 2 (1 mL) contains folic acid, biotin, and vitamin B , and vial 1 (4 mL) contains all the other vitamins. The 5 mL is 12 the daily dose for infants and children weighing 3 kg or more up to age 11 years, 65% of daily dose (2.6 mL vial 1 and 0.65 mL vial 2) for infants weigh- ing 1–3 kg, and 30% of daily dose (1.2 mL vial 1 and 0.3 mL vial 2) for infants weighing less than 1 kg. excessive organ accumulation of both manganese and cop- sodium chloride products. Amounts varied between manufac- per in patients who had received long-term PN.53-57 Therefore, turers and in different lots from the same manufacturer.62,71 the current multi-TE products available in the U.S. provide Pluhator-Murton et al62 calculated the amount of trace excessive copper and manganese. elements in a 2-L PN solution made with the tested compo- TE contamination of PN is also of concern. Beginning in nents, compared those numbers with the amounts expected the late 1970s, several reports described contamination of to be provided in the same PN solution, and found an extra PN formulations with zinc,58-62 copper,58,60-63 manga- 1.1 mg Zn, 0.08 mg Cu, 38 mcg Mn, 15 mcg Cr, and 21 mcg nese,58,62,64,65 chromium,62,66 and selenium.60,62,67 Nonnutrient Se. The amounts of contaminant Mn and Cr found in that contaminants such as aluminum, arsenic, and strontium were study were approximately 63% of the current recommended also found.62,68,69 Aluminum toxicity has been a serious con- daily requirement for Mn and 100% of the daily requirement cern, which has been at least partially addressed by the FDA.70 for Cr. Studies analyzing TE contents of PN component products Buchman et al71 reported substantial variation in levels of have shown several contaminants in amounts greater than 1 heavy metal contamination between PN formulations that mcg/L, including zinc, copper, manganese, chromium, sele- used components from varied manufacturers, as well as differ- nium, boron, aluminum, titanium, barium, cadmium, arsenic, ences in levels of contamination between adult, renal, and and strontium. TE contamination was found in all PN compo- pediatric formulations. Chromium contamination was substan- nents tested, even in those that were not intended to contain tial in all formulations evaluated but was greatest in a “renal” TEs. The greatest amounts of contamination were found in the formulation. Chromium contamination occurred primarily in amino acids, potassium chloride, calcium gluconate, and dextrose, amino acids, and TE components.

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Table 9. Parenteral Single-Vitamin Products Available in North America

Vitamin (Distributor) Concentration How Supplied Vitamin A Aquasol A (Hospira) 50,000 IU/mL 2-mL vials (IM) Vitamin Da (Calcijex, Abbott) 1 mcg/mL 1-mL vial sodium chloride, EDTA Paracalcitol (Zemplar, Abbott) 2 mcg/mL 1-mL vial Paracalcitol (Zemplar, Abbott) 5 mcg/mL 1- and 2-mL vial Doxercalciferol (Hectorol, Genzyme) 2 mcg/mL 1- and 2-mL vial Vitamin K Phytonadione (K ) (Hospira) 10 mg/mL 1-mL amp 1 Phytonadione (K ) (Hospira) 2 mg/mL 0.5-mL amp 1 Vitamin B 1 Thiamine (various) 100 mg/mL 1- and 2-mL Tubex, 2-mL multidose vials, 1-mL vial Vitamin B 6 Pyridoxine (various) 100 mg/mL 1-mL vials Vitamin B 12 Cyanocobalamin (various) 100 mg/mL 30-mL multidose vials Cyanocobalamin (various) 1000 mg/mL 10- and 30-mL multidose vials, 1-mL vial Vitamin C Ascorbic acid (various) 500 mg/mL 50-mL multidose vials, 1-mL amp Ascorbic acid (various) 1000 mg/mL 2-mL amp Folic acid (various) 5 mg/mL 10-mL multidose vial amp, ampule; EDTA, ethylenediaminetetraacetic acid; IM, intramuscular; IU, International Unit. Information based on manufacturer’s labeling informa- tion as of February 1, 2010. Manufacturers, products, and product information can change frequently. Adapted from Buchman AL, Howard LJ, Guenter P, Nishikawa RA, Compher CW, Tappenden KA. Micronutrients in parenteral nutrition: too little or too much? The past, present, and recommendations for the future. Gastroenterology. 2009;137(5)(suppl):S1-S6 with permission from Elsevier. aNo single vitamin products in the U.S. contain vitamin D as ergocalciferol (D ) or cholecalciferol (D ). This table lists analogs/metabolites of vitamin D. 2 3

Table 10. Parenteral Multi–Trace Element Products Available in North America

Content Zinc, mg Copper, Chromium, Manganese, Selenium,a How Product (Distributor) per mL (µmol) mg (µmol) mcg (µmol) mg (µmol) mcg (µmol) Supplied Adults Multitrace-4 (American Regent) 1 mL 1 (15.3) 0.4 (6.29) 4 (0.08) 0.1 (0.0018) 0 (0) 10-mL MDV Multitrace-4 Concentrate 1 mL 5 (76.48) 1 (15.73) 10 (0.2) 0.5 (0.0091) 0 (0) 1-mL SDV and (American Regent) 10-mL MDV 4-Trace Elements (Hospira) 5 mL 4 (61.18) 1 (15.73) 10 (0.2) 0.8 (0.0146) 0 (0) 5-mL SDV and 50-mL MDV Multitrace-5 (American Regent) 1 mL 1 (15.3) 0.4 (6.29) 4 (0.08) 0.1 (0.0018) 20 (0.25) 10-mL MDV Multitrace-5 Concentrate 1 mL 5 (76.48) 1 (15.73) 10 (0.2) 0.5 (0.0091) 60 (0.76) 1-mL SDV and (American Regent) 10-mL MDV Neonatal and Pediatrics Multitrace-4 Neonatal 1 mL 1.5 (22.94) 0.1 (1.57) 0.85 (0.02) 0.025 (0.0005) 0 (0) 2-mL SDV (American Regent) Multitrace-4 Pediatric 1 mL 1 (15.3) 0.1 (1.57) 1 (0.02) 0.025 (0.0005) 0 (0) 3-mL SDV (American Regent) Trace Elements 4, 1 mL 0.5 (7.65) 0.1 (1.57) 1 (0.02) 0.03 (0.0006) 0 (0) 10-mL MDV USP—Pediatric (American Regent)

MDV, multiple-dose vial; SDV, single-dose vial; USP, United States Pharmacopeia. Information based on manufacturer’s labeling information as of February 1, 2010. Manufacturers, products, and product information can change frequently.

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Table 11. Parenteral Individual Trace Element Products Available in North America

Concentration Elemental Trace Element (Distributor) Form per mL (µmol) How Supplied Copper Cupric chloride (Hospira) 0.4 mg/mL (6.29 µmol/mL) 10-mL vials Cupric sulfate, pentahydrate (various) 0.4 mg/mL (6.29 µmol/mL) 10-mL and 30-mL vials Cupric sulfate (various) 2 mg/mL (31.40 µmol/mL) 10-mL vials Chromium as chromic chloride, hexahydrate (various) 4 mcg/mL (0.08 µmol/mL) 10-mL and 30-mL vials Iron Ferumoxytol (AMAG Pharma) 30 mg/mL (0.53 mmol/mL) 17-mL vials Iron dextran (various) 50 mg/mL (0.89 mmol/mL) 1- and 2-mL vials Iron (Astra-Canada) 50 mg/mL (0.89 mmol/mL) 2-mL ampule (IM only) (American Regent) 20 mg/mL (0.36 mmol/mL) 2.5-mL, 5-mL, and 10-mL vials Sodium ferric gluconate (Sanofi-Aventis U.S., Watson) 12.5 mg/mL (0.22 mmol/mL) 5-mL ampules Manganese Manganese chloride, tetrahydrate (various) 0.1 mg/mL (0.02 µmol/mL) 10-mL vials Manganese sulfate, monohydrate (various) 0.1 mg/mL (0.02 µmol/mL) 10-mL and 30-mL vials Molybdenum as ammonium molybdate, tetrahydrate (various) 25 mcg/mL (0.26 µmol/mL) 10-mL vials Selenium as selenious acid (various) 40 mcg/mL (0.51 µmol/mL) 10-mL and 30-mL vials Zinc 1 mg/mL (15.30 µmol/mL) 10-mL and 30-mL vials Zinc sulfate (various) 5 mg/mL (76.50 µmol/mL) 5-mL and 10-mL vials Zinc sulfate (various) 1 mg/mL (15.30 µmol/mL) 10-mL vials Zinc chloride (various)

Information based on manufacturer’s labeling information as of February 1, 2010. Manufacturers, products, and product information can change frequently. IM, intramuscular.

Table 12. Parenteral Multivitamin Products Available in Europe

Folic Content A, D, E, K, B , B , B , B , B , B , C, Biotin, Acid, How 1 2 3 5 6 12 Product (Distributor) per mL IU IU IU mcg mg mg mg mg mg mcg mg mcg mcg Supplied Adult Cernevit (Baxter) 5 mL 3500 220a 11.2 0 3.5 4.1 46 17.3 4.5 6 125 69 414 5-mL powder vial for solution Vitalipid N Adult 10 mL 3300 200b 10 150 0 0 0 0 0 0 0 0 0 10-mL (Fresenius Kabi) ampulec Solivito N 10 mL 0 0 0 0 2.5 3.6 40 15 4 5 100 60 400 10-mL freeze- (Fresenius Kabi) dried vialc Pabrinex: ampule 5 mL 0 0 0 0 250 4 0 0 50 0 0 0 0 5-mL ampule no. 1 (Archimedes 10 mL 500 8 100 10-mL ampule Pharma) Pabrinex: ampule 5 mL 0 0 0 0 0 0 160 0 0 0 500 0 0 5-mL ampule no. 2d 10 mL 320 1000 10-mL ampule (Archimedes Pharma) Pediatric Vitalipid N Infant 10 mL 2300 400b 7 200 0 0 0 0 0 0 0 0 0 10-mL ampule (Fresenius Kabi)

IU, International Unit. Information based on manufacturer’s labeling information as of February 1, 2010. Manufacturers, products, and product informa- tion can change frequently. aCholecalciferol (D ). 3 bErgocalciferol (D ). 2 cVitalipid N Adult contains only fat-soluble vitamins and Solivito N contains only water-soluble vitamins. Can dissolve Solivito N in the Vitalipid N Adult to provide both fat- and water-soluble vitamins. dAlso contains anhydrous glucose: 1 g (5 mL) or 2 g (10 mL).

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How ampule ampule ampule ampule ampule ampule Supplied Cobalt, mcg (µmol) Fluoride, mg (µmol) , mg (µmol) (µmol) Iron, mg mcg (µmol) Molybdenum, Molybdenum, Selenium, mcg (µmol) mg (µmol) Manganese, Chromium, Chromium, mcg (µmol) Copper, Copper, mg (µmol) (µmol) Zinc, mg 1 mL 0.25 (3.82) 0.02 (0.32) 0 (0) 0.001 (0.02) 2 (0.03) 0 (0) 0 (0) 0.001 (0.008) 0.06 (3) 0 (0) 10-mL 1 mL 0.097 (1.49) 0.032 (0.5) 8 (0.16) 0.027 (0.5) 0 (0) 0 (0) 0.091 (1.63) 0 (0) 0 (0) 14 (0.24) 10-mL 1 mL 0.1 (1.53) 0.03 (0.47) 2 (0.04) 0.01 (0.2) 5 (0.06) 5 (0.05) 0.05 (0.9) 0.005 (0.04) 0.05 (2.63) 1.5 (0.03) 10-mL per mL Content 10 mL 6.5 (99.4) 1.24 (19.5) 10 (0.2) 0.275 (5.0) 32 (0.41) 19 (0.2) 1.1 (19.7) 0.13 (1) 0.95 (50) 0 (0) 10-mL 40 mL 10 (153) 0.48 (7.5) 15 (0.3) 0.200 (3.6) 70 (0.89) 25 (0.26) 1 (17.9) 0.0015 (0.012) 1.45 (76.3) 1.47 (0.025) 40-mL

(Fresenius Kabi) (Fresenius & Laboratoires & Kabi) sine NaK (Kohler) Pediatrique (Aguettant) Aguettant) Aguettant racutil (B.Braun) 10 mL 3.3 (50) 0.76 (12) 10 (0.2) 0.55 (10) 24 (0.3) 10 (0.1) 2.0 (35) 0.127 (1) 0.57 (30) 0 (0) 10-mL

Decan (Baxter Peditrace (Fresenius Peditrace (Fresenius Inzolen-Infantibus

Oligo-elements T Additrace Parenteral Multi–Trace Element Products Available in Europe Available Element Products 13. Parenteral Multi–Trace Table Product (Distributor) labeling information as of February 1, 2010. Manufacturers, products, and product can change frequently. Information based on manufacturer’s

Adults

Pediatrics and Neonates

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Over the years, the manufacturing processes have regressed after manganese infusion was discontinued; evolved so it is unclear as to the amount of TE contamination improvement required 6–12 months. in the current PN formulas. A.S.P.E.N. recommends that these In 2008, Hardy et al54 reviewed the medical literature after contamination studies be repeated on the current PN com- 2001. There were 11 additional reports that included a total ponent products. A.S.P.E.N. has multiple recommendations of 229 patients who required PN (75 adults and 154 chil- regarding the current multiple TE products as well as indi- dren). Hypermanganesemia occurred particularly in infants vidual dosing of some TEs. Therefore, each TE will be dis- with cholestasis, often within 3 weeks of the initiation of PN. cussed separately. Another study in which measurements of manganese con- Zinc. Zinc is included in the current multiple TE prod- tent in autopsy tissues were reported from 8 patients who uct in the U.S. The data that support the routine addition lived 2–21 years on PN showed significant manganese eleva- of 3–4 mg/d in all PN formulations are stronger than in tion in liver and kidney samples, especially in patients who any other TE.12 Individual parenteral zinc products are died of liver or renal failure.55 While the mechanism of man- also available and can be used to add additional zinc to ganese neurotoxic damage is not precisely known, a recent the PN formula. Patients with enterocutaenous fistulae, study56 using cultured rat astrocytes found manganese diarrhea, and intestinal drainage may require up to 12–17 induced mitochondrial dysfunction and alterations in gluta- mg of zinc per liter of lost fluid.71,72 Patients with severe mine/glutamate cycling. burns require much larger amounts of zinc per day to Current adult multiple TE products available in the U.S. compensate for losses through the burnt skin.73 A.S.P.E.N. provide 500–800 mcg manganese per day and the pediatric/ recommends no changes to the zinc concentrations in neonatal TE products provide 2–10 mcg/kg/d, and most the current parenteral multiple TE or individual zinc patients developing hypermanganesemia had received products. doses within these ranges. Hypermanganesemia is also seen Selenium. There is strong evidence that selenium should in Europe, where the most widely used products for adults be routinely added to all PN formulas.11 However, some of provide 265 mcg/d. A well-designed Japanese dose-finding the currently available parenteral multiple TE products in study showed adult PN patients maintained a stable whole- the U.S. do not contain selenium. Selenium is available as blood manganese level on a supplement of 55 mcg/d.79 Less an individual parenteral product that can be added to PN than this caused a fall in (RBC) manganese to formulas separately (Tables 10 and 11). However, the rec- values lower than control, whereas an increase in RBC manga- ommended daily parenteral intake of selenium has fluctu- nese and in MRI signal intensity was likely if 110 mcg or more ated considerably (Table 2). The current recommended was supplemented,79 which has also been shown in other parenteral intake is 20–60 mcg/d, which seems to be too studies.80 low, because patients receiving this level of daily intake fre- A.S.P.E.N. recommends that the dose of manganese in quently have low plasma concentrations of selenium.11 parenteral multiple TE products be decreased to 55 mcg/d A.S.P.E.N. recommends that selenium be routinely added to for adults and 1 mcg/kg/d in pediatric and neonatal prod- PN formulas, either in a multiple TE product or as a sepa- ucts with a maximum daily total dose of 55 mcg. Manganese rate component. A.S.P.E.N. also recommends that the adult dose should be further decreased or withheld in patients daily parenteral selenium requirement should be increased with significant cholestasis or hepatic dysfunction, elevated to 60–100 mcg per day.11 Patients who are deficient or who manganese levels, or in those with signs and are critically ill, septic, or have severe burns may benefit symptoms of manganese toxicity. In addition, A.S.P.E.N. rec- from short-term, very high daily doses administered sepa- ommends the amount of manganese contamination in a rate from the PN, but this remains controversial.74-78 standard adult composite PN formulation be limited to <40 Selenium is not included in any pediatric or neonatal mul- mcg/d. Contamination data for pediatric and neonatal PN for- tiple TE product currently available in the U.S. A.S.P.E.N. rec- mulas are not available and require further research. ommends that selenium be added to these products. A.S.P.E.N. Copper. is exemplified by Wilson’s dis- also recommends that selenium should routinely be provided ease, an inborn error of copper metabolism leading to high at a dose of 2 mcg/kg/d in all pediatric and neonatal PN concentrations of copper, particularly in the liver, brain, and formulas. kidney, which in turn leads to the development of , Manganese. In 2001, Dickerson53 reviewed 17 reports neurologic sequelae, and renal impairment.81 While copper of 389 patients on PN that developed hypermanganese- overload in PN patients has not been shown to mimic the mia (265 adults and 124 children). Most patients had no clinical aspects of Wilson’s disease, very elevated concen- clinical symptoms; a small number developed a Parkin- trations of hepatic copper, which meet the diagnostic crite- son-like syndrome, confusion, irritability, and occasional ria for Wilson’s disease (copper >250 mcg/g dry weight), seizures. Laboratory studies showed increased serum and have been reported. Blaszyk et al57 performed liver biopsies red blood cell manganese and increased basal ganglia on 28 long-term PN patients with cholestasis, and hepatic magnetic resonance image (MRI) signal intensities that copper ranged from 10–2248 mcg/g dry weight, and in 8 of

Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 A.S.P.E.N. Position Paper / Vanek et al 453 the 28 PN patients, hepatic copper was >250 mcg/g. The high chromium doses are without clinical consequence or are copper doses infused were not described in this paper. potentially toxic. In adults, there are no reported cases of In the previously referenced autopsy tissue study,55 cop- in patients on long-term PN, suggesting per concentrations were measured in heart, muscle, liver, that these high chromium concentrations are not toxic. This is and kidney. Copper was significantly elevated in liver and further supported by a study that found very high serum chro- kidney tissue, especially in patients who died of . mium concentrations and increased urinary chromium excre- These 8 patients received a commercial multiple TE formula- tion related to the implantation of hip prostheses in adult tion that met the 1979 recommendations for infusion of patients with no deterioration in renal function when observed 0.5–1.5 mg/d of copper. The subjects had received 1.4 mg/d over a 10-year period.89 Another study randomized uncon- of copper for a mean of 14 years. Copper balance studies trolled patients with diabetes to either a supplement with a reported by Shike et al82 indicated this amount was approxi- combination of chromium picolinate and biotin or placebo for mately 3 times the typical requirement. By analogy, with 90 days. The study group experienced a significant decrease cholestatic infants, it is likely that copper accumulates as a in hemoglobin A1c compared with the placebo group, and result of liver disease, but it is also possible that hepatic cop- there was no difference in adverse effects between the 2 per overload enhances the liver damage. groups.90 There are isolated reports of individuals who devel- Currently, the adult parenteral multiple TE products avail- oped renal failure due to tubular necrosis following the inges- able in the U.S. provide approximately 1 mg/d of copper. tion of large doses of chromium as chromium picolinate.91-96 A.S.P.E.N. recommends that the dose of copper in adult par- This toxicity did not appear to be due to the picolinate moiety enteral multiple TE products be lowered to 0.3–0.5 mg/d and and has been assumed related to chromium. So while increased limit the amount of contamination in a composite PN formu- levels of serum and tissue chromium occur with current PN lation to no more than 0.1 mg/d. Copper doses should be regimens, the toxicity of these levels at least in adults remains decreased or omitted in patients with significant cholestasis unknown. or hepatic dysfunction. Copper requirements are increased Chromium toxicity may be more of a concern in pediatric in severe burn patients.73 Because of the absence of contam- patients. In 1992, Moukarzel et al97 found that glomerular fil- ination data for pediatric and neonatal parenteral TE prod- tration rates (GFRs) in PN-dependent children were inversely ucts, no recommendations for product changes are currently correlated with their serum chromium concentration, their made, but investigation of copper contamination in these prod- cumulative parenteral chromium intake, and PN duration. The ucts should be required. investigators discontinued parenteral chromium supplementa- Chromium. Chromium toxicity varies depending on tion, and a year later, the children’s serum chromium concen- the chromium valency. Chromium IV, V, and VI are carci- trations were lower but still elevated, and their reduced GFR nogenic. Chromium in PN formulations, food, and oral was still below control patients who did not receive PN. The supplements is trivalent and considered nontoxic.1 Analy- investigators were unable to determine whether chromium sis of PN formulations showed that chromium was only in contamination had resulted in irreversible renal injury. the trivalent form.83 There are several reports in PN Buchman et al71 found renal tubular damage and high concen- patients, both adults and children, of serum and urine trations of chromium deposits in the kidneys of rodents after chromium concentrations 10–100 times normal val- receiving 1 week of PN; however, it was difficult to determine ues.84-87 Autopsy tissue data found similar elevations in if this was a cause-and-effect relationship. heart, muscle, liver, and kidney samples.55 A normal adult Current adult multiple TE products available in the U.S. diet provides approximately 35 mcg/d of chromium. provide 10–15 mcg/d of chromium. Based on oral absorption Recent studies have revised the estimated amount of in healthy individuals,88 the parenteral requirements may be as dietary chromium absorbed from the previous level of low as 0.14–0.87 mcg/d.10 Because PN components have sig- 10%–20% down to 0.4%–2.5%.88 This means the absorbed nificant chromium contamination, some physician investiga- amount of chromium from a standard adult oral diet is tors have stopped adding chromium to PN formulations, but only 0.4–0.9 mcg/d. Therefore, the parenteral requirement the consequences of such actions have not been evaluated. The is likely to be only one-tenth or less of the previously rec- requirements for chromium during PN with a high and con- ommended amounts of 10–15 mcg/d. tinuous IV dextrose load are not known, and despite chromium According to Pluhator-Murton et al’s data,62 chromium contamination, rare PN-dependent adult patients have been contamination of a 2-L PN composite formula is approxi- reported to require additional chromium in order to maintain mately 15 mcg per day, mainly from the 70% dextrose solu- glucose tolerance.98-101 Until contamination is reduced and the tion used, and is in addition to the 11 mcg/d intentionally issue of parenteral chromium toxicity is better understood, added from a multiple TE product. This amounts to a paren- A.S.P.E.N. recommends that in addition to the current multiple teral chromium dose that is 30–60 times greater than the cur- TE products that contain 10–15 mcg/d of chromium, a multiple rent estimated requirement. The key question is whether these TE product without added chromium should be made

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Table 14. Recommendations for Revised Daily Parenteral Dose element mixtures in the U.S. However, studies using a concen- of Chromium in Neonatal and Pediatric Patients tration of 0.5 mg/L have shown stability for 7 days of storage 102 Age Male Female at 4°C and 25°C. The current options for iron supplementation for adult PN 0–6 mo 0.0006 mcg/kg/d patients in the U.S. are: 7–12 mo 0.012 mcg/kg/d 1–3 y 0.22 mcg/d 1. Patients capable of absorbing oral administered iron 4–8 y 0.3 mcg/d who may be supplemented using an oral product 9–13 y 0.5 mcg/d 0.42 mcg/d 2. Addition of 1–5 mg/d of iron dextran to fat-free PN in patients without deficiency and those not having 14–18 y 0.7 mcg/d 0.48 mcg/d significant ongoing blood loss 3. Separate infusions of IV iron sucrose in doses of These recommendations are based on the Adequate Intake (AI) for these age groups and estimated oral absorption of chromium of 2%. Adapted 300 mg per infusion to give a total dose based on 103 from Moukarzel A. Chromium in parenteral nutrition: too little or too the Ganzoni formula so as to meet the deficit fol- much? Gastroenterology. 2009;137(5)(suppl):S18-S28 with permission lowed by daily infusions as above from Elsevier. available. Research on chromium requirements during PN and Which option is used in an individual patient depends on the effects of contamination on requirement for supplementa- his or her baseline iron stores and ongoing iron losses. tion is urgently needed. Iron supplementation in pediatric and neonatal PN patients The pediatric and neonatal multiple TE products available may be important in long-term therapy, but there is insufficient in the U.S. provide 0.05–0.2 mcg/d of chromium. Studies of evidence to develop definitive daily recommendations due to pediatric/neonatal PN patients on this level of supplementation potential toxicity. Many ill children and neonates also receive report serum chromium concentrations 4–42 times that of nor- blood transfusions in the hospital, which may be adequate. mal.10,86 Moukarzel10 recommended that the daily parenteral Children and neonates should be monitored for iron status dose of chromium for neonates and pediatric patients be radi- prior to initiating parenteral therapy using serum iron, transfer- cally reduced. In view of preliminary studies in newborns on rin, and levels. PN that demonstrate chromium nephrotoxicity, and because To permit a routine daily supply of parenteral iron, PN formulations have significant chromium contamination, research is required to examine the stability of iron additives A.S.P.E.N. recommends that the daily dose of chromium be to fat emulsion–containing admixtures. reduced to the levels recommended by Moukarzel (Table 14) Iodide. Iodide is currently included in the parenteral and that a pediatric/neonatal multiple TE product without multiple TE products available in Europe, but it is not added chromium should be available for use in this patient included in any of the products available in the U.S. population. (Tables 10 and 12). The amount of iodide contamination Iron. Iron is absorbed in the duodenum, and iron mal- in PN components is unclear but appears adequate to absorption is rarely the cause of simply meet basal requirements since thyroid function remains due to a short bowel. However, patients with a short bowel normal in most long-term PN patients.32 However, one often have disease that results in iron loss or have dietary study of 15 pediatric PN patients in Europe104 found an restrictions preventing an adequate intake of iron. In addi- inverse correlation between duration of PN and urinary tion, gastric surgery may reduce the availability of dietary iodide concentrations. While 9 (60%) of these patients iron. had iodide deficiency based on urinary iodide concentra- The requirement for iron in males and postmenopausal tions, thyroid function tests remained normal. In the past, women who do not have any source of blood loss is about 1 the widespread use of povidone-iodine solutions for skin mg/d. It is higher in menstruating women who on average cleansing of sites may have maintained a normal require an additional 0.51 mg/d. However, menstrual losses iodide status as studies have shown that iodine skin prepa- vary and may necessitate an intake as high as 3.4 mg/d. In ration can result in significant transcutaneous iodine absorp- patients on PN, iron requirements vary due to diseases causing tion.105 Since skin cleansing has widely moved to the use of blood loss or iatrogenic causes such as repeated blood draws. 2% , the risk of iodide deficiency and the Hence, there is a wide range of requirements in individuals, need for parenteral supplementation need to be investi- making a single recommendation for daily parenteral intake gated. Routine supplementation of PN with iodide could be difficult. beneficial, but more research is needed for adult, pediatric, Multiple TE products in Europe contain iron, but TE prod- and neonatal products.32 ucts in the U.S. do not contain iron. Stability of total nutrient Fluoride. Fluoride is also present in the multiple TE admixtures containing iron has prevented its addition to trace products used in Europe but is not included in any products

Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 A.S.P.E.N. Position Paper / Vanek et al 455 available in the U.S. (Tables 10 and 12). The amount of the newly recommended products, despite these substances fluoride contamination in PN is variable. Supplementation being present in the oral diet. A.S.P.E.N. is concerned that this of PN with fluoride could be beneficial, but more research process may require significant time, financial investment, is needed for adult, pediatric, and neonatal patient and other resources. Many companies may be reluctant to populations.31 make such a commitment on their own, especially for prod- Molybdenum. Molybdenum is present in most of the ucts that have a relatively low profit margin, in the absence of adult and some of the pediatric parenteral multiple TE requirements to do so from the FDA. A.S.P.E.N. is also con- products in Europe but none of the products in the U.S. cerned that industry, rather than incurring the expense of prod- Previous studies showed PN was contaminated with uct modification, could choose to eliminate products from the molybdenum, but it is unknown what the level of con- marketplace. This could result in devastating effects on the tamination is in current PN formulations. Although patients these same products are designed to treat. A.S.P.E.N. molybdenum is not routinely supplemented in PN in the will encourage the FDA not only to require the recommended U.S., only 1 case of deficiency in a patient on PN has been modifications but also to actively encourage and assist the reported (see Appendix 10). There are no significant data pharmaceutical industry in the development and approval of to warrant recommending routine molybdenum supplemen- safer and more effective vitamin and TE products. Ultimately, tation in PN formulas. Thus, no changes are recommended A.S.P.E.N.’s aim is that micronutrient products available in for adult, pediatric, and neonatal products. the U.S. and in other countries will meet a uniform standard, allowing manufacturers to experience larger and more finan- cially viable markets. Counterissues/Problems Definition The main problem with specifying trace element and vita- min dosages in nutrition products is the individual variabil- Summary/A.S.P.E.N. Recommendations ity of patient requirements. Nutrient needs vary as a result of The routine and appropriate provision of certain vitamins and prior deficiencies, disease state, surgery, and the presence of TEs in PN is essential in improving nutrition status, allowing sepsis or trauma. Also, micronutrient needs are increased improvement in the patient’s underlying disease process and with excessive losses that occur with vomiting, diarrhea, fis- in preventing complications of deficiency or toxicity. tulae output, aspirates, wound drainage, and burns. The The current parenteral multiple vitamin products commer- micronutrient dosages recommended by A.S.P.E.N. are cially available in the U.S. meet the requirements for most PN meant to meet basic nutrient needs for the majority of patients. However, a separate parenteral cholecalciferol or patients, while also acknowledging (or recognizing) that ergocalciferol product should be available for treatment of some patients may need greater amounts of certain nutri- patients with vitamin D deficiency who are unresponsive to ents, whereas other patients may need to have certain nutrients additional oral vitamin D supplementation or when oral sup- decreased or omitted. plementation is impossible. Although there are a large number of patients receiving The current parenteral multiple TE products that are com- PN, the reported incidence of TE in these patients mercially available in the U.S. require significant modification is very low. One reason may be that PN therapy is usually as follows: short term, less than 3–6 months, so the number of long-term Adult parenteral multiple TE products: PN patients, who are most at risk of low-level, chronic toxic- ity, is relatively small.106 Signs and symptoms related to TE •• Decrease copper to 0.3–0.5 mg/d toxicities may be missed if the patient is not specifically •• Decrease manganese to 55 mcg/d monitored for these complications. Toxicity may inadver- •• Product with no chromium (or a maximum of 1 tently be attributed to other factors rather than the accumula- mcg/d) tion of TE. •• Include selenium in all products and increase the Implementation of A.S.P.E.N.’s recommendations for dose to 60–100 mcg/d changes in the available parenteral multiple and individual vitamin and TE products will require product submissions to Pediatric/neonatal parenteral multiple TE products: and approval by the FDA. Some of the recommended changes have already been included in preparations that have been •• Product with no chromium safely and effectively used outside of the U.S. for many years. •• Decrease manganese to 1 mcg/kg/d in neonates It is recognized that the FDA may require submission of North •• Add selenium 2 mcg/kg/d in all pediatric/neonatal American–based studies that include safety and efficacy of preparations

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The recommendations regarding parenteral carnitine: •• Benefits of iodine supplementation of PN in adult, pediatric, and neonatal patients •• Provide 2–5 mg/kg/d carnitine either as part of a mul- tiple vitamin or multi-TE products or as an individual A.S.P.E.N. Novel Nutrient Task Force, product in all neonatal PN formulas Parenteral Multi-vitamin and Multi–Trace The recommendations regarding parenteral choline: Element Working Group and Board of Directors Selected Disclosures •• Provide 550 mg/d of choline routinely to adult PN A.S.P.E.N. Novel Nutrient Task Force, Parenteral Multi- formulations (requires development of either an indi- vitamin and Multi–Trace Element Working Group vidual choline product or addition of choline into Vincent W. Vanek, MD, FACS, FASPEN Chaira either a multiple vitamin or TE product) Peggy Borum, PhD, FASPEN •• Recommend routine parenteral administration in Alan Buchman, MD, MSPH, FACP, FACG, FACN, AGAFb newborns and pediatric patients with the following Theresa A. Fessler, MS, RD, CNSC dosing: Lyn Howard, MB, FRCP c  0–6 months: 125 mg/d Khursheed Jeejeebhoy, MBBS, PhD, FRCPC  7–12 months: 150 mg/d Marty Kochevar, MS, RPh, BCNSP  1–3 years: 200 mg/d Christina J. Valentine, MD, MS, RD d  4–8 years: 250 mg/d Consultant: Alan Shenkin, MB, ChB, PHD, FRCP, FRCPath  9–13 years: 375 mg/d  >13 years: adult amounts A.S.P.E.N. Board of Directors Jay Mirtallo, MS, RPh, BCNSP, FASHPe—President The recommendations for TE contamination in PN Phil Ayers, PharmD, BCNSP formulations: Praveen S. Goday, MD, MBBS, CNSC Carol Ireton-Jones, PhD, RD, LD, CNSDf •• Limit copper contamination to <0.1 mg/d total in a Tom Jaksic, MD, PhD typical adult PN formulation Elizabeth M. Lyman, MSN, RNg •• Limit manganese contamination to <40 mcg/d total Ainsley Malone, MS, RD, LD, CNSDh in a typical adult PN formulation Lawrence Robinson, BS, MS, PharmD •• In order to accomplish these recommendations, all Daniel Teitelbaum, MDi PN products should be taken into consideration Charles W. Van Way III, MD, FASPENj

The recommendations regarding future research (in order Commercial Relationshipa of priority): Member of Baxter’s Speakers Bureau bPartial holder of patent right to choline in PN; holder of •• Parenteral chromium requirements in adult, pediat- patent rights to IV catheter; consultant and speaker for ric, and neonatal PN patients (most urgent) Baxter •• Need further research and development of appro- cConsultant to Seaford, Inc in Mississiaugh, ON, Canada; priate monitoring strategies for trace element and Nutrition Advisory Board of Abbott International; holds a pat- and toxicity in PN patients ent for the use of Mitochondrial complex for nutrition assess- (urgent) ment; co-patentee for a formulation for improving cardiac •• Studies on TE contamination in the various PN com- function ponent products, especially manganese contamina- dConsultant to Fresenius Kabi tion in neonatal and pediatric PN formulations eConsultant to B. Braun •• Feasibility of adding parenteral iron products to PN fSpeaker, program development, Coram; speaker, Access formulas, to include fat emulsion stability and other Medical, Baxter potential incompatibilities gWebinar speaker for Nestle •• Benefits of carnitine supplementation of PN in adult hSpeakers Bureau, Abbott Nutrition and pediatric patients iA funded grant with Baxter •• Benefits of fluoride supplementation of PN in adult, jConsultant and speaker, Baxter; president, A.S.P.E.N. pediatric, and neonatal patients Rhoads Research Foundation; Foundation, St. Lukes Hospital

Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 (continued) Toxicity ision disorders ertigo Chronic (>30,000 mcg/d) Early pregnancy (>7800 mcg/d)—teratogenic with spontaneous abortions, birth defects, and learning disabilities Hypercalcemia—anorexia, nausea, vomiting, headache, weakness, fatigue, diarrhea, confusion, , tremor Hypercalcinuria—renal stones Metastatic with irreversible renal damage, altered mentation, and cardiovascular damage Acute (>150,000 mcg) Increased intracranial pressure Headache Nausea/vomiting V Blurred vision Muscular incoordination Bone malformations and fractures Dermatitis Alopecia Ataxia Muscle pain Membrane dryness Skin disorders and pruritus V Pseudotumor cerebri/HA Hepatocellular necrosis Hyperlipidemia Inhibits vitamin K

• • • • • • , GI, Deficiency State Night blindness* Follicular hyperkeratosis* Xerosis or Irreversible corneal lesions Immunodepression Metaplasia of respiratory GU epithelial cells Childhood— that result in deformation of the skeleton Hypocalcemia Bone pain and Hypophosphatemia Anorexia Adults—osteomalacia and osteopenia that can result in fractures deficiency

• • • • • • • A * Early signs of vitamin • • • • • gery, , or fever, gery, ferentiation and A transport—protein or zinc deficiency A Function/Source/Comments (ergocalciferol)—consumed in diet (eggs, , in diet (eggs, butter, (ergocalciferol)—consumed (cholecalciferol)—synthesized in skin during 2 3 needs or losses—burns, major trauma sur infection and fortified ) exposure to solar or artificial ultraviolet light  itamin D V Vitamin D Vitamin Sources: and dark-green leafy Group of compounds called Integral component of and iodopsins, light- sensitive proteins in retinal rod and cone cells Essential for vision, growth, cellular dif Patients () at risk of deficiency: Sources (2 forms): proliferation, reproduction, and the integrity of immune system Requires hydroxylation in the liver to 25-OH-D followed by hydroxylation in the kidneys to its active form of 1,25-(OH)2-D Maintains intra- and extracellular calcium phosphorous levels by enhancing GI absorption and promoting mobilization from bone mineral Pts at risk for deficiency: Also involved with growth and maturation of other cells, including immune and hematopoietic cells  GI dysfunction—diarrhea or fat malabsorption Chronic alcoholics Impaired vitamin

• • • • • • • • • • itamin D V Fat-Soluble Vitamins A Vitamin Appendix 1 Elements and Trace of Vitamins and Toxicity Efficiency, Function, Deficiency, FASPEN MD, FACS, Vanek, W. Vincent

457 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 (continued) Toxicity infusion can cause anaphylactoid may deliver infants with , hyperbilirubinemia, and kernicterus ery uncommon even with large doses (3200 ery uncommon even with large Liver impairment with depressed levels of vitamin K–dependent coagulation factors potentiating bleeding if pt has a coagulopathy or is on oral and can increase incidence of hemorrhagic stroke in these situations Impaired leukocyte function Preterm infants may be more susceptible to liver damage Rare Rapid IV reaction with dyspnea, flushing, and cardiovascular collapse V International Units/d) Pregnant woman taking large dose of vitamin K Pregnant woman taking large

• • • • • • , low vitamin Deficiency State Hemolytic anemia (only significant in infants) Increased platelet aggregation Causes retinal dysfunction, resulting in tunnel vision Decreased serum creatinine due to excessive urinary losses Skeletal lesions similar to muscular dystrophy Coagulopathy with excessive bleeding Rare in healthy adults Common in newborns due to immature liver K in , sterile gut, and poor placental transfer of vitamin K Fetal skeletal deformities (chondrodysplasia) Axonal neuropathy involving peripheral nerves, posterior column fibers, and gracillus nuclei causing ataxia and weakness Fetal intracranial hemorrhage Easy bruisability Mucosal bleeding Splinter hemorrhages Melena Hematuria

• • • • • • • • • • , and corn oils, including VII, IX, and X as well Function/Source/Comments (phylloquinone)—oral intake with green leafy (menaquinone)—synthesized by gut bacterial flora 1 2 , cholestatic liver disease, pancreatic gastric resection, or jejunoileal bypass surgery insufficiency, , or cholestasis dysfunction, or concentration vegetables with smaller amounts in milk, dairy products, , eggs, cereal, fruits, and other vegetables in colon but poorly absorbed itamin K Sources: oils (, soy and shortening), germ, nuts, green leafy margarine vegetables, sunflower and cotton seeds Group of compounds called Found in cell membranes of all tissues throughout the body and protects the cells from free radical formation oxidation reactions Pts at risk for deficiency: Sources (2 forms): proteins C and S, all of which are vital in the clotting cascade and normal blood clotting Functions in the posttranslational γ- of clotting factors II (prothrombin), Required for the synthesis of other proteins in plasma, bone, and kidney Pts at risk for deficiency: Antioxidant and free radical scavenger Elderly or very young with inadequate oral intake of vitamin D disease), celiac disease, Pts with regional enteritis (Crohn’s Pts with liver dysfunction or renal failure Certain drugs—, cimetidine, Pts with prolonged steatorrhea, pancreatitis, cystic fibrosis, Premature infants and with severe malnutrition, liver Pts with and on high oxygen V Vitamin K Vitamin

• • • • • Pts supplemented with ω-3 fatty acids • • • • itamin K Vitamin E Vitamin V Appendix 1 (continued)

458 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 (continued) Toxicity Rare Easily cleared from the kidney so toxicities are rare and have never been reported from oral thiamine alone No toxicity reported No toxicity reported

• • • • Deficiency State ophthalmoplegia, , and ataxia term memory loss and confabulation but otherwise normal cognition Oral-buccal lesions such as cheilosis, glossitis, and angular stomatitis Dry beriberi—causes peripheral neuropathy resulting in paresthesias, anesthesia, and weakness, mostly of the lower extremities Seborrheic dermatitis Wet Wet beriberi—causes cardiovascular symptoms such as cardiomyopathy, edema, tachycardia, dyspnea, oliguria, , metabolic lactic acidosis Wernicke- Wernicke’s disease— Wernicke’s psychosis—short- Korsakoff

• • • • • • ATP ATP ge doses of salicylates, A [CoA] to link A AD) Function/Source/Comments gan meats (liver, kidney, and heart); lean cuts of kidney, gan meats (liver, needs—fever, infection, trauma, burns,  needs—fever, s disease), or short bowel syndrome containing thiamin antagonists , pregnancy, lactation, strenuous hyperparathyroidism, pregnancy, exertion, adolescent growth prolonged tx Sources: enriched and fortified grains, cereals, bakery products; or ; ; and seeds/nuts Coenzyme required for oxidative of α-keto acids (eg, pyruvate → coenzyme to Krebs cycle and the conversion of α-ketoglutarate → within the Krebs cycle) and for activity of succinyl CoA transketolase in the pentose phosphate pathway Inadequate thiamin availability results in inadequate synthesis and abnormal High carbohydrate intake increases thiamin requirements Pts at risk for deficiency: Sources: enriched and fortified grains, cereals, bakery products; meats; poultry; ; and dairy products Component of 2 flavin coenzymes Pts with malabsorption syndromes, cystic fibrosis, , celiac disease, , regional enteritis (Crohn’ Pts with cholestasis, biliary obstruction, liver disease, or renal failure Pts on certain medications such as lar Pts on long-term PN broad-spectrum , megadoses of vitamin A and E, A broad-spectrum antibiotics, megadoses of vitamin cholestyramine Underdeveloped countries—thiamin-poor diets or Alcoholics Refeeding syndrome PN without thiamine supplementation Pts with (FMN) Flavin adenine dinucleotide (F Pts with  losses—dialysis, diuresis, malabsorption,

Breast-fed newborns • • • • • • • ) ) 1 2 thiamine] ater-Soluble Vitamins ater-Soluble W Thiamin [also spelled (vitamin B Appendix 1 (continued) Riboflavin (vitamin B

459 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 (continued) Toxicity Nicotinamide has no reported toxicity Nicotinic acid in high doses (3–9 g/d) can cause: Rare Flushing Nausea and vomiting Liver toxicity Blurred vision Impaired glucose tolerance High doses (10–20 g/d) have been reported to cause diarrhea and fluid retention

• • • , and niacin 6 Deficiency State Ocular disturbances such as itching, burning, dryness, corneal , and photophobia Normochromic, normocytic anemia Frequently accompanied by vitamin B Seen also in carcinoid syndrome in which tryptophan is diverted to other synthetic pathways Rare and usually in combination with other vitamin B deficiencies Listlessness and fatigue —“4 Ds” Growth retardation Infertility deficiency with their associated symptoms Abortion and neonatal death Dermatitis (also, glossitis, stomatitis, vaginitis) Diarrhea (also vomiting) Dementia—, dizziness, , irritability depression, disorientation, delusions, catatonia Death

 Scrotal and vaginal skin changes • • • • • • • • • •

, burns, or and niacin 6 (involved in , synthesis Function/Source/Comments gery, trauma, burns, or fractures gery, s disease—autosomal recessive congenital disorder such as the conversion of tryptophan to niacin and functions in xanthine oxidase, succinic dehydrogenase, and glutathione reductase oxidative enzyme systems etc), thyroid dysfunction, diabetes, or alcoholism Essential for proper functioning of vitamin B Pts at risk for deficiency: Sources: and tryptophan-containing foods such as milk and eggs (niacin is unique among vitamins in that it can be formed in the body from dietary tryptophan) Niacin includes nicotinic acid and nicotinamide Nicotinamide functions in 2 coenzyme systems, NAD and NADP Pts at risk for deficiency: Sources: meat, whole grain cereals, and legumes Component of CoA from carbohydrate, of heme and sterols, release energy fat, and ketogenic amino acids) acyl carrier protein (necessary for fat synthesis) Pts at risk for deficiency: These coenzymes are present in all cells and essential many metabolic processes, including glycolysis, metabolism, and tissue respiration  Catalyzes many oxidative-reduction reactions in the body Pts on psychotropic drugs, tricyclic antidepressants, or Pts with or who avoid dairy products Pts with malabsorption (celiac disease, short bowel syndrome, Pregnancy and lactation Pts with sur Pts with malabsorption, thyroid dysfunction, cancer alcoholism Pts on isoniazid therapy for Pts with carcinoid syndrome (tryptophan is metabolized to 5-OH tryptophan and instead of nicotinic acid) Hartnup’ that interferes with absorption of tryptophan Chronically malnourished Alcoholics

• •

• • • • • • • • ) ) 3 5 Appendix 1 (continued) Pantothenic acid (vitamin B Niacin (vitamin B

460 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 (continued) Toxicity , if taken in high doses for a prolonged However period of time (treatment PMS or certain mental disorders), it can cause ataxia, peripheral neuropathies, and severe sensory neuropathy with photosensitivity is rare

No toxicity reported • • , depression, and Deficiency State (paresthesias of the hands and feet) sense Impaired mentation and insomnia Paresthesias Poor wound healing Increased susceptibility to infection Sudden death Peripheral nerve, spinal cord, and/or cerebral damage Usually accompanies deficiencies of other Stomatitis, angular cheilosis, and glossitis Irritability confusion Convulsions Dermatitis Normochromic, normocytic, sideroblastic anemia In infants, various neurologic symptoms and abdominal distress Abdominal pain, vomiting, and diarrhea Adrenal cortical failure Peripheral neuropathy Impaired vibration and position

 Abnormalities of skin and hair • • • • • • • • • • • • • • • • 12 metabolism such from food sources 6 12 from binding with R factors , liver, pork, eggs, , soy , liver, 12 Function/Source/Comments -IF receptors 12 , erythrocytes, and other tissues convert these forms into as isoniazid, , , ethanol, and theophylline and phosphate, which are essential coenzymes in transamination and decarboxylation reactions Sources: , fish, kidney Comprises 3 forms: pyridoxine, pyridoxal, and pyridoxamine Liver Pts at risk for deficiency: beans, , whole wheat, , and Sources: fish, eggs, and milk Must be converted to one of its coenzyme forms, or 5′-deoxyadenosylcobalamin These reactions are important in the transformation of certain amino acids and in the metabolism of lipids nucleic acid, as well conversion of tryptophan to niacin These coenzymes are also essential for Adequate absorption depends on: Usually seen in conjunction with other B vitamin deficiencies Certain medications inhibit vitamin B Ileal B Pancreatic proteases to free B Secretion of IF by gastric parietal cells to bind B Dietary intake Acid-pepsin in to liberate B

• • • • • • • • • 6 12 Vitamin B Vitamin Vitamin B Vitamin Appendix 1 (continued) (cobalamin)

461 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 ge (continued) Toxicity Folic acid and the inhibit uptake of each other in the GI tract and possibly at the brain cell membrane, so lar doses of folic acid (>400 mcg) can precipitate seizures in epileptics on phenytoin

• Deficiency State memory isional disturbances Leukopenia Neural tube defects ( and ) in newborns of mothers not taking folate supplement Megaloblastic anemia Glossitis Diarrhea Impaired cell-mediated immunity Dementia Weight Weight loss Unsteadiness Confusion Depression Impaired mentation and Delusion Psychosis V

• • • • • • • • • , tropical THFA ) n , lactation, infancy, , lactation, infancy, Function/Source/Comments , , leafy vegetables, legumes, some fruits , chronic hemolytic anemia, , another (eg, converts methylmalonyl CoA to succinyl CoA, another (eg, converts methylmalonyl CoA which is vital in lipid and carbohydrate metabolism) the methyl folate back to [THFA], metabolically active form of folic acid, which has numerous functions, including synthesis of thymidylate and DNA) is needed for formation nerves otal vegetarians Functions: Pts at risk for deficiency: Sources: liver (as much as 50% of folate in food destroyed with ) Folate and folacin are generic descriptors for compounds that have nutrition properties and chemical structures similar to those of folic acid (pteroylglutamate, PTE-Glu Folic acid must be converted to its active form, Functions as coenzymes that transport single carbon fragments from one compound to another in amino acid metabolism and synthesis of , which are essential in DNA Deficiency leads to impaired cell division and alterations in protein synthesis Pts at risk for deficiency: T  absorption—pernicious anemia, total gastrectomy sprue, celiac disease, resection of terminal ileum, gastric intestinal parasites bypass surgery,  requirements—pregnancy Pts on ethanol, neomycin, colchicine, potassium, aminosalicylic acid, , proton pump inhibitors Coenzyme that shifts hydrogen atoms from one carbon to Coenzymes that transfer methyl groups (eg, convert Coenzymes also convert homocysteine to methionine, which hyperthyroidism, alcoholism, megadoses of vitamin C Chronic alcoholics Malabsorption—celiac disease, inflammatory bowel and short bowel syndrome  cell division/metabolism—trauma, burns, infections, cancer lactation, and early infancy pregnancy,

• • • • • • • • Folate Appendix 1 (continued)

462 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 (continued) ge doses of Toxicity ge amounts of vitamin C can cause false- ithdrawal from high chronic doses should be Rare Doses >500 mg/d can cause nausea and diarrhea Pts with renal failure, kidney stones, or disease should avoid lar Lar No toxicity reported vitamin C positive fecal occult blood and glycosuria testing and may hinder or anticoagulation therapy W gradual to avoid “rebound scurvy”

• • • • • • Deficiency State stress and infection structures (bone , teeth, and connective tissue) Mild deficiency Severe deficiency Dry scaly dermatitis Pallor Glossitis Nausea and vomiting Impaired mentation Hyperesthesias Muscle pain Hair loss Elevated serum and bile pigments Anorexia Anorexia Fatigue Muscle pain Increased susceptibility to Scurvy of the collagenous Weakening Bleeding gums Petechiae and ecchymosis Perifollicular hemorrhage Impaired wound healing Anemia with arthralgia Joint effusions Fatigue Depression

• • • • • • • • • • • •

, eggs, and dairy geries, trauma, burns, cancer ATP required for conversion of biotin to its ATP Function/Source/Comments , egg , soy , cereals, and yeast , egg yolk, soy flour, -containing water-soluble vitamin, which can also be -containing water-soluble metabolism its excretion in bile acids cells vidin, a biotin-binding glycoprotein, is found only in raw Sources: fruits (especially citrus fruits) and vegetables with smaller amounts in meat, fish, poultry products Necessary for: Pts at risk for deficiency: Sources: liver synthesized by intestinal Magnesium and active coenzymes Biotin functions as a component of 4 enzymes that transport carboxyl units to various substrates as follows: acetyl CoA carboxylase (required for ), (required for gluconeogenesis), propionyl carboxylase (for propionate metabolism), and CoA carboxylase (required for catabolism 3-methylcrotonyl CoA of branched-chain amino acids) Pts at risk for deficiency: Antioxidant and free radical scavenger A amounts of raw eggs can cause eggs and consumption of large Pregnancy and lactation Alcoholics Pts with partial or total gastrectomy burns Collagen synthesis via hydroxylation of proline and lysine Carnitine and neurotransmitter synthesis Enhanced intestinal absorption of nonheme iron Hepatic microsomal hydroxylation of cholesterol required for Reduction of toxic transition metals Reductive protection of folic acid and vitamin E Immune-mediated and antibacterial functions of white blood Smokers Pregnancy and lactation Pts with major sur Pts on PN

• • • • • • • • • Vitamin C Vitamin (ascorbic acid) Biotin Appendix 1 (continued)

463 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 (continued) ge quantities can lead to Toxicity ilson’s disease—hereditary condition of copper ilson’s oxic levels of airborne chromium No toxicity reported from dietary chromium Chronic: accumulates in liver (hepatic necrosis and cirrhosis), kidneys (renal failure), brain (neurologic disorders), and corneas Chronic (years of 20–80 mg/d)—mottling teeth, of tendons and ligaments, exostoses, and increased brittleness of bones Chronic ingestion of lar with goiter or hyperthyroidism T W toxicity Acute (rare): nausea, vomiting, diarrhea, epigastric abdominal pain, coma, oliguria, acute renal failure, hepatic necrosis, vascular collapse, and death Acute, high dose (5–10 g)—death Allergic dermatitis Allergic Skin ulcers Bronchogenic carcinoma

• • • • • • • • Deficiency State glycemia and glucosuria ery rare and only reported in Hyper refractory to insulin Peripheral neuropathy Encephalopathy Hyperlipidemia Hypochromic, microcytic anemia Neutropenia Osteopenia Depigmentation of skin and hair Skeletal abnormalities Neurologic abnormalities Contributes to dental caries Newborns—spontaneous abortions, stillbirths, congenital abnormalities, hypothyroidism, dwarfism, deafness and severe mental retardation (cretinism), increased perinatal and infant mortality V 3 long-term PN patients Adults—thyroid goiter and hypothyroidism, impaired mentation

• • • • • • • • • • • • • • Function/Source/Comments , older children and adults continue to benefit , (especially shellfish), nuts, legumes, gy expenditure and are important in growth ’s liver, American , and wheat germ have high liver, ’s Sources: chromium value of many foods unknown but yeast, calf bioavailability of chromium Enhances the ability of insulin to bind receptors on the cell surface and thereby participates in metabolism of carbohydrates, protein, and fat Pts at risk of deficiency: Sources: liver and seeds Incorporated into metalloenzymes that are involved with connective tissue formation; metabolism of iron (ceruloplasmin), cholesterol, and glucose; myelin synthesis; conversion of to in the brain, serotonin synthesis, melanin pigment formation; and antioxidant participating in the immune system Pts at risk of deficiency: Sources: fluorinated water and tea Pts at risk of deficiency: Sources: seafood, iodized table salt, and certain baked and dairy products Essential nutrient that is incorporated into , thyroxine (T4) and tri-iodothyronine (T3), which modulate resting ener development Assists in enamel formation of teeth and helps avoids caries, especially during maximal tooth formation (first 8 years of life); however from consumption of fluoridated water Burns, trauma, short bowel syndrome PN pts without chromium supplementation infants PN pts without copper supplementation Chronic peritoneal dialysis Infants and children who drink nonfluoridated water

• • • • • • • • • • • Iodine Trace Elements Trace Chromium Copper Fluoride Appendix 1 (continued)

464 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 (continued) Toxicity or —excessive total body iron that accumulates in stores and RE system, little consequence Hemochromatosis Hereditary or acquired (chronic hemosiderosis) Classic triad Neurotoxicity (primarily associated with oversupply associated with chronic PN) Excess of 10–15 g/d can cause gout-like syndrome with elevated serum molybdenum, uric acid, and xanthine oxidase Even moderate doses of molybdenum can cause increased urinary excretion of copper and possible copper deficiency Cirrhosis Diabetes mellitus Hyperpigmentation (gray tinge) of the skin Other Fatigue and sterility Testicular Arthropathy Cardiac arrhythmias Hypothyroidism

• • • • • • • , Deficiency State Most common nutrient deficiency in U.S. Microcytic, hypochromic anemia (causing tachycardia, and fatigue, pallor, altered mental and motor development) Glossitis Impaired temperature regulation in the cold Decreased resistance to infection Deficiency states not well documented but some reports of dermatitis and hypocholesterolemia Deficiency rare but was reported in a long-term PN patient causing amino acid intolerance, irritability visual field defects, coma; patient also noted to have hypermethioninemia, increased urinary excretion of xanthine and sulfite, decreased serum uric acid

• • • • • • • , gy TIBC, transferrin Function/Source/Comments spleen, bone , and circulating iron bound to carrier spleen, bone marrow, protein transferrin incorporation in hemoglobin and myoglobin ATP release from oxidative and in energy generation; detoxifying drugs, , and pesticides; biosynthesis of aldosterone, , and sex hormones; and synthesis of DNA, unsaturated fatty acids, carnitine, collagen, and neurotransmitters omen in childbearing ages saturation Sources: meat, eggs, vegetables, fortified cereals Forms of iron in body Ionic forms of iron: Functions: Lab tests—serum iron, serum ferritin, Pts at risk for deficiency: Sources: whole grains and cereals and, to a lesser extent, fruits and vegetables Incorporated into metalloenzymes involved with ener release, fatty acid and cholesterol synthesis, release of lipids from the liver Sources: milk, beans, breads, and cereals Incorporated into several enzymes, including aldehyde oxidase, xanthine and sulfite oxidase Pts at risk for deficiency: Ferric (Fe3+) Ferrous (Fe2+) Deficient in copper intake or have dysfunction metabolism Present in hemoglobin (60% of iron body) Myoglobin (4% of iron in body) Iron-containing enzymes (5%–15% of iron in body) Remaining iron is as storage (hemosidum) in liver Involved in transport and storage of oxygen by its Incorporated into nonheme metalloenzymes that are involved Growing children W Chronic blood loss

• • • • • • • • • • • Molybdenum Iron Manganese Appendix 1 (continued)

465 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 production of  Toxicity cholesterol enderness and loss of fingernails smell to breath (from Nausea and vomiting Loss of hair and nails Diarrhea Peripheral neuropathy Fatigue Irritability and altered mental status Chronic (>20 mg/d orally) dimethylselenide in body and release from the lungs) T Abdominal pain Acute (>200 mg orally): Epigastric abdominal pain Nausea and vomiting Diarrhea Decreased serum copper levels (hypocupremia) Microcytosis and neutropenia Reduced HDL Impaired immune function

• • • • • • • • • • • Deficiency State Deficiency state not well characterized but in 3 long- term PN patients with low serum selenium levels, muscular discomfort or weakness Cardiomyopathy has also occurred in PN patients with low selenium levels Skin rash of face, groins, hands, and feet Delayed sexual development Impaired wound healing and immune function Blunting of taste and smell Growth retardation Diarrhea Anemia Alopecia

• • • • • • • • • • binding; , , alcoholic synthesis , liver, and some meats , liver, , eggs, and seafood (especially ) Function/Source/Comments cirrhosis, diabetes mellitus malabsorptive disorders, pregnancy regulation; of DNA to RNA; synthesis of gene regulation; transcription of DNA heme, long-chain fatty acids, and prostaglandins; cholesterol transport; stabilization of cell membrane lipids; sexual maturation and reproduction; immune function Sources: seafood, kidney Incorporated at the active site of glutathione peroxidase, an enzyme that catalyzes the breakdown of hydroperoxides and has metabolic interrelationships with vitamin E, an antioxidant Participates in enzymatic conversion of thyroxine to its more active metabolite, tri-iodothyronine Cofactor for protein and DNA Sources: meat, liver Essential nutrient participating in multiple metalloenzyme involving zinc in most central metabolic pathways, including metabolism of protein, fat, and carbohydrates; DNA Pts at risk for deficiency: Chronic PN without zinc supplementation Pts with severe diarrhea, inflammatory bowel disease,

• • • • • • • Zinc Selenium ATP, adenosine triphosphate; CoA, coenzyme A; GI, gastrointestinal; GU, genitourinary; HA, headache; HDL, high-density lipoprotein; IF, intrinsic factor; IV, intravenous; NAD, nicotinamide adenine intrinsic factor; IV, A; GI, gastrointestinal; GU, genitourinary; HA, headache; HDL, high-density lipoprotein; IF, adenosine triphosphate; CoA, coenzyme ATP, TIBC, tetrahydrofolic acid; THFA, nicotinamide adenine dinucleotide phosphate; PMS, premenstrual syndrome; PN, parenteral nutrition; Pts, patients; RE, reticuloendothelial; dinucleotide; NADP, total iron binding capacity; tx, treatment. Appendix 1 (continued)

466 Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 A.S.P.E.N. Position Paper / Vanek et al 467

Appendix 1 References Appendix 2

Berger MM. Vitamin C requirements in parenteral nutrition. Gastroenterology. Vitamin A and Parenteral Nutrition 2009;137(5)(suppl):S70-S78. Biesalski HK. Vitamin E requirements in parenteral nutrition. Gastroenterol- Christina J. Valentine, MD, MS, RD ogy. 2009;137(5)(suppl):S92-S104. Boosalis MG. Vitamins. In: Matarese LE, Gottschlich MM, eds. Contem- Introduction porary Nutrition Support Practice. Philadelphia, PA: Saunders; 1998: 145-162. Vitamin A (retinol), a fat-soluble vitamin, was initially iden- 1 Braunschweig C. Minerals and trace elements. In: Matarese LE, Gottschlich tified in 1928 and coined the “anti-infective” vitamin. Since MM, eds. Contemporary Nutrition Support Practice. Philadelphia, PA: that time, vitamin A and its active compounds have become Saunders; 1998:163-173. identified with many other vital functions, including cellular Choi EH, Strum W. Hypocupremia-related myeloneuropathy following gastro- differentiation, vision, epithelial integrity, immune function, 2 jejunal bypass surgery. Ann Nutr Metab. 2010;57(3-4):190-192. growth, development, and reproduction. The A DeLuca HF. Vitamin D and the parenteral nutrition patient. Gastroenterology. active compounds, β-carotene, α-carotene, and cryptoxan- 2009;137(5)(suppl):S79-S91. thin, are biologically interdependent based on their structural Forbes A. Iron and parenteral nutrition. Gastroenterology. 2009;137(5) and/or functional relationships. Of the 500 found (suppl):S47-S54. naturally, only 50 have provitamin A activity. The primary Hardy G. Manganese in parenteral nutrition: who, when, and why should we provitamin A active compound after oxidative of 3 supplement? Gastroenterology. 2009;137(5)(suppl):S29-S35. the 15,15′ double bond is the trans-β-carotene. Vitamin A Heimburger DC. Nutritional diseases. In: Cecil Textbook of Medicine. 20th ed. activity is often expressed as retinol equivalents, 1 mcg all- Philadelphia, PA: Saunders; 1998:1139-1175. trans-retinol = 6 mcg all trans-β-carotene = 12 mcg other 2 4 Jeejeebhoy K. Zinc: an essential trace element for parenteral nutrition. Gastro- provitamin carotenoids. The Dietary Reference Intakes, enterology. 2009;137(5)(suppl):S7-S12. published by the Institute of Medicine, more specifically Kelly DG. Guidelines and available products for parenteral vitamins and trace describe retinol activity equivalents (RAEs) where 1 RAE = elements. JPEN J Parenter Enteral Nutr. 2002;26(5):S34-S36. 1 mcg retinol = 12 mcg β-carotene = 24 mcg α-carotene = 24 Lehninger AL. Vitamins and coenzymes. In: Lehninger AL, ed. Biochemistry. mcg β-cryptoxanthin. Dietary sources of preformed vitamin 2nd ed. New York: Worth; 1977:335-360. A are found in a high concentration in liver (3000–15,000 5 Moukarzel A. Chromium in parenteral nutrition: too little or too much? Gastro- mcg retinol/100 g). Milk and whole eggs are also good food enterology. 2009;137(5)(suppl):S18-S28. sources with 30–70 mcg retinol/100 mL and 100–300 Nielsen FH. Micronutrients in parenteral nutrition: boron, silicon, and fluoride. mcg/100 g, respectively. β-Carotene equivalents are high in Gastroenterology. 2009;137(5)(suppl):S55-S60. carrots (2000–7000 mcg/100 g), green leafy vegetables O’Donnell KB, Simmons M. Early-onset copper deficiency following Roux- (2000–3000 mcg/100 g), yellow sweet potatoes (2000–4000 5 en-Y gastric bypass. Nutr Clin Pract. 2011;26(1):66-69. mcg/100 g), and (1000–1500 mcg/100 g). Otten JJ, Pitze Hellwig J, Meyers LD, eds. Dietary Reference Intakes: The Bioconversion from provitamin A carotenoids is, however, Essential Guide to Nutrient Requirements. Washington, DC: National variable and ranges from a conversion efficiency of 3.6–28:1 6 Academies Press; 2006. by weight. Pazirandeh S, Burns, DL. Overview of dietary trace metals. UpToDate Online 12.3, last updated 6/29/2004. Metabolic Effects Pazirandeh S, Burns, DL. Overview of fat-soluble vitamins. UpToDate Online 12.3, last updated 1/14/2004. Dietary retinyl esters are hydrolyzed to retinol in the intestinal Pazirandeh S, Lo CW, Burns, DL. Overview of water-soluble vitamins. UpTo- lumen, taken up into the intestinal cell and reesterified into Date Online 12.3. Published 9/8/2004. retinyl esters (REs), coupled to chylomicrons, and released 7 Schrier SL. Diagnosis and treatment of vitamin B12 and folic acid deficiency. into the bloodstream via the thoracic duct. The chylomicron UpToDate Online 12.3, last updated 8/12/2004. remnants containing RE are taken up by the liver through an 7 Schrier SL. Etiology and clinical manifestations of vitamin B12 and folic acid apolipoprotein E receptor. Vitamin A is kept in the liver peri- deficiency. UpToDate Online 12.3, last updated 8/25/2004. sinusoidal stellate cells and, when released for cellular events, Shearer MJ. Vitamin K in parenteral nutrition. Gastroenterology. 2009;137(5) is bound to retinol-binding protein and coupled to transthyre- 7 (suppl):S105-S118. itin to avoid renal clearance. Serum levels do not correlate Shenkin A. Selenium in intravenous nutrition. Gastroenterology. 2009;137(5) with liver stores. 8 (suppl):S61-S69. Vitamin A’s major role in vision is photoreceptor function. Shike M. Copper in parenteral nutrition. Gastroenterology. 2009;137(5) Vitamin A in the 11-cis isoform combines with photoreceptor 8 (suppl):S13-S17. to form rhodopsin. The metabolic effects of vitamin A in Zimmermann MB. Iodine: it’s important in patients that require parenteral mucosa-associated are related to expression of 7 nutrition. Gastroenterology. 2009;137(5)(suppl):S36-S46. cytokeratins and terminal differentiation.

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Reliable Assessment for Deficiency In the hospital, patients with pressure ulcers,20 wounds, or 21 and Toxicity burns must receive adequate vitamin A for restoration of epithelial surfaces. In fact, topical application of Deficiency signs manifest first as night blindness9 followed by and glycolic acid improved mouth healing and subsequent xerophthalmia9,10 and blindness. Infectious diseases are often mouth opening in inhalation-burn patients.21 Detailed monitor- associated with because of altered epi- ing of vitamin A intake and laboratory assessment is, however, thelial keratinization. In addition, immune function may critical because toxicity has been documented in patients with be affected by vitamin A status.3 >25% burns on enteral supplementation.22 In a case report, 2 Vitamin A status is traditionally assessed by serum retinol patients on prolonged enteral feeding for 272 and 180 days or the concentration of retinol binding protein (RBP).11 The demonstrated elevated liver enzymes and toxic concentrations normal range of serum retinol concentration is 1–3 µmol/L of vitamin A22 on an intake of 1–2 L of 102 mcg/100 mL vita- measured by high-performance liquid min A per day in their enteral food source. (HPLC)12 with RBP correlates of <0.48 mmol/L associated The mechanism of vitamin A toxicity in the liver is not with severe vitamin A deficiency.13 In periods of stress, serum fully understood but appears to occur when the dose of vitamin retinol is not reliable and the RBP-to- ratio is a A exceeds the available RBP.23 The fat-storing cells then pro- better marker for deficiency.14 In addition, when field testing duce a matrix of laminin and type III collagen that results in the status of vitamin A, it is easier to use a radioimmunoas- hepatic fibrosis24 and a characteristic picture on biopsy. say for RBP concentration rather than HPLC technology.13 Because of the importance of vitamin A to T cell function,25 Preformed vitamin A is absorbed at rates of 70%–90%, but immunity can be compromised by vitamin A deficiency. Linear if ingestion is excessive or the vitamin A is given by intramus- growth has been improved in children <18 months of age with cular or intravenous injection, thereby bypassing gastrointesti- human immunodeficiency virus (HIV) on vitamin A supple- nal regulation, toxicity can result.15 In contrast, provitamin mentation.26 However, in a randomized trial in Tanzania, sources are absorbed at lower rates of 20%–50%.15 women with HIV disease showed no significant increase in The cleavage of provitamin A carotenoids to retinal is highly CD4, CD8, or CD3 counts.27 Care must be taken in interpret- regulated, making them unlikely to cause toxicity. ing low serum vitamin A levels in patients with protein calorie Vitamin A toxicity can present with elevated intracranial malnutrition since stores may be adequate, but the liver may pressure (leading to symptoms including vomiting, head- not release vitamin A due to a low RBP.28 aches). Bony abnormalities have also been described with vita- Supplementation of vitamins is often practiced to prevent min A toxicity, most likely due to vitamin A antagonism of or attenuate cancer risk. However, in a large (N = 8171 women) vitamin D at the receptor level,16 resulting in bone resorption study with random and blinded assignment to supplementa- and decreased bone formation.17 tion, β-carotene supplementation conveyed no protection from Retinyl esters in serum, which are normally <0.2 µmol/L in cancer incidence or mortality.29 Patients with renal failure have the fasting state,18 can be measured using HPLC to detect reduced RBP renal clearance and are at risk for developing toxicity. vitamin A toxicity. In a retrospective study to determine the Serum retinol concentrations have been found to be status of vitamin A in transplant dependent on age, gender, and season of the year.19 Older patients with acute renal failure, investigators found 17 of 19 volunteers, especially males, and autumn were associated with patients had abnormally high levels.30 higher serum retinol levels in a large trial in France.19 When the hepatobiliary cycle is defective and intestinal absorption is impaired, as can be the case in short bowel syndrome (SBS), patients have been found to have lower Modifications for Special Clinical serum concentrations of vitamin A.31 Home parenteral nutri- Conditions—Adults and Pediatrics tion (PN) patients with SBS can become vitamin A deficient (Burns, Cholestasis, HIV, / without a parenteral vitamin A source and develop night , Renal Failure, Trauma, blindness.32 Since vitamin A is adsorbed onto glass and plastic Sepsis, Intestinal Injury, Cystic Fibrosis) containers and oxidized to a nonphysiologic by light exposure, vitamin A deficiency can develop unless the vitamin Vitamin A is a fat-soluble vitamin absorbed from the core of is added to the PN solutions just prior to infusion.33 A case the complex micelle. Deficiency can result from inadequate report after for obesity has also described dietary intake or defective intestinal delivery due to abnormal night blindness that corrected after vitamin A therapy.8 hepatobiliary function or damaged epithelial integrity. The individual with cystic fibrosis (CF) is at particular risk Deficiency can also occur with impaired vitamin A mobiliza- for vitamin A depletion not only because of fat malabsorption tion from the intestine (abetalipoproteinemia) or the liver but also due to zinc deficiency.34 In a recent Cochrane review, (protein calorie malnutrition and zinc deficiency lead to however, there was no evidence-based recommendation for reduced RBP formation). vitamin A in a patient with CF.35 In fact, serum retinol has been

Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 A.S.P.E.N. Position Paper / Vanek et al 469 found to be elevated in preadolescent children with CF on an supplementation does correlate with increased breast milk elevated vitamin A intake of 816 ± 336 mcg retinol activity concentrations and a low likelihood of serum vitamin A level equivalents per day (165% ± 69% of the recommended dietary in the infant.43 allowance).36 With all special conditions reviewed, it was apparent that a relatively narrow window exists between deficiency and toxic- Considerations in Neonates ity; therefore, it is essential that the clinician investigate all For the healthy infant 0–6 months, the advisable intake of supplements and food sources the patient is ingesting to pre- vitamin A is 400 mcg/d RAE. From 6 months to 1 year, the dict adequacy37 and practice prudent supplementation. vitamin A intake should increase to 500 mcg/d RAE.4 Preterm infant requirements are higher because of low stores and the need for increased growth and development.44 Mechanical Modifications for Gender and ventilation or use in the neonatal intensive care unit the Elderly increases the need for vitamin A.45 Recommendations for par- Knowledge of typical blood concentrations and dietary intakes enteral and enteral nutrition for the preterm infant range from related to sex and age can be helpful in baseline assessment in 700–1500 International Units/kg/d.44,46 the clinical setting. In a large cohort (N = 12,741) examined Delivery to the preterm infant on parenteral vitamin A for retinol, α-tocopherol, and β-carotene serum concentrations, can be compromised by losses in the delivery system.47,48 retinol concentrations were higher in older volunteers, espe- This can result in as little as 17%–66% of the expected cially male participants, in France.19 Vitamin A supplementa- amount being received. European studies have demonstrated tion has not been demonstrated to reduce the incidence of enhanced delivery when the preterm infant is given a vita- infection in the older nursing home patient.38 In fact, when min product admixed in intravenous fat emulsion (IVFE).49 examining dietary intakes in the United States, women tend to In the U.S., we have yet to have access to these vitamin have intakes of vitamin A from food above the estimated aver- products. In the U.S., patients receive parenteral fat-soluble age requirement (EAR), and with typical supplementation, vitamin products not approved for admixture in IVFE. Many they ingest almost 3 times the EAR.39 Thirty percent of U.S. clinicians will therefore give injections of vitamin A to the residents use vitamin supplements regularly.37 Modifications extremely preterm infant to reduce the likelihood of chronic of the diet should be consistent with these data. disease.50

Considerations in Pregnancy Drug and Nutrient Interactions and Lactation Vitamin A supplementation (VAS) may enhance the concur- Vitamin A recommendations are higher in pregnancy and lac- rent delivery of vaccinations.51 To reduce mortality after 6 tation to support growth and cell differentiation.40,41 The months, a study was done to determine if VAS at the time of Dietary Reference Intakes are dependent on age and range vaccination had a beneficial effect.51 The investigators found from 750–770 mcg/d RAE for pregnant women 14–18 years that the effect of VAS was not helpful in -vaccinated and 19–50 years, respectively.4 , used for , is a girls who did not have up-to-date diphtheria--pertussis known teratogen in pregnancy and should be avoided.42 vaccine but had a benefit in lowering mortality in children Lactation increases demands for vitamin A, and recom- with no record of at study enrollment. Of mendations are 1200–1300 mcg/d RAE for 14- to 18-year- important note is that VAS did reduce the risk of developing olds and 19- to 50-year-old women, respectively.4 Maternal xerophthalmia in all cases.51

Table A2.1. Recommended Intake Based on Dietary Reference Intake4

Infant Infanta 7–12 Child Child Male Male Female Female Preg Preg Lact Lact Life Stage 0–6 mo mo 1–3 y 4–8 y 9–13 y 14+ y 9–13 y 14 + y 14–18 y 19+ y 14–18 y 19+ y Vitamin A, mcg/d, RAEb 400 500 300 400 600 900 600 700 750 770 1200 1300

Lact, lactating; Preg, pregnant. aInfant refers to the term infant; the preterm infant requirements are estimated to be 750–1500 International Units/kg/d,52 keeping in mind that 3.3 Inter- national Units of vitamin A = 1 RAE. bRetinol activity equivalents (RAEs) consist of 1 RAE = 1 mcg retinol, 12 mcg β-carotene, 24 mcg α-carotene, or 24 mcg b-cryptoxanthin (DRI).

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Conclusion National Health and Nutrition Examination Survey. Am J Clin Nutr. 2000;72(5):1170-1178. Vitamin A and its active compounds are important for vision, 13. Gamble MV, Ramakrishnan R, Palafox NA, Briand K, Berglund L, Blaner skin, growth, development, reproduction, and immune func- WS. Retinol binding protein as a surrogate measure for serum retinol: tion. Dietary insufficiency, fat malabsorption, and calorie, studies in vitamin A–deficient children from the Republic of the Marshall protein, or zinc deficiency can all predispose the patient to Islands. Am J Clin Nutr. 2001;73(3):594-601. vitamin A deficiency, resulting in poor outcomes in any of the 14. Rosales FJ, Ross AC. A low molar ratio of retinol binding protein to trans- vitamin A–related functions. Toxicity is less common but can thyretin indicates vitamin A deficiency during inflammation: studies in rats occur with intravenous nutrition, liver disorders, or renal dys- and a posterior analysis of vitamin A–supplemented children with measles. function. The use of synthetic therapy during preg- J Nutr. 1998;128(10):1681-1687. nancy should be avoided. Serum retinol or the retinol binding 15. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of protein transthyretin ratio can be used to assess deficiency. vitamin A. Am J Clin Nutr. 2006;83(2):191-201. Retinyl levels can be used to establish toxicity. 16. Rohde CM, Manatt M, Clagett-Dame M, DeLuca HF. Vitamin A antago- nizes the action of vitamin D in rats. J Nutr. 1999;129(12):2246-2250. Recommendations 17. Johansson S, Melhus H. Vitamin A antagonizes calcium response to vita- min D in man. J Bone Miner Res. 2001;16(10):1899-1905. To avoid deficiency or toxicity, a careful approach to dietary 18. Krasinski SD, Russell RM, Otradovec CL, et al. Relationship of vitamin intake should take into account the current recommendations A and vitamin E intake to fasting plasma retinol, retinol-binding protein, for healthy people. Considerations and special monitoring are retinyl esters, carotene, alpha-tocopherol, and cholesterol among elderly needed for hospitalized individuals. Recommended intakes of people and young adults: increased plasma retinyl esters among vitamin vitamin A (mcg/d RAE) can be seen in Table A2.1. A–supplement users. Am J Clin Nutr. 1989;49(1):112-120. 19. Faure H, Preziosi P, Roussel AM, et al. Factors influencing blood con- Appendix 2 References centration of retinol, alpha-tocopherol, vitamin C, and beta-carotene 1. Green HN, Mellanby E. Vitamin A as an anti-infective agent. Br Med J. in the French participants of the SU.VI.MAX trial. Eur J Clin Nutr. 1928;2:691-696. 2006;60(6):706-717. 2. Olson JA. Recommended dietary intakes (RDI) of vitamin A in humans. 20. Singer P. Nutritional care to prevent and heal pressure ulcers. Isr Med Am J Clin Nutr. 1987;45(4):704-716. Assoc J. 2002;4(9):713-716. 3. Stephensen CB. Vitamin A, infection, and immune function. Annu Rev 21. Salles AG, Gemperli R, Toledo PN, Ferreira MC. Combined tretinoin and Nutr. 2001;21:167-192. glycolic acid treatment improves mouth opening for postburn patients. 4. Institute of Medicine of the National Academies. Dietary Reference Aesthetic Plast Surg. 2006;30(3):356-362. Intakes (DRIs): For Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cho- 22. Bremner NA, Mills LA, Durrani AJ, Watson JD. Vitamin A toxicity in lesterol, Protein and Amino Acids. Washington, DC: National Academies burns patients on long-term enteral feed. Burns. 2007;33(2):266-267. Press; 2005. 23. Kent G, Gay S, Inouye T, Bahu R, Minick OT, Popper H. Vitamin A–con- 5. U.S. Department of Agriculture. Dietary Reference Intakes: Recom- taining lipocytes and formation of type III collagen in liver injury. Proc mended Intakes for Individuals. 2010. http://fnic.nal.usda.gov/nal_display Natl Acad Sci U S A. 1976;73(10):3719-3722. /index.php?info_center=4&tax_level=3&tax_subject=256&topic_ 24. Ramanathan VS, Hensley G, French S, et al. id=1342&level3_id=5140&level4_id=0&level5_id=0&placement_ inducing intra-hepatic cholestasis: a rare case report. Exp Mol Pathol. default=0 2010;88(2):324-325. 6. Tang G. Bioconversion of dietary provitamin A carotenoids to vitamin A in 25. Ahmad SM, Haskell MJ, Raqib R, Stephensen CB. Vitamin A sta- humans. Am J Clin Nutr. 2010;91(5):1468S-1473S. tus is associated with T-cell responses in Bangladeshi men. Br J Nutr. 7. Biesalski HK, Nohr D. New aspects in vitamin a metabolism: the role of 2009;102(6):797-802. retinyl esters as systemic and local sources for retinol in mucous epithelia. 26. Villamor E, Mbise R, Spiegelman D, et al. Vitamin A supplements amelio- J Nutr. 2004;134(12)(suppl):3453S-3457S. rate the adverse effect of HIV-1, , and diarrheal infections on child 8. Spits Y, De Laey JJ, Leroy BP. Rapid recovery of night blindness due growth. Pediatrics. 2002;109(1):E6. to obesity surgery after vitamin A repletion therapy. Br J Ophthalmol. 27. Fawzi WW, Msamanga GI, Spiegelman D, et al. A randomized trial of 2004;88(4):583-585. multivitamin supplements and HIV disease progression and mortality. N 9. Tielsch JM, Sommer A. The of vitamin A deficiency and Engl J Med. 2004;351(1):23-32. xerophthalmia. Annu Rev Nutr. 1984;4:183-205. 28. Mehta S, Fawzi W. Effects of vitamins, including vitamin A, on HIV/AIDS 10. Pirie A. Vitamin A deficiency and child blindness in the developing world. patients. Vitam Horm. 2007;75:355-383. Proc Nutr Soc. 1983;42(1):53-64. 29. Lin J, Cook NR, Albert C, et al. Vitamins C and E and beta carotene sup- 11. Feranchak AP, Gralla J, King R, et al. Comparison of indices of vitamin plementation and cancer risk: a randomized controlled trial. J Natl Cancer A status in children with chronic liver disease. Hepatology. 2005;42(4): Inst. 2009;101(1):14-23. 782-792. 30. Lipkin AC, Lenssen P. Hypervitaminosis a in pediatric hematopoietic 12. Stephensen CB, Gildengorin G. Serum retinol, the acute phase response, stem cell patients requiring renal replacement therapy. Nutr Clin Pract. and the apparent misclassification of vitamin A status in the third 2008;23(6):621-629.

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31. Luo M, Estivariz CF, Schleicher RL, et al. Prospective analysis of serum 51. Benn CS, Aaby P, Nielsen J, Binka FN, Ross DA. Does vitamin A supple- carotenoids, vitamin A, and tocopherols in adults with short bowel syn- mentation interact with routine vaccinations? An analysis of the Ghana drome undergoing intestinal rehabilitation. Nutrition. 2009;25(4):400-407. Vitamin A Supplementation Trial. Am J Clin Nutr. 2009;90(3):629-639. 32. Forbes GM, Forbes A. Micronutrient status in patients receiving home par- 52. Greene HL, Phillips BL. Vitamin dosages for premature infants. Pediat- enteral nutrition. Nutrition. 1997;13(11-12):941-944. rics. 1988;81(1):173-174. 33. Howard L, Chu R, Feman S, Mintz H, Ovesen L, Wolf B. Vitamin A deficiency from long-term parenteral nutrition. Ann Intern Med. Appendix 3 1980;93(4):576-577. 34. Palin D, Underwood BA, Denning CR. The effect of oral zinc supplemen- Thiamine (Vitamin B ) in Enteral and 1 tation on plasma levels of vitamin A and retinol-binding protein in cystic Parenteral Nutrition fibrosis. Am J Clin Nutr. 1979;32(6):1253-1259. 35. O’Neil C, Shevill E, Chang AB. Vitamin A supplementation for cystic Theresa A. Fessler, MS, RD, CNSC fibrosis. Cochrane Database Syst Rev. 2008;(1):CD006751. 36. Graham-Maar RC, Schall JI, Stettler N, Zemel BS, Stallings VA. Elevated Introduction vitamin A intake and serum retinol in preadolescent children with cystic fibrosis. Am J Clin Nutr. 2006;84(1):174-182. Thiamine (also spelled thiamin) was the first B vitamin to be 37. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in discovered and is also known as vitamin B and aneurin. 1 adults: scientific review. JAMA. 2002;287(23):3116-3126. is a coenzyme in the metabolism 1,2 38. Murphy S, West KP Jr, Greenough WB III, Cherot E, Katz J, Clement of carbohydrates and branched-chain amino acids. L. Impact of vitamin A supplementation on the incidence of infection in Thiamine is water soluble, stable at acidic pH, and unstable elderly nursing-home residents: a randomized controlled trial. Age Ageing. in alkaline solutions and with exposure to ultraviolet (UV) 3 1992;21(6):435-439. light. The major food sources of thiamine are various 39. Kennedy E, Meyers L. Dietary Reference Intakes: development and uses whole, enriched, or fortified grain products and pork. Other for assessment of micronutrient status of women—a global perspective. sources include legumes, poultry, processed meats, and soy- 1,3 Am J Clin Nutr. 2005;81(5):1194S-1197S. based meat substitutes. 40. Gerster H. Vitamin A—functions, dietary requirements and safety in humans. Int J Vitam Nutr Res. 1997;67(2):71-90. Metabolism and Functions 41. Strobel M, Tinz J, Biesalski HK. The importance of beta-carotene as a source of vitamin A with special regard to pregnant and Thiamine functions in several phosphorylated forms, chiefly as women. Eur J Nutr. 2007;46(suppl 1):I1-I20. the coenzyme form thiamine pyrophosphate (TPP), which is 42. Garcia-Bournissen F, Tsur L, Goldstein LH, et al. Fetal exposure to isotret- sometimes referred to as thiamine diphosphate (TDP). Thiamine inoin: an international problem. Reprod Toxicol. 2008;25(1):124-128. is necessary for decarboxylation of α-keto acids, as well as 1,4 43. Bahl R, Bhandari N, Wahed MA, Kumar GT, Bhan MK; WHO/CHD transketolation reactions of hexose and pentose . -Linked Vitaming A Group. Vitamin A supplementation of Thiamine is absorbed mainly in the jejunum, by carrier-medi- women postpartum and of their infants at immunization alters breast milk ated active transport at lower concentrations and by passive retinol and infant vitamin A status. J Nutr. 2002;132(11):3243-3248. at higher concentrations. Only a small percentage of 44. Greer FR. Fat-soluble vitamin supplements for enterally fed preterm a high oral dose is absorbed. Absorption declines at a dose 2 2 infants. Neonatal Netw. 2001;20(5):7-11. above 5 mg. Thiamine is carried in erythrocytes and plasma 45. Van Marter LJ. Strategies for preventing bronchopulmonary dysplasia. and is not stored to a significant extent in any tissues but is in Curr Opin Pediatr. 2005;17(2):174-180. more significant amounts in muscle, heart, liver, kidney, and 3 46. Greene HL, Smith R, Pollack P, Murrell J, Caudill M, Swift L. Intra- brain. Urinary excretion is increased when serum levels ele- venous vitamins for very-low-birth-weight infants. J Am Coll Nutr. vate and decreased when serum levels are low, with maximum 1991;10(4):281-288. excretion 2 hours after oral intake. The biological half-life of 47. Shenai JP, Stahlman MT, Chytil F. Vitamin A delivery from parenteral ali- thiamine has been determined to be 9–18 days, and the adult 1 mentation solution. J Pediatr. 1981;99(4):661-663. body is thought to contain approximately 30 mg. 48. Thomas DG, James SL, Fudge A, Odgers C, Teubner J, Simmer K. Deliv- ery of vitamin A from parenteral nutrition solutions in neonates. J Paediatr Thiamine Deficiency and Toxicity Child Health. 1991;27(3):180-183. 49. Haas C, Genzel-Boroviczeny O, Koletzko B. Losses of vitamin A and The thiamine deficiency disease has long been known as E in parenteral nutrition suitable for premature infants. Eur J Clin Nutr. “beriberi.” Thiamine deficiency symptoms include anorexia, 2002;56(9):906-912. weight loss, mental abnormalities, muscle weakness, and 50. Tyson JE, Wright LL, Oh W, et al. Vitamin A supplementation for enlarged heart. Muscle is seen in “dry” beriberi, and extremely-low-birth-weight infants. National Institute of Child Health “wet” beriberi is characterized by the presence of edema due 1 and Human Development Neonatal Research Network. N Engl J Med. to congestive heart failure. Prolonged mild thiamine defi- 5 1999;340(25):1962-1968. ciency can lead to peripheral nerve damage.

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Thiamine deficiency as it occurs in modern industrialized the normal range listed as 74–222 nmol/L9 or 80–150 nmol/L.10 countries is better known as an acute neurologic disorder called Magnetic resonance imaging is currently the most useful Wernicke’s encephalopathy (WE). Symptoms of WE include method to confirm WE.5 opthalmoplegia, ataxia, and confusion.5 Without prompt treat- Data are lacking on adverse effects of excessive oral thia- ment, WE progresses to irreversible brain damage known as mine intake, and thus a tolerable upper intake level (UL) has Korsakoff’s psychosis and can also result in coma or death. not been determined.2 Parenteral thiamine is considered safe, Korsakoff’s syndrome is characterized by chronic severe loss yet there is a low risk of serious allergic reaction. Thus, it is of working memory or of recent events, with memory recommended that parenteral thiamine be diluted in 100 mL of deficits of events up to months prior.5 WE has been historically normal saline or 5% dextrose solution and infused over a found in chronic alcoholic patients but has also been reported in period of 30 minutes and that treatment be done in a facility patients who were given parenteral nutrition (PN) without mul- equipped to treat anaphylactic reaction.5 tivitamins. Reasons for not using multiple vitamins in PN in these cases were attributed to iatrogenic error, shortage of mul- tivitamin product, and, in Japan, cost issues resulting from a Requirements for Healthy Individuals national health insurance policy change.4,6 The recommended requirements for thiamine have been deter- WE has been reported in other malnourished patients such mined by the Institute of Medicine of the National Academy as those who have undergone gastrointestinal surgery and in of Sciences and published in 1998.1 The Recommended patients with , small bowel obstruc- Dietary Allowance (RDA) for thiamine for adults is 1.1 mg tion, anorexia nervosa, gastrointestinal disorders, and various (females) to 1.2 mg (males) per day and 1.4 mg per day for . In some cancers, thiamine is used by rapidly growing pregnancy and lactation. Criteria used for establishing adult tumors, and some chemotherapeutic drugs can interfere with thiamine requirements included the amount needed to main- thiamine function.5,7 Since thiamine is lost in dialysate, poorly tain erythrocyte transketolase activity, urinary thiamine excre- nourished renal patients on dialysis are at risk for thiamine tion, and other information. The requirements for children and deficiency. Patients with due to chronic teenagers were established by extrapolation methods using diuretic use are also at risk, as magnesium is a cofactor in tran- adult data. The RDA for children is 0.5 mg/d for ages 1–3 sketolase reactions and in conversion of thiamine to thiamine years, 0.6 mg/d for ages 4–8 years, 0.9 mg/d for ages 9–13 pyrophosphate.5 years, and 1–1.2 mg/d for ages 14–18 years. The Adequate Because intestinal absorption is limited, the recommended Intake (AI) of thiamine for infants was determined by using treatment for WE is intravenous (IV) or intramuscular (IM) information on infants fed breast milk from well-nourished administration of thiamine.5 In a recent study, 100 mg of IV mothers. The AI is 0.2 mg/d for infants aged 0–6 months and thiamine for 3 days normalized neurologic symptoms of WE in 0.3 mg/d for infants aged 6–12 months.1,2 6 of 7 patients who received PN without multivitamins,4 but higher doses are advised. Patients with suspected or diagnosed WE should receive 500 mg of IV thiamine hydrochloride 3 Requirement Modifications in Specific times per day for 2–3 days and, if favorable response occurs, Conditions followed with 250 mg thiamine per day, given IV or IM, for 3–5 The RDA for thiamine is 1.4 mg/d for pregnancy and lactation. days.5 Prophylactic treatment with 250 mg of IM thiamine per Because of its function in carbohydrate metabolism, thia- day for 3–5 days has been recently recommended for malnour- mine needs are likely related to energy utilization and body ished patients at risk for WE.5 Those who are deficient in thia- size. Thiamine needs are higher for patients on dialysis, mine are most likely deficient in several other vitamins, and those with malabsorption, or during pregnancy or lactation thus treatment with IV multivitamin mixtures is prudent. In the with more than 1 infant.1 United Kingdom, for example, a high-potency B-complex for- mulation (Pabrinex) has been used in the treatment of WE.8 Erythrocyte transketolase activity and erythrocyte TPP are Thiamine Content in Current PN and 2 tests that have been used to measure thiamine status. Enteral Nutrition Regimens Erythrocyte transketolase activity is low in thiamine- Aside from the need for parenteral thiamine and B-complex depleted individuals and increases after the addition of TPP supplements for use in deficiency states, there are no data to to lysed erythrocytes, but the test has limitations in that it suggest that new products are needed for PN regimens, except, has not correlated well with thiamine intake in several studies, of course, not to exclude thiamine. Current adult parenteral and there are likely genetic and other individual differences multivitamin products in the U.S. contain 6 mg of thiamine that affect enzyme activity.1 Erythrocyte TPP declines at a sim- hydrochloride per daily dose.11-13 Other products, available in ilar rate as in other tissues in a thiamine-deficient state. Europe, contain 3.1 and 3.51 mg thiamine per dose.14,15 Measurement of erythrocyte TPP itself has been found to be a Pediatric parenteral multivitamin solutions in the U.S. provide more consistent and specific indicator, with normal range of 1.2 mg thiamine per daily dose.13,16 All of these products meet 70–90 nmol/L.1 A whole-blood TPP test is also available, with or exceed the RDA or AI levels.

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Enteral nutrition (EN) formulas in the U.S. provide ade- 6. Shikata E, Mizutani T, Kokubun Y, Takasu T. ‘Iatrogenic’ Wernicke’s quate thiamine to meet or exceed RDA or AI levels, if suffi- encephalopathy in Japan. Eur Neurol. 2000;44:156-161. cient amounts of formula are ingested to meet energy needs. 7. Kuo S-H, Debnam JM, Fuller GN, deGroot J. Wernicke’s encephalopa- Standard adult EN formulas contain 1.6–4 mg thiamine per thy: an underrecognized and reversible cause of confusional state in cancer 1500–2000 kcal. Standard pediatric enteral formulas contain patients. Oncology. 2009;76:10-18. 17,18 1.7–2.5 mg thiamine per 1000 kcal. Standard formulas for 8. Thomson AD, Cook CC, Touquet R, Henry JA. The Royal College of Phy- 19,20 term infants contain 0.06–0.1 mg thiamine per 100 kcal. sicians report on alcohol: guidelines for managing Wernicke’s encepha- Formula for premature infants contains 0.175–0.25 mg thia- lopathy in the accident and emergency department. Alcohol Alcohol. 20,21 mine per 100 kcal. 2002;37(6):513-521. One recent study confirmed that current PN and EN regi- 9. Fischbach FT, Dunning MB II. Manual of Laboratory and Diagnos- 22 mens provide adequate thiamine for premature infants. A tic Tests. 8th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott recent Japanese study confirms a significant decline in blood Williams & Wilkins; 2009. 23 levels of thiamine in children receiving PN without thiamine. 10. Mayo Clinic. Mayo Medical Laboratories website. http://www.mayomedical laboratories.com/test-catalog/print.php?unit_code=81019. Accessed January Recommendations 10, 2010. 11. M.V.I. Adult (multi-vitamin infusion) [product description]. Lake Forest, •• Thiamine is of critical importance during enteral IL: Hospira; 2007. Reference EN–1511. Also accessed August 21, 2009, and parenteral feeding, especially in malnourished from Hospira at http://www.hospira.com/Files/EN-1511MVIADULT- patients. WebPI.pdf •• Multivitamins, specifically thiamine, should never 12. M.V.I.-12 (multivitamin infusion without vitamin K) [product description]. be omitted in PN regimens. Lake Forest, IL: Mayne Pharma. http://www.hospira.com/Files/MVI-12_ •• Standard adult and pediatric multivitamins for IV PI.pdf. Accessed August 21, 2009. infusion provide greater than the established RDA or 13. Infuvite Adult and Infuvite Pediatric Multiple Vitamins for Infusion [prod- AI dose of thiamine. uct description]. Boucherville: Sandoz Canada; 2007. •• Standard EN formulas generally provide greater than 14. Cernevite multivitamins for infusion [product information]. Updated or equal to the RDA dose of thiamine when providing December 8, 2004. http://www.rxlist.com/cernevit-drug.htm. Accessed full energy needs. August 20, 2009. •• Supplemental parenteral thiamine or B-complex 15. Solivito N. Fresenius Kabi. http://admin.safescript.com/drugcgic.cgi/ product, in addition to that provided in standard EN DRUG?764957184+0. Accessed August 20, 2009. or PN, should be provided for patients who are symp- 16. M.V.I. Pediatric Multi-Vitamins for Infusion [package insert]. Lake Forest, tomatic or at high risk for thiamine deficiency and IL: Mayne Pharma. http://www.hospira.com/Files/MVI_pediatric_PI.pdf. those at risk for refeeding syndrome in general. Accessed August 21, 2009. •• Supplemental parenteral thiamine and/or B-complex 17. Abbott Nutrition website. http://abbottnutrition.com/products/product_ vitamins, in addition to that provided in standard EN comparison.aspx. Accessed January 11, 2012. or PN, should be administered to patients at risk or 18. Nestle Nutrition—Products and Applications website. http://www.nestle- symptomatic for WE. nutrition.com/Products/Default.aspx. Accessed January 11, 2012. 19. Gerber Start healthy, stay healthy nutrition system. Infant formulas product Appendix 3 References comparison chart. http://medical.gerber.com/nirf/cm2/upload/6C34C11D- 1. Institute of Medicine, Food and Nutrition Board. Thiamine. In: Dietary C300-488B-85B9-3460EE85F0B8/Nutrient_Comparison_Chart.pdf. Reference Intakes for Thiamine, Riboflavin, Niacin, Vitamin B6, Folate, Accessed January 11, 2012. Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: 20. Abbott Nutrition. Pediatric nutrition product guide, 2011. http://abbott- National Academy of Sciences; 1998. nutrition.com/downloads/pediatric-nutrition-product-guide-2011.pdf. 2. Otten JJ, Pitzi Hellwig J, Meyers LD, eds. Dietary Reference Intakes: Accessed January 11, 2012. The Essential Guide to Nutrient Requirements. Washington, DC: National 21. Gerber for medical professionals. Good Start Premature24, nutrition Academies Press; 2006. information. http://medical.gerber.com/products/ProductDetails.aspx?article 3. Butterworth RF. Thiamin. In: Shils ME, Shike M, Ross AC, Caballero B, Id=AFEC861C-E661-4E6A-AB25-8C2B09A94B83&CatId=20eb51b Cousins RJ, eds. Modern Nutrition in Health and Disease. 10th ed. Phila- 9-6b1f-46b1-9cba-74b5b342c944#NutritionProfile. Accessed January 11, delphia, PA: Lippincott, Williams & Wilkins; 2006:426-433. 2012. 4. Francini-Pesenti F, Brocadello F, Manara R, Santelli L, Laroni A, Caregaro 22. Friel JK, Bessie JC, Belkhode SH, et al. Thiamine, riboflavin, pyridoxine, L. Wernicke’s syndrome during parenteral feeding: not an unusual compli- and vitamin C status in premature infants receiving parenteral and enteral cation. Nutrition. 2009;25:142-146. nutrition. J Pediatr Gastroenterol Nutr. 2001;33(1):64-69. 5. Sechi GP, Serra A. Wernicke’s encephalopathy: new clinical settings and 23. Masumoto K, Esumi G, Teshiba R, et al. Need for thiamine in peripheral recent advances in diagnosis and management. Lancet Neurol. 2007;6: parenteral nutrition after abdominal surgery in children. JPEN J Parenter 442-455. Enteral Nutr. 2009;33(4):417-422.

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Appendix 4 cells before and after the addition of FAD. The increase in activity by this addition is an index of Requirements and Metabolism of Riboflavin deficiency. Less than 20% (ratio <1.2) is acceptable, (Vitamin B ) and Niacin (Vitamin B ) in 1.2–1.4 is subnormal, and >1.4 is a deficient state. 2 3 Parenteral Nutrition Riboflavin Toxicity Has Not Been Described Khursheed N. Jeejeebhoy, MBBS, PhD, FRCPC Clinical effects of deficiency. In a deficiency state, there may be sore throat, stomatitis, glossitis, and seborrheic dermatitis Introduction of the face, trunk, and scrotum. In addition, photophobia and The need for any vitamin can be expressed in 3 different ways. vascularization of the cornea have been observed. Marrow The traditional way was called Recommended Daily Allowance aplasia and a normocytic normochromic anemia may occur. (RDA), which is established and periodically revised by the Food and Nutrition Board. For the labeling of foods, the Normal Requirements (RDI) was established by the Food and Drug Administration (FDA). It was based initially on the high- The oral intake should be 0.6 mg/1000 kcal. Hence, in an aver- est 1968 RDA for each nutrient, to ensure that needs were met age adult, intake should be 1.2–1.6 mg/d. For patients receiv- for all age groups. The Dietary Reference Intakes (DRI) are ing PN, the American Medical Association (AMA)1 the most recent set of dietary recommendations established by recommends 3.6 mg/d in adults. In other studies, 1.8–10 mg the Food and Nutrition Board of the Institute of Medicine, has been used and shown to be adequate biochemically.2,3 In 1997–2001. They replace previous RDAs and may be the basis patients on home PN, infusion of the current formulation given for eventually updating the RDIs. These definitions need to be daily maintained biochemical stability but when given 3 times kept in mind when the intake of patients on parenteral nutri- a week caused deficiency.4 tion (PN) is being considered. The currently available paren- teral multivitamin mixture available in North America provides Modifications for Cirrhosis, Cancer, Renal riboflavin 3.6 mg/d and niacin as niacinamide 40 mg/d. The pediatric formulation provides 0.56 mg of riboflavin per day. Failure, Trauma, Sepsis, and Burns In critically ill patients, the addition of 10 mg of riboflavin per day maintained normal levels when measured on average Riboflavin (B ) 3 2 16 days after start of PN. On the other hand, in cancer Metabolic Effect patients, biochemical deficiency was noted despite 7.2 mg/d of riboflavin.5 Riboflavin is a component of mono and dinucleotides com- plexed with adenine as flavin mononucleotide (FMN) and flavin Modification for Gender and the Elderly adenine dinucleotide (FAD). These compounds combine with proteins to form enzymes called . These enzymes There is no effect of age on riboflavin requirements, but the are concerned with dehydrogenation and oxidation reactions DRI for women is about 0.2 mg lower than it is for men. involving pyruvate, acetyl-CoA, and amino acids. In the pro- cess, the flavin becomes reduced by accepting hydrogen. The Relevance to Pregnancy, Lactation, and reduced form is reoxidized and again available to accept hydro- gen. It also acts as part of the electron transfer chain. Pediatric Populations Reliable assessment of deficiency and toxicity. There are 3 During pregnancy and lactation, an additional 0.3–0.5 mg/d methods to assess riboflavin status. should be given, making the total intake 1.5–2.1 mg/d. In infants, 2 mL of the pediatric formulation, giving 0.56 mg/d, 6 1. Urinary excretion. The urine riboflavin should be maintained riboflavin balance. at least 80 mcg/g creatinine. In deficiency, it falls below 27 mcg/g creatinine. However, catabolic Niacin states increase riboflavin excretion as do drugs such as antibiotics and phenothiazines, making urinary Metabolic Effects excretion less reliable. 2. Erythrocyte riboflavin levels can be measured and Niacin in the form of nicotinamide is a component of 2 nucle- used to detect deficiency and should be at least 10 otides. These nucleotides are nicotinamide adenine mono- mcg/dL red cells. (NAD) and di-(NADP) nucleotides. They combine with 3. The most reliable method assessing riboflavin status various carrier proteins to form enzymes concerned with is by the glutathione reductase activity in red blood electron transfer reactions related to energy metabolism.

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Reliable Assessment of Deficiency and Toxicity

Blood levels of niacin are not a reliable index of niacin sta- tus. 1N-methylnicotinamide and its 2-pyridone derivative are measured in the urine to assess niacin status. The excretion of <0.8 mg 1N-methynicotinamide per 24 hours is a sign of deficiency. Another way of assessing status is the ratio of 1N-methynicotinamide and its 2-pyridone derivative. A ratio of <1.0 is a sign of deficiency.

Clinical Effects of Deficiency Figure A4.1. Comparison of parenteral intake with Recommended Daily Allowance (RDA), Reference Daily Intake Clinical niacin deficiency is called pellagra and is due to both (RDI), and Dietary Reference Intakes (DRI). a poor intake of niacin and to a deficiency or reduced conver- sion of tryptophan to niacin. Clinical deficiency is the result of Relevance to Pregnancy, Lactation, and a complex disorder involving not only a lack of niacin and Pediatric Populations tryptophan but also an excessive intake, which inhibits the conversion of tryptophan to niacin. There must also be During pregnancy and lactation, an additional 2 and 5 NE/d is concurrent deficiencies of riboflavin, thiamine, and pyridox- respectively recommended. For those aged 0–1 year, adequate ine, which are needed for this conversion. Pellagra presents as intake is 2–4 mg/d; age 1–8 years, 5–6 mg/d; age 9–13 years, a wasting disease with dermatitis of the exposed areas due to 9–12 mg; and 14 mg and above, it is in the adult range. photosensitivity. Fatigue, insomnia, and apathy are followed by confusion, hallucinations, disorientation, and finally psy- chosis. Widespread mucosal inflammation causes glossitis, Comparison of Intravenous Intake stomatitis, vaginitis, and diarrhea. With the RDA, RDI, and DRI The parenteral intake based on available formulations easily meets Requirements the requirements based on RDA, RDI, and DRI (Figure A4.1). Tryptophan is converted to niacin in the body, and therefore it is necessary to define niacin intake as niacin equivalents Conclusions (NEs). Sixty milligrams of tryptophan is equivalent to 1 mg There are no good controlled studies to evaluate the exact need niacin. This conversion requires the presence of thiamine, of riboflavin and niacin in PN. However, the available data riboflavin, and pyridoxine. suggest that the current formulation will meet requirements in The recommended oral intake is 6.6 mg of NE per 1000 stable patients. In critically ill patients, riboflavin intake of 10 kcal. Thus, about 13–18 mg/d should be taken by adults. For mg, which is 3 times the amount in the usual dose of the cur- PN, the AMA recommends 40 mg/d in adults.1 In home PN rent formulation, will maintain biochemical stability. In patients, 100 mg twice weekly avoids deficiency.7 However, patients with cancer, it appears that much larger doses of ribo- daily infusion of the current formulation is required to main- flavin and niacin may be required to maintain normal bio- tain normal levels of niacin.4 chemistry. In these patients, further studies need to be done.

Appendix 4 References Modifications for Cirrhosis, Cancer, Renal 1. Vanamee P, Shils ME, Burke AW, et al. Multivitamin preparations for par- Failure, Trauma, Sepsis, and Burns enteral use: a statement by the nutrition advisory group. JPEN J Parenter Cancer patients receiving PN had biochemical deficiency of Enteral Nutr. 1979;3:258-261. niacin despite receiving 40 mg/d. In the same study, niacin 2. Stromberg P, Shenkin A, Campbell RA, et al. Vitamin status during total status was measured in only 1 patient receiving 80 mg/d and parenteral nutrition. JPEN J Parenter Enteral Nutr. 1981;5:295-299. 5 was normal. 3. Bradley JA, King RFJC, Schorah CJ. Vitamins in intravenous feeding: a study of watersoluble vitamins and folate in critically ill patients receiving Modification for Gender and the Elderly intravenous nutrition. Br J Surg. 1978;65:492-494. 4. Mikalunas V, Fitzgerald K, Rubin H, McCarthy R, Craig RM. Abnormal There is no modification for age. The DRI for women is set at vitamin levels in patients receiving home total parenteral nutrition. J Clin about 1–2 mg/d lower than it is in men. Gastroenterol. 2001;33:393-396.

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5. Inulet RI, Norton JA, Nichoalds GE, Maher MM, White DE, Brennan nausea, vomiting, abdominal cramps, hypoglycemia, MF.Water-soluble vitamins in cancer patients on parenteral nutrition: a pro- increased sensitivity to insulin, and neurological symptoms spective study. JPEN J Parenter Enteral Nutr. 1987;11:243-249. such as numbness, paresthesias, muscle cramps, and stagger- 1 6. Levy R, Herzberg GR, Andrews WL, Sutradhar B, Friel JK. Thiamine, ing gait. riboflavin, folate, and vitamin B12 status of low birth weight infants receiving parenteral and enteral nutrition. JPEN J Parenter Enteral Nutr. Requirement in Parenteral Nutrition 1992;16:2141-2647. 7. Howard L, Bigaouette J, Chu R, et al. Water soluble vitamin requirements A Recommended Dietary Allowance (RDA) has not been set in home parenteral nutrition patients. Am J Clin Nutr. 1983;37:421-428. due to insufficient available scientific evidence. Daily Adequate Intake (AI) of pantothenic acid levels has been Appendix 5 established by the Food and Nutrition Board of the U.S. Institute of Medicine based on pantothenic acid sufficient to Pantothenic Acid replace urinary excretion. No adverse effects have been asso- ciated with high intakes of pantothenic acid.1 Parenteral nutri- Peggy Borum, PhD tion (PN) pantothenic acid recommendations are derived from the deliberations of expert panels.5,6 Pantothenic acid is stable Introduction in a 3-L plastic bag of PN while stored in darkness at 2–8°C for 96 hours or during 24 hours of simulated infusion initiated Pantothenic acid is a water-soluble B vitamin that functions as immediately after mixing.7 a component of coenzyme A.1 Modifications Due to Gender, Age, Metabolic Function Pregnancy, and Lactation Since coenzyme A is involved in many aspects of metabo- Several different groups of patients, including children, have lism, including , pantothenic acid is been maintained on PN with commercial intravenous multivi- important in most areas of metabolism.1 Clinical and basic tamin products with no evidence of pantothenic acid defi- science research publications are somewhat limited com- ciency or toxicity.8,9 Elevated blood concentrations of pared with many other micronutrients. However, recently pantothenic acid in patients receiving PN are usually associ- developed analytical methods have been used to expand our ated with the presence of renal disease.10 understanding of the metabolic roles of pantothenic acid. Peroxisome proliferator-activated receptor α (PPARα) is associated with increased fatty acid catabolism and is com- Recommendations monly targeted for the treatment of hyperlipidemia. PPARα activation with fibrate in healthy human volun- teers was associated with greater than a 5-fold decrease in Pantothenic Acid urinary pantothenic acid excretion, suggesting that it may prove useful as an indicator of PPARα-induced fatty acid Population Recommendation Reference 2 β-oxidation in humans. In male rats, pantothenic acid sup- Oral nutrition: adults AI = 5 mg/d 1 plementation stimulates the ability of adrenal cells to secrete Oral nutrition: pregnant females AI = 6 mg/d 1 corticosterone and and induces adrenal hyper- 3 Oral nutrition: breastfeeding AI = 7 mg/d 1 responsiveness to ACTH stimulation. New clinical uses of females pantothenic acid are also being investigated. Although more Oral nutrition: children, 0–6 mo AI = 1.7 mg/d 1 data from randomized controlled studies are needed, there Oral nutrition: children, 7–12 mo AI = 1.8 mg/d 1 are results suggesting that pantothenic acid combined with Oral nutrition: children, 1–3 y AI = 2 mg/d 1 vitamin C contributes to the healing and treatment of surgi- cal wounds.4 Oral nutrition: children, 4–8 y AI = 3 mg/d 1 Oral nutrition: children, 9–13 y AI = 4 mg/d 1 Oral nutrition: children, 14–18 y AI = 5 mg/d 1 Reliable Assessment Methods of PN: adults 15 mg/d 5 Deficiency and Toxicity PN: term infants and children 5 mg/d 6 Pantothenic acid deficiency is very rarely observed in humans. PN: preterm infants and children 2.5 mg/kg/d 6 Signs and symptoms of deficiency may include irritability and restlessness, fatigue, apathy, , sleep disturbances, AI, Adequate Intake; PN, parenteral nutrition.

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Appendix 5 References dose was detected unmetabolized in the urine. If active metabo- lites were included, the urine amount was somewhat greater. 1. Otten JJ, Hellwig JP, Meyers LD, eds. Pantothenic acid. In: Dietary Refer- ence Intakes: The Essential Guide to Nutrient Requirements. Washington, Metabolic Effects DC: National Academies Press; 2006:270-273. 2. Patterson AD, Slanar O, Krausz KW, et al. Human urinary metabolomic Pyridoxine hydrochloride is an inactive compound and is profile of PPARalpha induced fatty acid beta-oxidation. J Proteome Res. metabolized in the liver to the active moieties PLP, the primary 2009;8(9):4293-4300. form bound to serum albumin in plasma, and pyridoxamine-5′- 2,3 3. Jaroenporn S, Yamamoto T, Itabashi A, et al. Effects of pantothenic acid phosphate (PMP). PLP undergoes oxidation in the liver to 5 supplementation on adrenal steroid secretion from male rats. Biol Pharm 4-pyridoxic acid, which is excreted. Bull. 2008;31(6):1205-1208. PLP functions as a coenzyme for aminotransferases that 4. Ellinger S, Stehle P. Efficacy of vitamin supplementation in situations with catalyze the formation of α-keto acids from their respective wound healing disorders: results from clinical intervention studies. Curr amino acids. PLP is also important in the hepatic transsulfura- Opin Clin Nutr Metab Care. 2009;12(6):588-595. tion pathway (via the PLP-dependent enzymes β-synthase and 5. Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutri- cystathionine γ-lyase), as well as in decarboxylation and dehy- tion. JPEN J Parenter Enteral Nutr. 2004;28:S39-S70. dration reactions. Carnitine biosynthesis requires PLP- 6. Greene HL, Hambidge KM, Schanler R, Tsang RC. Guidelines for the dependent 3-hydroxytrimethyl-lysine aldolase. PLP plays an use of vitamins, trace elements, calcium, magnesium, and phosphorus active role in both and gluconeogenesis and is in infants and children receiving total parenteral nutrition: report of the the coenzyme for glycogen phosphorylase. Vitamin B may 6 Subcommittee on Pediatric Parenteral Nutrient Requirements from the also play a role in lipid metabolism and in the maintenance of Committee on Clinical Practice Issues of the American Society for Clini- normal immune function, although these roles remain some- cal Nutrition [published errata appear in Am J Clin Nutr. 1989;49(6):1332 what speculative. PLP-dependent δ-aminolevulinate synthase and 1989;50(3):560]. Am J Clin Nutr. 1988;48:1324-1342. is important for heme biosynthesis. 7. Dahl GB, Jeppsson RI, Tengborn HJ. Vitamin stability in a TPN mixture As with other B vitamins, exposure of vitamin B to sun- 6 6 stored in an EVA plastic bag. J Clin Hosp Pharm. 1986;11(4):271-279. light leads to destruction, although this has not been shown in 7 8. Moore MC, Greene HL, Phillips B, et al. Evaluation of a pediatric multiple all studies. vitamin preparation for total parenteral nutrition in infants and children, I: blood levels of water-soluble vitamins. Pediatrics. 1986;77(4):530-538. Reliable Assessment for Deficiency and 9. Norton JA, Nichoalds GE, Maher MM, White DE, Brennan MF. Water- soluble vitamins in cancer patients on parenteral nutrition: a prospective Toxicity

study. JPEN J Parenter Enteral Nutr. 1987;11(3):243-249. Vitamin B6 deficiency has been associated with seborrheic 8 9 10. Shils ME, Baker H, Frank O. Blood vitamin levels of long-term adult home dermatitis, microcytic anemia, a peripheral neuropathy, epi- 10,11 total parenteral nutrition patients: the efficacy of the AMA-FDA parenteral lepsy, abnormal electroencephalograms, depression, and 12 multivitamin formulation. JPEN J Parenter Enteral Nutr. 1985;9(2):179-188. confusion. A glove and stocking sensory neuropathy has also been reported in B toxicity with ingestion of large doses 6 Appendix 6 (1–6 g/d for 2–40 months) of pyridoxine.13,14 The Food and Nutrition Board set a tolerable upper limit of 100 mg/d14 in Vitamin B (Pyridoxine) adults. Toxicity has not been reported from parenteral admin- 6 istration of currently recommended doses. Alan L. Buchman, MD, MSPH, FACP, FACG, High-performance liquid chromatography (HPLC) is the FACN, AGAF; Lyn Howard, MB, FRCP; and primary method for determination of vitamin B in both 6 Alan Shenkin, MB, ChB, PHD, FRCP, FRCPath plasma and tissues.15 The plasma concentration of PLP reflects the hepatic concentration.16,17 PLP <20 nmol/L is associated with vitamin B deficiency,14,18 although at this Introduction 6 level, some individuals will exhibit no signs of deficiency.19,20 Vitamin B consists of several related compounds, including As with choline,21 plasma PLP is very high in the and 6 pyridoxal (PL), pyridoxine, and pyridoxamine and their respec- slowly decreases to normal adult concentrations over the tive 5′-phosphates. In parenteral nutrition (PN) formulations, first year of life.22 The concentration of PLP at which defi- pyridoxine is supplied as pyridoxine hydrochloride because this ciency occurs in the neonate is unknown. Erythrocyte PLP compound is more stable than other forms of the vitamin.1 It is reflects plasma PLP except in individuals who have received phosphorylated to its active form, pyridoxal-5′-phosphate (PLP), very high doses.23 Plasma PL and PLP are more affected by by the liver, the site of primary metabolism.2,3 In a study of nor- critical illness than red or white cell concentrations, suggesting mal volunteers infused with vitamin B , plasma steady-state that intracellular concentrations are a better measure of status 6 concentration was reached within 30 minutes, and the serum in such patients.24 Whole-blood vitamin B concentrations 6 half-life was only a few minutes4; only 6.7% of the administered (normal >40 nmol/L) fluctuate with the menstrual cycle.25

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Significant fluctuation has also been observed with mea- Modification for Gender and the Elderly surements of the activation of erythrocyte aspartate and ala- nine aminotransferase enzyme activities on incubation with The Dietary Reference Intake (DRI) was reduced in 1998 from PLP (normal <1.25 to <1.8, respectively),26 thereby limiting that recommended in 1989 to an estimated average require- their usefulness. Urinary 4-pyridoxic acid excretion (normal ment of 1.1 mg/d and a DRI of 1.3 mg/d for both male and >3 µmol/d) or urinary total vitamin B (normal >0.5 µmol/d) female adults, with slightly higher intakes recommended for 6 reflects recent intake rather than a deficiency or toxicity the elderly (1.7 mg/d for men >51 years and 1.5 mg/d for state.14 An increase in plasma homocysteine following a women >51 years).14 methionine load has also been used to indicate vitamin B 6 deficiency (normal: <1.25–1.8).27 However, high plasma homocysteine concentration may be related to other factors, Relevance to Pregnancy, Lactation, such as choline deficiency, in the PN patient.28 Erythrocyte and the Pediatric Population glutamic oxaloacetic activity also reflects pyri- A study in 6 preterm infants who received 63% of their energy doxine status.29 requirements via PN indicated that a pyridoxine dose of 394 ± With regard to PN, serum PLP concentration was decreased 243 mcg/100 kcal/d (equivalent to current recommendations) in 3 of 30 patients who required nightly PN and were awaiting maintains normal serum pyridoxal concentrations in blood intestinal transplantation, although no identifiable symptoms samples obtained during PN infusion.41 were present.30 A low level was not reported when the blood The American Medical Association–Nutrition Advisory samples were obtained following the discontinuation of the Group (AMA-NAG) recommendations indicated that chil- nightly PN. Pyridoxine hydrochloride, 2.4 mg/d, was insuffi- dren <10 kg should receive 10% of the general pediatric cient to maintain normal serum PLP in a group of adult South dose per kilogram.42 At a later meeting sponsored by the African patients who required prolonged PN,31 although FDA, experts noted that term infants and children up to age Howard et al32 found that urinary 4-pyridoxic acid excretion 11 years could all receive the same vitamin dose, which is remained normal at this dose. Three milligrams of daily intra- somewhat more than the RDA for 0–12 months and slightly venous pyridoxine hydrochloride was sufficient to maintain less than the Recommended Daily Allowance (RDA) for normal pyridoxine status in a group of Japanese adult patients older children.42 Using the AMA-NAG recommendations, requiring PN,33 and a study of long-term home PN-requiring Moore et al43 reported that term infants and children main- patients indicated this dose was sufficient to maintain normal tained normal plasma glutamic oxaloacetic transaminase plasma concentrations.34 activities. Whole-blood pyridoxine concentrations were elevated in Elevated serum pyridoxic acid concentrations have been some patients who received 4 mg daily,35 although at this dose, described with doses of 300–700 mcg/d.44 For infants, the Inculet et al36 found that urinary excretion remained normal adequate oral intake (AI) was based on the amount of vita- but became substantially elevated when the dose was doubled. min B in human milk. This dose was extrapolated, based on 6 Urinary excretion probably reflects the infused dose. Hariz et expected weight for older infants (7–12 months).14 For older al37 also found that 4.5 mg/d of pyridoxine maintained some- children, estimated average requirements (EARs) and RDAs what elevated vitamin B concentration in the blood of chil- are extrapolated based on adult data. The current RDA is 1.9 6 dren who received home PN after a week of therapy, although mg/d for pregnancy and 2 mg/d for lactation.14 neither the form of vitamin B nor urinary excretion was 6 reported. It is to be noted that Shils et al34 found that the amount of pyridoxine contained in an intravenous multivitamin formu- Drug and Nutrient Interactions lation was nearly double that indicated on the label. PL kinase, which catalyzes the phosphorylation of vitamin B , 6 Based on the above results, the Food and Drug requires zinc as a cofactor. Niacin, folate, and carnitine require Administration (FDA) recommendation to increase vitamin B vitamin B for their biosynthesis and metabolism. 6 6 supply to 6 mg/d during PN seems to lack experimental sup- Vitamin B is antagonized by hydralazine, , iso- 6 .38 However, such an intake will not be harmful and will niazid, levodopa and other medications, and ethanol.27 ensure an adequate vitamin B intake in those patients who are Isoniazid and hydralazine cause increased excretion of pyri- 6 already depleted or who have a high amino acid intake. doxine in urine. Vitamin B requirement in such individuals is 6 therefore probably higher than the recommendations for a healthy population, but data are not available to identify the Modification for Cirrhosis, Renal requirement more precisely. Failure, Trauma, Sepsis, and Burns Renal insufficiency has been associated with decreased vita- min B status as indicated by decreased plasma PLP, elevated Conclusions and Clinical Recommendations 6 urinary pyridoxic acid (PA), and elevated post–methionine The current recommended dose of 6 mg daily for adults and load homocysteine concentration.39,40 extrapolated pediatric dosing appears adequate and appropriate.

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Appendix 6 References 20. Brussard JH, Lowik MR, Vanden Berg H, et al. Micronutrient status, with special reference to vitamin B6. Eur J Clin Nutr. 1997;51:S32-S38. 1. Saidi B, Warthesen JJ. Influence of pH and light on the kinetics of vitamin 21. Buchman AL, Sohel M, Moukarzel A, et al. Plasma choline in normal new- B degradation. J Agric Food Chem. 1983;31:876-880. borns, infants, toddlers, and very-low-birth-weight neonates requiring total 6 2. Anderson BB, Perry GM, Clements JE, Greany MF. Rapid uptake and parenteral nutrition. Nutrition. 2001;17:18-21. clearance of pyridoxine by red blood cells in vivo. Am J Clin Nutr. 22. Hamfelt A, Tuvemo T. Pyridoxal phosphate and folic acid concentration 1989;50:1059-1063. in blood and erythrocyte aspartate aminotransferase activity during preg- 3. Merill AH. Metabolism of vitamin B-6 by human liver. J Nutr. nancy. Clin Chim Acta. 1972;41:287-298. 1984;114:1664-1674. 23. Bhagavan HN, Coleman M, Coursin DB. The effect of pyridoxine hydro- 4. Zempleni J, Kubler W. The utilization of intravenously infused pyridoxine chloride on blood serotonin and pyridoxal phosphate contents in hyperac- in humans. Clin Chim Acta. 1994;229:27-36. tive children. Pediatrics. 1975;55:437-441. 5. Shultz TD, Leklem JE. Urinary 4-pyridoxic acid, urinary vitamin B , and 24. Vasilaki AT, McMillan DC, Kinsella J, Duncan A, O’Reilly DS, Talwar 6 plasma pyridoxal phosphate as measures of vitamin B status and dietary D. Relation between pyridoxal and pyridoxal phosphate concentrations in 6 intake in adults. In: Leklem JE, Reynolds RD, eds. Methods in Vitamin B plasma, red cells and white cells in patients with critical illness. Am J Clin 6 Nutrition. New York: Plenum; 1981:289-292. Nutr. 2008;88:140-146. 6. Chen MF, Boyce HW Jr, Triplett L. Stability of the B vitamins in mixed 25. Contractor SF, Shane B. Estimation of vitamin B compounds in human 6 parenteral nutrition solution. JPEN J Parenter Enteral Nutr. 1983;7: blood and urine. Clin Chim Acta. 1968;21:71-77. 462-464. 26. Raica N Jr, Sauberlich HE. Blood cell transaminase activity in human vita- 7. Van der Holst A, Martens HJM, de Goede PNEC. Analysis of water- min B deficiency. Am J Clin Nutr. 1964;15:67-72. 6 soluble vitamins in total parenteral nutrition solution by high pressure 27. Machey AD, Davis SR, Gregory JF III. Vitamin B . In: Shils ME, Shike 6 liquid chromatography. Pharm Weekly. 1989;11:169-174. M, Ross CA, Caballero B, Cousins RJ, eds. Modern Nutrition in Health 8. Mueller JF, Vilter RA. Pyridoxine deficiency in human beings induced by and Disease. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; desoxypyridoxine. J Clin Invest. 1950;29:193-201. 2006:452-459. 9. Snyderman SE, Holt LE, Carretero R, Jacobs K. Pyridoxine deficiency in 28. Compher CW, Kinosian BP, Stoner NE, et al. Choline and vitamin B12 the human infant. J Clin Nutr. 1953;1:200-207. deficiencies are interrelated in folate-replete long-term total parenteral 10. Bessey OA, Adam DJ, Hansen AE. Intake of vitamin B and infantile con- nutrition patients. JPEN J Parenter Enteral Nutr. 2002;26:57-62. 6 vulsions: a first approximation of requirements of pyridoxine in infants. 29. Kishi H, Folkers K. Improved and effective assays of the glutamic oxalo- Pediatrics. 1957;20:33-44. acetic transaminase by the coenzyme-apoenzyme system (CAS) principle. 11. Kretsch MJ, Sauberlich HE, Newbrun E. Electroencephalographic changes J Nutr Sci Vitamino (Tokyo). 1976;22:225-234. and peridontal status during short-term vitamin B-6 depletion of young, 30. Matarese LE, Dvorchik I, Costa G, et al. Pyridoxal-5′-phosphate defi- non-pregnant women. Am J Clin Nutr. 1991;53:1266-1274. ciency after intestinal and multivisceral transplantation. Am J Clin Nutr. 12. Hawkins WW, Barksky J. An experiment on human vitamin B depriva- 2009;89:204-209. 6 tion. Science. 1948;108:284-286. 31. Labadarios D, O’Keefe SJD, Dicker J, et al. Plasma vitamin levels in 13. Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy patients on prolonged total parenteral nutrition. JPEN J Parenter Enteral from pyridoxine abuse: a new megavitamin syndrome. N Engl J Med. Nutr. 1988;12:205-211. 1983;309:445-448. 32. Howard L, Bigaouette J, Chu R. Water soluble vitamin requirements in 14. Food and Nutrition Board, Institute of Medicine. Vitamin B . In: Dietary home parenteral nutrition patients. Am J Clin Nutr. 1983;37:421-428. 6 Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B , Folate, 33. Kishi H, Nishii S, Ono T, et al. Thiamin and pyridoxine requirements dur- 6 Vitamin B , Pantothenic Acid, Biotin, and Choline. Washington, DC: ing intravenous hyperalimentation. Am J Clin Nutr. 1979;32:332-338. 12 National Academies Press; 1998. 34. Shils ME, Baker H, Frank O. Blood vitamin levels of long-term adult home 15. Bitsch R, Moller J. Analysis of B vitamins in foods using a high-perfor- total parenteral nutrition patients: the efficacy of the AMA-FDA parenteral 6 mance liquid chromatographic method. J Chromatogr. 1989;463:207-211. multivitamin formulation. JPEN J Parenter Enteral Nutr. 1985;9:179-188. 16. Lumeng L, Ryan MP, Li TK. Validation of the diagnostic value of plasma 35. Dempsey DT, Mullen JL, Rombeau JL, et al. Treatment effects of par- pyridoxal 5′-phosphate measurements in vitamin B in the rat. J Nutr. enteral vitamins in total parenteral nutrition patients. JPEN J Parenter 6 1978;108:545-553. Enteral Nutr. 1987;11:229-237. 17. Lumeng L, Li TK. Vitamin B metabolism in chronic : pyri- 36. Inculet RI, Norton JA, Nichoalds GE, et al. Water-soluble vitamins in can- 6 doxal phosphate levels in plasma and the effects of acetylaldehyde on pyri- cer patients on parenteral nutrition: a prospective study. JPEN J Parenter doxal phosphate synthesis and degradation in human erythrocytes. J Clin Enteral Nutr. 1987;11:243-249. Invest. 1974;53:693-704. 37. Hariz MB, De Potter S, Corriol O, et al. Home parenteral nutrition in chil- 18. Lui A, Lumeng L, Aronoff GR, Li TK. Relationship between body store of dren: bioavailability of vitamins in binary mixtures stored for 8 days. Clin vitamin B and plasma pyridoxal-P clearance: metabolic balance studies in Nutr. 1993;12:147-153. 6 humans. J Lab Clin Med. 1985;106:491-497. 38. Department of Health and Human Services, Food and Drug Administra- 19. Brussard JH, Lowik MR, Vanden Berg H, et al. Dietary and other determi- tion. Postmarketing studies for approved human drug and licensed biologi- nants of vitamin B parameters. Eur J Clin Nutr. 1997;51:S39-S45. cal products; status reports. Fed Reg. 2000;65:64607-64619. 6

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Table A7.1. Factors Impairing Vitamin B Absorption 39. Lindner A, Bankson D, Stehman-Breen C, et al. Vitamin B6 metabolism 12 and homocysteine in end-stage renal disease and chronic renal insuffi- • Gastric resection, atrophic gastritis, or pernicious anemia: ↓ ciency. Am J Kidney Dis. 2002;39:134-145. gastric acid, proteases, and intrinsic factor 40. Robinson K, Gupta A, Dennis V, et al. confers an • Chronic pancreatitis, cystic fibrosis: ↓ pancreatic proteases independent increased risk of in end-stage renal disease • Bacterial overgrowth or small intestinal parasites: consume and is closely linked to plasma folate and pyridoxine concentrations. Cir- B -IF complex 12 culation. 1996;94:2743-2748. • Ileal resection or ileitis: eliminate or ↓ B -IF receptors 12 41. Friel JK, Bessie JC, Belkhode SL, et al. Thiamine, riboflavin, pyridoxine, • Genetic absence of TC II: ↓ tissue distribution and vitamin C status in premature infants receiving parenteral and enteral IF, intrinsic factor; TC, transcobalamin. nutrition. J Pediatr Gastroenterol Nutr. 2001;33:64-69. 42. Greene HL, Hambidge KM, Schanler R, et al. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorous in infants A number of factors listed in Table A7.1 can disrupt B 12 and children receiving total parenteral nutrition: report of the Subcommit- absorption. Very large doses of sublingual or oral crystalline tee on Pediatric Parenteral Nutrition Requirements from the Committee on B (500–1000 mcg/d) are ±1% absorbed by mass action even 12 Clinical Practice Issues of the American Society for Clinical Nutrition. Am if IF is absent. The sublingual and oral routes seem equally J Clin Nutr. 1988;48:1324-1342. effective and may be preferred to a monthly intramuscular 3-6 43. Moore MC, Greene HL, Phillips B, et al. Evaluations of a pediatric multiple injection. Patients with amblyopia or patients with vitamin preparation for total parenteral nutrition in infants and children, 1: B deficiency who smoke have increased urinary 12 blood levels of water-soluble vitamins. Pediatrics. 1985;77:530-538. losses and should receive a new form of B , hydroxocobala- 12 44. Greene H, Smith A, Murrell J, et al. HPLC measurement of pyridoxine min, which is a potent antagonist. This compound is vitamins in infants receiving total parenteral nutrition. JPEN J Parenter currently available only in a parenteral form. Cyanocobalamin, Enteral Nutr. 1989;12:1A. the traditional salt, is used in oral, sublingual, and parenteral multivitamin formulations and risks worsening tobacco/B 12 Appendix 7 ophthalmic symptoms.7 Vitamin B has an enterohepatic cycle. Each day, about 1.4 12 Vitamin B µg B is secreted into the bile, and approximately half of this is 12 12 recaptured if IF is present. If IF is absent or the distal ileum has Lyn Howard, MD, FRCP been resected, clinical B deficiency can develop in a few 12 months. In comparison, B deficiency in vegans develops over 12 many years. In normal circumstances, B is excreted chiefly in Introduction 12 the stool. Fecal B reflects unabsorbed B from food or bile, 12 12 Vitamin B or cobalamin is essential for normal blood forma- desquamated intestinal cells, and B synthesized by colonic 12 12 tion and normal neurologic function.1 bacteria. After a parenteral injection of B , if the circulating 12 In the United States, the median adult B intake from vitamin exceeds TC binding capacity, the excess is secreted in 12 food is 5 mcg/d for men and 3.5 mcg/d for women. Since B the urine. Vitamin B toxicity has not been described. 12 12 occurs only in animal products, strict vegetarians (vegans) may develop B deficiency unless they take a supplement. 12 Absorption of dietary B is a complicated process. It Metabolic Function 12 depends on gastric acid and pepsin to release food-bound B . Vitamin B is the cofactor for 2 enzymes. With methionine 12 12 The released B binds to R proteins secreted by the salivary synthetase, B transfers a from circulating 12 12 glands and gastric mucosa. In the alkaline pH of the duode- methyltetrahydrofolate to homocysteine, forming tetrahydro- num, pancreatic proteases digest the R proteins, and liberated folate and methionine. Tetrahydrofolate is required for deoxy- B binds to intrinsic factor (IF). IF is a glycoprotein secreted ribonucleic acid (DNA) synthesis. With L-methylmalonyl-CoA 12 by the gastric parietal cells. The B -IF complex travels down mutase, adenosyl B isomerizes L-methylmalonyl-CoA to 12 12 the and attaches to specific receptors in the dis- succinyl CoA. tal ileum. The B -IF is internalized into the ileal enterocyte; The hematologic effect of B deficiency is identical to 12 12 B is then broken off and enters the circulation bound to trans- folate deficiency since both vitamins are involved in methyl 12 cobalamin (TC) carrier proteins I, II, or III. Most circulating transfer, a step toward DNA synthesis. The defect is most B (>80%) is attached to TC I, which seems to be physiologi- apparent in rapidly dividing cells and in the bone marrow, 12 cally inert; 10%–15% of circulating B is attached to TC II. gut lining, and cervix mucosa. In the bone marrow, red cell 12 Tissues have TC II receptors, allowing them to capture B as precursors are large with primitive nuclei and are called 12 needed.2 The liver takes up 50% of dietary B and provides megaloblasts. The peripheral blood shows anemia with mac- 12 the main storage site. The average B hepatic content is 1.0 rocytosis of red blood cells, neutropenia with hyper­ 12 pg/g of tissue. The total body B12 content is 1–3 mg. segmented polymorphs, and thrombocytopenia. Deficient

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patients are pale, fatigued, and short of breath. They may Table A7.2. Reasons to Continue 5 mcg/d of Vitamin B as the Adult Parenteral Multivitamin Dose complain of a sore tongue, loss of , flatulence, and 12 constipation due to abnormal functioning of the macrocytic • Although this dose results in serum B12 levels at upper limits bowel. No gynecologic symptoms have been described. The of normal, there is no evidence for a B toxicity syndrome. 12 hematologic and bowel symptoms improve after a few weeks • High serum levels may reflect daily parenteral B infusion of B therapy. 12 12 rather than tissue levels that are probably normal. The neurologic effects of B deficiency develop more • Parenteral B is delivered into the systemic circulation rather 12 12 slowly and reflect a lack of adenosyl B . Twenty-five percent than the portal system, and thus first-pass uptake of 50% by 12 of patients with the neurologic syndrome have no hematologic the liver and binding to appropriate transcobalamin (TC) manifestations. The clinical picture may include a peripheral carrier proteins are likely to be less efficient. In addition, 25% sensory neuropathy with tingling, numbness, and reduced of systemic blood “first passes” the kidneys. Immediate loss of significant amounts of B in the urine is probable. vibration and position sense, especially in the legs; motor 12 • B secreted into the bile may not be recaptured because of 12 weakness with gait disturbances; and central deficits such as loss of ileal receptors. loss of concentration and memory, leading to premature • Smokers have increased urinary B losses as thiocyanate. dementia. Occasionally, there are visual changes, impotency, 12 and loss of bowel and bladder control. Lindenbaum et al8 and later Beck9 described neuropsychiatric disorders caused by Recommended Daily Allowance (RDA), which, however, is cobalamin deficiency in the absence of anemia and macrocyto- only 50% absorbed.10 Serum B tends to be elevated in 12 sis. This suggests all neuropsychiatric patients should be patients receiving chronic parenteral nutrition (PN), usually in screened for B deficiency. Neurological deficits come on the 700- to 900-pg/mL range.10 This might suggest that paren- 12 slowly, and full reversibility with B treatment is less certain. teral 5 mcg/d is excessive, but there are several good reasons, 12 summarized in Table A7.2, to continue this generous dose. Elkhatib et al11 speculated that high serum B in long-term 12 Reliable Assessment Methods PN patients might be a marker for intestinal failure–associated Evaluation of B starts with relatively nonspecific hemato- liver disease. They studied 13 patients with short bowel syn- 12 logic tests such as hemoglobin concentration, hematocrit, red drome (<200 cm residual small bowel) and complete terminal cell count, and mean red cell volume. Serum or plasma B ileum resection who had been on PN for 6.1 ± 3 years. All 12 levels are the most common specific test ordered, but they patients had at least 1 liver biopsy for presumed intestinal fail- develop late after tissue levels are already depleted. Plasma or ure–associated liver disease. The biopsies were evaluated and serum values can be normal despite tissue deficiency because scored for the degree of steatosis, inflammation, and fibrosis. of recent intake. In parenteral patients receiving daily B infu- There was no correlation between serum B concentration and 12 12 sions, serum B levels are hard to interpret. The lower limit of liver pathology, nor was there any correlation with hepatic 12 serum B for adults is 120–180 pmol/L or 170–250 pg/mL. chemistries taken just prior to the liver biopsy. Thus, in these 12 Normal serum values are 300–900 pg/mL. The value varies circumstances, the high serum B was not a marker of intesti- 12 with the laboratory method used. nal failure–associated liver disease. Measurement of serum methylmalonic acid (MMA) is cur- Gender.Women have higher serum B values and higher 12 rently the most sensitive and specific test of B depletion. It transcobalamin levels compared with men.12 However, this 12 measures adenosyl-B function. If patients with established does not appear to indicate a higher requirement for B in 12 12 B deficiency are supplemented inadequately, MMA rises in women. 12 95%, but serum B is low (<200 pg/mL) in only 69%. False Age. Tables 4–7 in the main section show recommended 12 MMA positives are seen in severe renal failure or major vol- B intakes enterally and parenterally for neonates, infants, 12 ume depletion. MMA specificity is confirmed when the high children, adolescents, and adults. The liver of well-nour- value subsides with B supplementation. ished babies contains only 25–30 mcg B . Breast milk 12 12 Elevated homocysteine and increased urinary excretion of from vegan mothers tends to be low (0.23 mcg/d), and these after loading (FIGLU test) are infants may develop increased urinary MMA concentra- seen in both B and folic acid deficiency and reflect the methyl tions at 2–14 months,13 indicating B deficiency. The pedi- 12 12 group transfer function of these 2 vitamins. As a result, these atric parenteral dose is generous and will certainly build tests are not as specific as MMA for pinpointing B depletion. pediatric liver stores rapidly. There are no known adverse 12 consequences of providing this generous amount of B . 12 Pregnancy. Serum B concentrations decline in early Vitamin B Requirements in Parenteral 12 12 pregnancy, and by the sixth month, they are about half the Nutrition nonpregnancy concentration. This may reflect the mother’s Adult parenteral multivitamin products provide 5 mcg/d of expanded intravascular volume. In the third trimester, trans- crystalline cyanocobalamin. This is similar to the oral B cobalmin II increases to about a third more than in the 12

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nonpregnant women. The RDA for pregnancy is 2.6 mcg 12. Fernandez-Costa F, van Tonder S, Metz J. A sex difference in serum cobal- B per day. Again, this is more than covered by the usual amin and transcobalamin levels. Am J Clin Nutr. 1985;41:101-136. 12 parenteral dose of 5 mcg B per day. 13. Specker BL, Black A, Allen L, Morrow F. Vitamin B12: low milk con- 12 Lactation. Healthy B -replete mothers secrete approxi- centrations are related to low serum concentrations in vegetarian women 12 mately 0.33 mcg B per day in breast milk. This amount and to methylmalonic aciduria in their infants. Am J Clin Nutr. 1990;52: 12 decreases to 0.25 mcg B per day after 6 months. The RDA 1073-1076. 12 for lactation is 2.8 mcg B per day. This again is more than 12 met in women supported by PN (5 mcg B per day). 12 Appendix 8 Recommendations for B in Parenteral NutritionThe current 12 dose of 5 mcg/d for adults generously meets requirements. Folate and Parenteral Nutrition When patients with short bowel syndrome are gradually weaned off PN, B adequacy needs to be checked at interval Lyn Howard, MD, FRCP 12 since most of these patients have lost their ileum and therefore B -IF receptors. Alternatively, supplements can be started 12 Introduction from the onset of weaning. If the patient smokes, hydroxoco- balamin, rather than cyanocobalamin, is the compound of Folate functions as a coenzyme in single-carbon transfer reac- choice. Commercial sublingual, oral, and multivitamin prepa- tions and exists in many chemical forms. It has a critical role rations currently use , and it would be desir- in , purine, and amino acid metabolism. able if this can be changed. Food folate (pteroyl polyglutamate) consists of a p-ami- nobenzoic acid molecule linked at one end to a pteridine ring Appendix 7 References and at the other to 2–7 glutamate molecules. This glutamate 1. Food and Nutrition Board, Institute of Medicine. Vitamin B . In: Dietary 12 side chain is highly polar, and folate is not absorbed by the Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, small intestine until most of the side chain is removed by Vitamin B , Pantothenic Acid, Biotin, and Choline. Washington, DC: 12 folate conjugases, which are secreted by small bowel entero- National Academies Press; 1998:306-356. cytes. Once the polyglutamate is converted to the monoglu- 2. Hall CA, Finkler AE. Function of transcobalamin II: a B12 binding protein tamate, folate is actively transported into the enterocyte by a in human plasma. Proc Soc Exp Biol Med. 1966;123:55-58. saturable pH-dependent process. The bioavailability of food 3. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with folate (polyglutamate) is about 50%. All folate supplements high doses of vitamin B12 without intrinsic factor. Acta Med Scand. are in the monoglutamate form, which is 100% bioavail- 1 1968;184:247-258. able. In 1998, the United States made fortification of cereal 4. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy of vitamin grains with folate monoglutamate mandatory to ensure an B12 deficiency: comparison between the sublingual and oral route. J Clin intake of at least 400 mcg/d. This was done to reduce the Pharmocol. 2003;56:635-638. incidence of neural tube birth defects (NTD) in the in utero 1 5. Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as infants. This fortification appears to have decreased NTD 1 an alternative to oral and parenteral cobalamin supplementation. Lancet. by 50%. 1999;354:740-741. Total body folate is approximately 22 mg in healthy adults, 2 6. Yazaki Y, Chow G, Mattie M. A single center, double blinded, randomized and half of this is stored in the liver. Folate circulates primar- controlled study to evaluate the relative efficacy of sublingual and oral ily as methyltetrahydrofolate (methyl-THF) bound to protein vitamin B complex administration in reducing total serum homocysteine carriers. It is transported into cells by a specific receptor. In the levels. J Altern Complement Med. 2006;12:881-885. cell, folate is attached to membrane carriers or folate binding 3 7. Freeman AG. Sublingual cobalamin for pernicious anemia. Lancet. protein-mediated systems. These transport systems are not 1999;354:2080. saturated under physiologic conditions, so folate influx into 8. Lindenbaum J, Healton EB, Savage DG et al. Neuropsychiatric disorders tissues can be expected when supplements are given and caused by cobalamin deficiency in the absence of anemia or macrocytosis. plasma folate rises. In the cell, folate is stored as the polygluta- N Engl J Med. 1988;318:1720-1728. mate form. 9. Beck WS. Neuropsychiatric consequences of cobalamin deficiency. Adv Folate catabolism starts with cleavage of the intracellular Intern Med. 1991;36:33-56. polyglutamate to monoglutamate, which is then acetylated and 10. Chanarin I. The Megaloblastic . 2nd ed. Oxford, UK: Blackwell excreted in the urine. Folate is also excreted into the bile, but Scientific; 1979. much of this is reabsorbed. Fecal folate losses reflect unab- 11. Elkhatib I, Cao W, Rao S, Buchman AL. Serum B12 concentration is sorbed food folate, folate excreted into the bile, and folate syn- 4 elevated in patients receiving chronic parenteral nutrition, but is not a thesized by the intestinal microflora. There are no data on gut marker of intestinal failure–associated liver disease. J Clin Gastroenterol. losses in extreme short bowel patients maintained on long- 2010;44(8):571-574. term home parenteral nutrition (PN).

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Metabolic Function Appendix A8.1. Factors Leading to Folic Acid Deficiency 1. Inadequate intake Common in alcoholics The main function of folate compounds is to transfer 1-carbon 2. Increased requirement Pregnancy moieties, such as methyl and formyl groups, to organic com- Infancy pounds. These 1-carbon moieties are chiefly obtained from Malignancy , which in turn is converted to . The most critical Increased hematopoiesis l-carbon transfers of folate are (1) the conversion of homocys- Hemodialysis teine to methionine, (2) the addition of C and C in purine 2 8 3. Malabsorption Tropical sprue synthesis, and (3) the of deoxyuridylic acid to Celiac disease form thymidylic acid in pyrimidine synthesis. This last reac- Drugs; phenytoin, barbiturates tion is unique in that dihydrofolate (DHF) is formed rather 4. Impaired metabolism Inhibitors of dihydrofolate than tetrahydrofolate (THF). DHF must be reduced by dihy- reductase; , drofolate reductase before it can reenter the donor pool. A pentamidine number of drugs, such as methotrexate, , and Alcohol trimethoprim, can inhibit , inducing Rare enzyme deficiencies; dihydrofolate reductase folate deficiency. Table A8.1 summarizes the many causes of folate deficiency. The clinical presentation reflects the defect in purine and pyrimidine metabolism, especially in rapidly Vitamin B status, age, gender, and renal insufficiency also 6 dividing cells in the bone marrow and in intestinal and cervi- affect plasma homocysteine levels. cal epithelia. Cytoplasmic development is normal, but Urinary folate is not a sensitive index of folate status. impaired deoxyribonucleic acid (DNA) synthesis and delayed cell division result in large cells with primitive nuclei. In the bone marrow, these are most striking in the red cell series and Folate Requirements in PN termed megaloblasts. These cells eventually lose their nuclei In the early years of PN, a number of patients died with an and move into the circulation as macrocytes. Other hemato- acute megaloblastic crisis occurring within a few weeks of poietic cells are also affected. Polymorphs develop increased starting the therapy.6 Wardrop et al7 suggested the mechanism nuclear segmentations, and platelets are reduced in number. could be alcohol toxicity. At that time, parenteral fat was not Folate-deficient patients are pale, fatigued, and short of available, so all needed calories were given as dextrose, with its breath. They may also have a sore tongue, angular cheilosis, attendant hyperglycemic problems, or as a dextrose-alcohol loss of appetite, flatulence, and constipation related to their mixture. The toxic effect of alcohol on hematopoiesis was well macrocytic bowel. All these symptoms subside after a few known.8 Later investigators described this syndrome in PN weeks of folate therapy. This clinical picture is identical to the patients not receiving any alcohol.9 They found, however, an hematologic effects of vitamin B deficiency. This reflects association with high levels of glycine and methionine. Folate 12 the fact that folate and B are both involved in the conversion supplementation prevented this syndrome. A later speculation 12 of methyl-THF to THF, which then receives 2 carbon moi- pointed to the common practice of using mostly glycine to eties to form N methylene THF (the active form for purine provide nonessential amino acid nitrogen. Glycine is a highly 5,10 and pyrimidine synthesis). soluble amino acid. It was suggested that excessive glycine Folate toxicity has not been described. may block the serine-glycine conversion, which provides the l-carbon moieties that convert THF to N5,10 methylene THF, the active form in purine and pyrimidine synthesis. In those early Reliable Assessment Methods years, folate was not always added to short-term PN. After Erythrocyte folate is the best test for long-term folate defi- supplemental folate was shown to avoid this megaloblastic ciency, and it correlates fairly well with folate concentrations syndrome, 200 mcg/d was added. This has now been increased in other tissues such as the liver.5 Deficiency is present when to 400 mcg/d of folate monoglutamate to cover patients with erythrocyte folate is below 140 ng/mL. longstanding malnutrition and depleted folate stores. Most PN Serum folate less than 4 ng/mL indicates a negative folate patients have high normal serum folate levels.1 balance, but it does not distinguish between a transient reduction in folate intake and chronic folate deficiency. The Age normal serum concentration is 6–20 ng/mL. Plasma homocysteine rises with folate deficiency, but dif- Tables 4–7 in the main section show recommended folate ferent laboratories use different upper limits. Greater than 14 intakes enterally and parenterally in neonates, children, ado- µmol/L is perhaps the most commonly used value. Elevated lescents, and adults. The amount is expressed as mcg/kg/d for plasma homocysteine is also seen in vitamin B deficiency. small infants (<3.0 kg), but thereafter it is a standard pediatric 12

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dose in mcg/d. The parenteral dose is 30% higher than the 7. Wardrop CAJ, Heatley RV, Tennant GB, Hughes LE. Acute folate defi- enteral dose until adulthood, when it is the same, 400 mcg/d. ciency in surgical patients on amino acid/ethanol intravenous nutrition. Lancet. 1975;2:640-642. Pregnancy 8. Herbert V, Zalinsky R, Davidson CS. Correlates of folate deficiency with alcoholism and associated macrocytosis, anemia and liver disease. Ann The U.S. 1998 mandate for folate fortification of cereal fol- Intern Med. 1963;58:977-988. lowed the publication of several studies showing that pericon- 9. Conner H, Newton VDJ, Preston FE, Woods HF. Oral methionine load- ceptional folate supplementation reduced the risk of a second ing as a cause of acute serum folate deficiency: its relevance to parenteral NTD in mothers who have had this complication by as much as nutrition. Postgrad Med J. 1978;54:318-320. 10,11 35%–40%. A randomized study in Hungary evaluated the 10. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and effect of a multivitamin providing 800 mcg/d of folic acid or risk of recurrent neural tube defects. J Am Med Assoc. 1993;269:1257-1261. placebo in 4753 women planning a pregnancy but with no prior 11. Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA. Periconceptional 12 history of NTD. The study was prematurely terminated after vitamin use, dietary folate, and the occurrence of neural tube defects. Epi- there were 6 cases of NTD in the controls and none in the group demiology. 1995;6:219-226. receiving vitamin supplementation. The effect of supplemental 12. Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube folate alone was not assessed. Currently, the evidence for a defects by periconceptional vitamin supplementation. N Engl J Med. protective effect of folate supplements or fortified food or both 1992;327:1832-1835. is much stronger than that for natural food folate. Preliminary data indicate a 50% reduction in NTDs since cereal fortifica- Appendix 9 tion was required.1 Current parenteral multivitamin products provide 400 mcg/d. There is no specific pregnancy product. It Biotin seems wise to recommend increasing folate acid in the adult formula so as provide for women who become pregnant and are Peggy Borum, PhD dependent on PN. There are no known adverse consequences of this increased amount in nonpregnant adults. Introduction Biotin is a water-soluble B vitamin that functions as a coen- 1 Recommendation for Folic Acid in PN zyme in bicarbonate-dependent carboxylation reactions. The current dose of 600 mcg/d for adults appears to gener- Metabolic Function ously meet requirements even for females who are pregnant or lactating. If the patient has short bowel syndrome and is being Biotin metabolism does not appear to be the same in all tissues weaned off PN, monitoring erythrocyte folate and starting oral of the body. Biotin deficiency in rats results in a decrease of supplements are appropriate. Most short bowel patients retain pyruvate carboxylase and of propionyl-CoA carboxylase of their duodenum and some of their jejunum, and these are the about 90% in adipose tissue, jejunum, and spleen but only a 40% chief sites for folate absorption, and thus oral supplementation decrease in heart, indicating that the effect of biotin deficiency can be effective. differs among organs.2 Biotin plays an important role in the metabolism of glucose, amino acids, and fatty acids as it func- Appendix 8 References tions as a coenzyme for 4 carboxylases. It is known that biotin 1. Food and Nutrition Board, Institute of Medicine. Folate. In: Dietary Refer- plays a role in immune function, cell proliferation, and fetal ence Intakes for Thiamin, Riboflavin, Niacin, Vitamin B , Folate, Vitamin 6 development. New evidence suggest that biotin also plays an B , Pantothenic Acid, Biotin, and Choline. Washington, DC: National 12 important role in regulating expression of encoding cyto- Academies Press; 1998:196-305. kines and their receptors, oncogenes, genes involved in glucose 2. Hoppner K, Lampi B. Folate levels in human liver from autopsies in Can- metabolism, and genes that play a role in cellular biotin homeo- ada. Am J Clin Nutr. 1980;33:862-864. stasis. Data suggest that biotinyl-AMP functions in the activation 3. Wagner C. Symposium on the subcellular compartmentation of folate of soluble guanylate cyclase, biotin deficiency increases nuclear metabolism. J Nutr. 1996;126:1228s-1234s. translocation of NF-κB, and biotin functions in remodeling of 3,4 4. Krumdieck CL, Fukushima K, Fukushima T, Shiota T, Butterworth CE Jr. by of . Biotin is covalently A long term study of the excretion of folate and pterins in a human subject attached to specific lysine residues in histones in a reversible 5 after ingestion of C14 folic acid, with observations on the effect of diphe- process that depends on the exogenous biotin supply. In addition nylhydantoin administration. Am J Clin Nutr. 1978;31:88-93. to biotin serving as a coenzyme for pyruvate carboxylase, biotin 5. Wu A, Chanarin I, Slavin G, Levi AJ. Folate deficiency in the alcoholic— also influences both the synthesis and degradation of pyruvate 6 its relationship to clinical and hematological abnormalities, liver disease carboxylase. In mice, biotin deficiency may upregulate tumor and folate stores. Br J Hematol. 1975;29:469-478. necrosis factor (TNF)–α production, and biotin excess may 6. Ballard HS, Lindenbaum J. Megaloblastic anemia complicating hyperali- downregulate TNF-α production, leading to the suggestion that 7 mentation therapy. Am J Med. 1974;456:740-742. biotin status influences inflammatory diseases.

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Reliable Assessment Methods of significantly to more than 2 standard deviations above refer- 15 Deficiency and Toxicity ence levels. When adult patients on long-term PN have plasma biotin concentrations above the normal range, the patients usu- Biotin deficiency has been documented in individuals con- ally have some form of renal dysfunction.16 suming raw egg whites over long periods and in patients After studying 3 patients with clinical symptoms of biotin receiving parenteral nutrition (PN) that does not contain bio- deficiency on biotin-free PN and using large doses of biotin tin. There is not a good laboratory test for detecting biotin therapy (100 µg/d in all patients; an initial larger dose of 1 deficiency, so the condition is usually identified by its symp- mg/d for 1 week plus 10 mg/d for 7 weeks in 1 patient), some toms. Biotin deficiency may result in dermatitis (red scaly rash investigators “speculate that the biotin supplement currently around eyes, nose, and mouth), conjunctivitis, alopecia, and recommended for pediatric patients (20 micrograms/day) may abnormalities such as depression, leth- not be adequate therapy for biotin deficiency and might not argy, hallucinations, and of the extremities. Biotin even be adequate to maintain normal biotin status during TPN deficiency in infants may result in , lethargy, devel- [total parenteral nutrition].”17 opmental delays, and withdrawn behavior.1 Modifications Due to Gender, Age, Requirement in PN Pregnancy, and Lactation A Recommended Dietary Allowance (RDA) has not been set Individuals an oral diet may be at greater risk for biotin due to insufficient available scientific evidence. Daily deficiency than previously recognized. Women who smoke Adequate Intake (AI) of biotin levels has been established by appear to have accelerated biotin metabolism, which results in the Food and Nutrition Board of the U.S. Institute of marginal biotin deficiency.18 In a recent study, 18 of 22 preg- Medicine based on extrapolation from the amount of biotin nant women had laboratory characteristics of marginal biotin in human milk. People with a genetic deficiency deficiency that responded to biotin supplementation.19 Biotin and people on hemodialysis or peritoneal dialysis treatment status of pregnant women affects the developing fetus. Culture may have an increased requirement for biotin. No adverse of human embryonic palatal mesenchymal (HEPM) cells in effects of excess biotin have been reported in humans or the biotin-deficient and biotin-physiological (control) media animals. No toxicity has been observed in patients receiving for 5 weeks showed a decrease in biotin after 1 week and up to 200 mg orally and up to 20 mg parenterally to treat decreased proliferation of HEPM cells in the biotin-deficient biotin-responsive inborn errors of metabolism and acquired state after 2 weeks of culture (41.3% of the control). Nuclei of biotin deficiency. Due to insufficient data on adverse effects, biotin-deficient cells also had decreased numbers of biotinyl- the upper tolerable intake limit (UL) could not be deter- ated histones compared with control cells. Suppressed prolif- mined.1 PN biotin recommendations are derived from the eration of mesenchymal cells “may delay or inhibit the growth deliberations of expert panels.8,9 of palatal processes in embryos and thus it may partially con- Biotin is stable in a 3-L plastic bag while stored in darkness tribute to the mechanisms for cleft palate induction.”20 at 2–8°C for 96 hours or during 24 hours of simulated infusion initiated immediately after mixing.10 There have been several Recommendations reports of biotin deficiency in patients on PN with varying prevalence rates. In 49 patients receiving home PN, 3 had Biotin symptoms of biotin deficiency, including dry eyes and or hair loss.11 In another study, patients on biotin-free Population Recommendation Reference PN for 1 month had clinical symptoms consistent with biotin Oral nutrition: adults AI = 30 mcg/d 1 deficiency, reduced plasma biotin concentrations, and decreased Oral nutrition: pregnant females AI = 30 mcg/d 1 propionyl CoA carboxylase activity. After 4 months of biotin- Oral nutrition: breastfeeding AI = 35 mcg/d 1 supplemented PN, both plasma biotin concentrations and pro- females pionyl CoA carboxylase activity increased to near-normal Oral nutrition: children, 0–6 mo AI = 5 mcg/d 1 12 levels. Almost half of 13 children on home PN for 1.5 months Oral nutrition: children, 7–12 mo AI = 6 mcg/d 1 to 7 year and 17 hospitalized infants and children receiving PN Oral nutrition: children, 1–3 y AI = 8 mcg/d 1 had initially low levels of plasma biotin. Biotin rose sharply Oral nutrition: children, 4–8 y AI = 12 mcg/d 1 during the first month of supplementation with 60 mcg/d of par- Oral nutrition: children, 9–13 y AI = 20 mcg/d 1 13 enteral biotin but returned to the normal range. However, in Oral nutrition: children, 14–18 y AI = 25 mcg/d 1 another study of 102 children receiving all or part of their nutri- PN: adults 60 mcg/d 8 tion needs from home PN, only 1 case of biotin deficiency was PN: term infants and children 20 mcg/d 9 14 recognized. Plasma biotin concentrations of term infants and PN: preterm infants and children 8 mcg/kg/d 9 children on biotin-supplemented PN were maintained at refer- ence levels, but the biotin levels of preterm infants increased AI, Adequate Intake; PN, parenteral nutrition.

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Appendix 9 References 18. Sealey WM, Teague AM, Stratton SL, Mock DM. Smoking accelerates biotin catabolism in women. Am J Clin Nutr. 2004;80(4):932-935. 1. Otten JJ, Hellwig JP, Meyers LD, eds. Biotin. In: Dietary Reference 19. Mock DM. Marginal biotin deficiency is common in normal human preg- Intakes: The Essential Guide to Nutrient Requirements. Washington, DC: nancy and is highly teratogenic in mice. J Nutr. 2009;139(1):154-157. National Academies Press; 2006:196-201. 20. Takechi R, Taniguchi A, Ebara S, Fukui T, Watanabe T. Biotin deficiency 2. Velázquez-Arellano A, Hernández-Esquivel Mde L, Sánchez RM, et al. affects the proliferation of human embryonic palatal mesenchymal cells in Functional and metabolic implications of biotin deficiency for the rat heart. culture. J Nutr. 2008;138(4):680-684. Mol Genet Metab. 2008;95(4):213-219. 3. Gravel RA, Narang MA. Molecular genetics of biotin metabolism: old Appendix 10 vitamin, new science. J Nutr Biochem. 2005;16(7):428-431. 4. Rodriguez-Melendez R, Zempleni J. Regulation of gene expression by bio- Molybdenum in Parenteral Nutrition tin. J Nutr Biochem. 2003;14(12):680-690. 5. Hassan YI, Zempleni J. Epigenetic regulation of chromatin structure and Marty Kochevar, MS, RPh, BCNSP gene function by biotin. J Nutr. 2006;136(7):1763-1765. 6. Rodríguez-Fuentes N, López-Rosas I, Román-Cisneros G, Velázquez- Introduction Arellano A. Biotin deficiency affects both synthesis and degradation of pyruvate carboxylase in rat primary hepatocyte cultures. Mol Genet Metab. Molybdenum functions as a cofactor for a limited number of 2007;92(3):222-228. enzymes in humans. The Institute of Medicine’s Food and 7. Kuroishi T, Endo Y, Muramoto K, Sugawara S. Biotin deficiency up- Nutrition Board has developed Adequate Intakes (AIs) for regulates TNF-alpha production in murine macrophages. J Leukoc Biol. infants (2–3 mcg/d) and Recommended Dietary Allowances 2008;83(4):912-920. (RDAs) for children and adults (17–50 mcg/d) (Table A10.1). 8. Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutri- The average dietary intake of molybdenum by adult men and tion. JPEN J Parenter Enteral Nutr. 2004;28:S39-S70. women is 109 and 76 mcg/d, respectively. The tolerable upper 9. Greene HL, Hambidge KM, Schanler R, Tsang RC. Guidelines for the intake level (UL) is 2 mg/d based on impaired reproduction 1 use of vitamins, trace elements, calcium, magnesium, and phosphorus in and growth in animals. infants and children receiving total parenteral nutrition: report of the Sub- In the United States, parenteral molybdenum is available as committee on Pediatric Parenteral Nutrient Requirements from the Com- a single-entity trace element injection (Table 11 in the main mittee on Clinical Practice Issues of the American Society for Clinical paper). The United States Pharmacopeia (USP) includes Nutrition [published errata appear in Am J Clin Nutr. 1989;49(6):1332 and molybdenum as a substrate in its “Trace Elements Injection” 3 1989;50(3):560]. Am J Clin Nutr. 1988;48:1324-1342. monograph, but no such multiple trace element injection 10. Dahl GB, Jeppsson RI, Tengborn HJ. Vitamin stability in a TPN mixture product containing molybdenum is available in the United stored in an EVA plastic bag. J Clin Hosp Pharm. 1986;11(4):271-279. States. 11. Forbes GM, Forbes A. Micronutrient status in patients receiving home par- enteral nutrition. Nutrition. 1997;13(11-12):986. Metabolic Function 12. Velázquez A, Zamudio S, Báez A, Murguía-Corral R, Rangel-Peniche B, Carrasco A. Indicators of biotin status: a study of patients on prolonged Molybdenum has been shown to act as a cofactor for a limited total parenteral nutrition. Eur J Clin Nutr. 1990;44(1):11-16. number of enzymes: sulfite oxidase, xanthine oxidase, and 13. Marinier E, Gorski AM, de Courcy GP, et al. Blood levels of water-soluble aldehyde oxidase. These enzymes are involved in the catabo- vitamins in pediatric patients on total parenteral nutrition using a multiple lism of sulfur amino acids and heterocyclic compounds, vitamin preparation. JPEN J Parenter Enteral Nutr. 1989;13(2):176-184. including purines and . A clear molybdenum defi- 14. Vargas JH, Ament ME, Berquist WE. Long-term home parenteral nutrition ciency syndrome has not been achieved in animals, despite in pediatrics: ten years of experience in 102 patients. J Pediatr Gastroen- major reduction in the activity of these enzymes. Rather, terol Nutr. 1987;6(1):24-32. is based on a genetic defect that pre- 1 15. Moore MC, Greene HL, Phillips B, et al. Evaluation of a pediatric multiple vents sulfite oxidase synthesis. vitamin preparation for total parenteral nutrition in infants and children, I: blood levels of water-soluble vitamins. Pediatrics. 1986;77(4):530-538. Reliable Assessment Methods 16. Shils ME, Baker H, Frank O. Blood vitamin levels of long-term adult home total parenteral nutrition patients: the efficacy of the AMA-FDA paren- Plasma and serum molybdenum concentrations are very low teral multivitamin formulation. JPEN J Parenter Enteral Nutr. 1985;9(2): in humans and are difficult to measure. As a consequence, 179-188. there are few reports on plasma or serum molybdenum con- 17. Mock DM, Baswell DL, Baker H, Holman RT, Sweetman L. Biotin defi- centrations. Plasma concentrations do not reflect molybde- ciency complicating parenteral alimentation: diagnosis, metabolic reper- num status and cannot be used as an indicator of estimating 1 cussions, and treatment. J Pediatr. 1985;106(5):762-769. requirements.

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Table A10.1. Dietary Reference Intake: Molybdenum2 The primary route of molybdenum excretion is the urine. Urinary molybdenum reflects dietary intake, increasing as Life Stage Group RDA/AI*, mcg/d dietary intake increases. Although related to dietary intake, uri- Infants nary molybdenum alone does not reflect status. 0–6 mo 2* Several biochemical changes have been observed in special 7–2 mo 3* situations. In molybdenum cofactor deficiency, urinary sulfate Children was low and urinary sulfite was present. Serum uric acid con- 1–3 y 17 centrations were low, urinary xanthine and hypoxanthine 4–8 y 22 increased, and plasma methionine was increased. However, Males these observations have not been associated with molybdenum 9–13 y 34 intakes in normal, healthy people and cannot be used as indica- 14–18 y 43 tors for estimating molybdenum requirements. 19–30 y 45 31–50 y 45 50–70 y 45 Requirements in Parenteral Nutrition >70 y 45 Females The published, estimated daily molybdenum parenteral nutri- 9–13 y 34 tion (PN) requirements from various professional groups are 14–18 y 43 listed in Table A10.2. Most professional groups indicate the 19–30 y 45 need for molybdenum in long-term (eg, home PN) patients. 9 31–50 y 45 Abumrad et al in 1981 reported a case of a 24-year-old 50–70 y 45 man suffering from intolerance to amino acids, mainly l-methi- >70 y 45 onine, while on prolonged PN (18 months). The patient dis- Pregnancy played tachycardia, tachypnea, central scotomas, night ≤18 y 50 blindness, and irritability, leading to coma. The symptoms dis- 19–30 y 50 appeared with discontinuation of the administered l–amino 31–50 y 50 acid solutions. Biochemical abnormalities included high Lactation plasma methionine and low serum uric acid levels associated ≤18 y 50 with increased urinary excretion of sulfite, thiosulfate, hypo- 19–30 y 50 xanthine, and xanthine with decreased urinary excretion of 31–50 y 50 uric acid. Treatment with ammonium molybdate (300 mcg/d) Recommended Dietary Allowances (RDAs) in bold type; Adequate improved the clinical condition, reversed the sulfur handling Intakes (AIs) in ordinary type followed by an asterisk (*). defect, and normalized uric acid production. This is the only

Table A10.2. Published Parenteral Nutrition Requirements for Molybdenum

Group Adult Pediatric AGA 20014 [Not discussed] [Not discussed] A.S.P.E.N. 20025 “Not routinely added” “Although not a conventional addition, molybdenum supplementation may be appropriate in long term TPN therapy.” ESPGHAN/ESPEN 20056 Not applicable “An intravenous molybdenum supply of 1 mg/kg per day (0.01 mmol/kg per day) seems adequate and is recommended for the LBW infant. GOR D” “For infants and children an intravenous molybdenum supply of 0.25 mg/kg per day (up to a maximum of 5.0 mg/day) is recommended. GOR D”a ESPEN 20097 “0.2–0.26 micromole/day”b [19–25 Not applicable mcg/d]c Critical Care Nutrition 20098 [Not discussed] [Not discussed]

AGA, American Gastroenterological Association; A.S.P.E.N., American Society for Parenteral and Enteral Nutrition; ESPEN, European Society for Clinical Nutrition and Metabolism; ESPGHAN, European Society of Paediatric Gastroenterology, Hepatology and Nutrition; GOR D, grade of recom- mendation—grade D. aDirectly quoted from publication. Doses appear to be incorrect (increased) by a factor of 1000. bParenteral intake provided by proprietary sources for home parenteral nutrition use in Europe. cCalculated mcg values from micromole amounts per day.

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published case of PN-induced molybdenum deficiency in man. 2. Berner YN, Shuler TR, Nielsen FH, Flombaum C, Farkouh SA, Shike M. 1 The National Academy of Sciences/Institute of Medicine Selected ultratrace elements in total parenteral nutrition solutions. Am J notes that molybdenum deficiency has not been observed in Clin Nutr. 1989;50:1079-1083. healthy people, and the only case that might be considered a 3. Trace elements injection. In: The United States Pharmacopeia, 30th rev., dietary deficiency is that of Abumrad et al. and The National Formulary, 25th ed. Rockville, MD: The United States While there are no reports of molybdenum deficiency in Pharmacopeial Convention; 2007:334-351. infants, low birth weight (LBW) infants might be at risk 4. American Gastroenterological Association Clinical Practice and Practice because they are born before adequate stores can be acquired, Economics Committee. AGA Technical Review on Parenteral Nutrition. have rapid growth requiring increased intakes, and frequently Gastroenterology. 2001;121:970-1001. 10 receive PN. Friel and coworkers performed a molybdenum 5. A.S.P.E.N. Board of Directors and the Clinical Guidelines Task Force. balance study in 16 LBW infants on PN. They speculate that an Guidelines for the use of parenteral and enteral nutrition in adult and intravenous intake of 1 mcg/kg/d would be adequate for the pediatric patients [erratum published in: JPEN J Parenter Enteral Nutr. LBW infant. 2002;26:144]. JPEN J Parenter Enteral Nutr. 2002;26(suppl):1SA-138SA. The amount of molybdenum provided daily as part of the 6. Koletzko B, Goulet O, Hunt J, et al. Guidelines on paediatric parenteral background contamination of current PN formulations in the nutrition of the European Society of Paediatric Gastroenterology, Hepa- U.S. is uncertain. In Sweden (1977), the amount of assayed tology and Nutrition (ESPGHAN) and the European Society for Clinical molybdenum provided in a PN balance study was a mean of 9.9 Nutrition and Metabolism (ESPEN): 7. Iron, minerals and trace elements. 11 mcg/d (range, 8.6–11 mcg/d). In (1981), the amount J Pediatr Gastroenterol Nutr. 2005;41:S39-S46. of assayed molybdenum in PN products (used to compound PN 7. Staun M, Pironi L, Bozzetti F, et al. ESPEN guidelines on parenteral formulations) ranged from <5 to 15 mcg/L. The total amount of nutrition: home parenteral nutrition (HPN) in adult patients. Clin Nutr. 12 molybdenum infused daily was 10 mcg/d or less. In the U.S. 2009;28:467-479. (1989), the amount of daily molybdenum in a model PN formu- 8. Critical Care Nutrition website. Clinical Practice Guideline. http://www. lation was calculated (from individual assays of PN products) criticalcarenutrition.com/index.php?option=com_content&task=view&id 2 to be 244 mcg/d. No more recent publications of PN molybde- =17&Itemid=100. May 2009. Accessed August 13, 2010. num contamination amounts are available. 9. Abumrad NN, Schneider AJ, Steel D, Rogers LS. Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdate therapy. Recommendations for Molybdenum Am J Clin Nutr. 1981;34:2551-2559. in PN 10. Friel JK, MacDonald AC, Mercer CN, et al. Molybdenum requirements in low-birth-weight infants receiving parenteral and enteral nutrition. JPEN J Parenter Enteral Nutr. 1999;23;155-159. 1. Only 1 case of molybdenum deficiency in PN (none 11. Jacobson S, Wester PO. Balance study of twenty trace elements during in the diet) has been reported. total parenteral nutrition in man. Br J Nutr. 1977;37:107-126. 2. The amount of molybdenum provided as a contami- nant in current U.S. PN products is uncertain. 12. Phillips GD, Garnys VP. Trace element balance in adults receiving parenteral 3. The commercial U.S. availability of a single-entity nutrition: preliminary data. JPEN J Parenter Enteral Nutr. 1981;5:11-14. molybdenum injection should be retained. References 4. Plasma and urine molybdenum levels do not indicate nutrient status or requirements. 1. Otten JJ, Pitzi Hellwig J, Meyers LD, eds. Dietary Reference Intakes: 5. Practitioners should be alert for a constellation of The Essential Guide to Nutrient Requirements. Washington, DC: National signs and biochemical abnormalities described in Academies Press; 2006. the Abumrad et al9 case as potential indicators for 2. Dudrick SJ. Rhoads Lecture: a 45-year obsession and passionate pursuit molybdenum PN supplementation. of optimal nutrition support: puppies, pediatrics, surgery, geriatrics, home 6. Further research is needed to assess the level of TPN, A.S.P.E.N., et cetera. JPEN J Parenter Enteral Nutr. 2005;29(4): molybdenum contamination of U.S. PN products. 272-287. 3. Centers for Disease Control and Prevention (CDC). Lactic acidosis traced Appendix 10 References to thiamine deficiency related to nationwide shortage of multivitamins for 1. National Academy of Sciences, Institute of Medicine, Food and Nutri- total parenteral nutrition—United States, 1997. MMWR Morb Mortal Wkly tion Board. Molybdenum. In: Dietary Reference Intakes for Vitamin A, Rep. 1997;46(23):523-528. Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, 4. Centers for Disease Control (CDC). Deaths associated with thiamine-defi- Molybdenum, Nickel, Silicon, Vanadium, and Zinc. 2001. http://fnic. cient total parenteral nutrition [erratum in: MMWR Morb Mortal Wkly Rep. nal.usda.gov/nal_display/index.php?info_center=4&tax_level=4&tax_ 1989;38(5):79]. MMWR Morb Mortal Wkly Rep. 1989;38(3):43-46. subject=256&topic_id=1342&level3_id=5141&level4_id=10590. 5. Alloju M, Ehrinpreis MN. Shortage of intravenous multivitamin solution Accessed August 13, 2010. in the United States. N Engl J Med. 1997;337(1):54; author reply 54-55.

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6. Firdose R, Chalekson J, Leonard J, Smith M, Elamin EM. Is daily MVI 26. Biesalski HK. Vitamin E requirements in parenteral nutrition. Gastroenter- required in patients receiving parenteral nutrition? Int J Clin Pract. ology. 2009;137(5)(suppl):S92-S104. 2002;56(10):728-731. 27. Shearer MJ. Vitamin K in parenteral nutrition. Gastroenterology. 7. Romanski SA, McMahon MM. Metabolic acidosis and thiamine defi- 2009;137(5)(suppl):S105-S118. ciency. Mayo Clin Proc. 1999;74(3):259-263. 28. Berger MM. Vitamin C requirements in parenteral nutrition. Gastroenter- 8. Hahn JS, Berquist W, Alcorn DM, Chamberlain L, Bass D. Wernicke ology. 2009;137(5)(suppl):S70-S78. encephalopathy and beriberi during total parenteral nutrition attributable 29. Borum PR. Carnitine in parenteral nutrition. Gastroenterology. to multivitamin infusion shortage. Pediatrics. 1998;101(1):E10. 2009;137(5)(suppl):S129-S134. 9. Shike M. Copper in parenteral nutrition. Gastroenterology. 2009;137(5) 30. Buchman AL. The addition of choline to parenteral nutrition. Gastroenter- (suppl):S13-S17. ology. 2009;137(5)(suppl):S119-S128. 10. Moukarzel A. Chromium in parenteral nutrition: too little or too much? 31. Nielsen FH. Micronutrients in parenteral nutrition: boron, silicon, and Gastroenterology. 2009;137(5)(suppl):S18-S28. fluoride. Gastroenterology. 2009;137(5)(suppl):S55-S60. 11. Shenkin A. Selenium in intravenous nutrition. Gastroenterology. 32. Zimmermann MB. Iodine: it’s important in patients that require parenteral 2009;137(5)(suppl):S61-S69. nutrition. Gastroenterology. 2009;137(5)(suppl):S36-S46. 12. Jeejeebhoy K. Zinc: an essential trace element for parenteral nutrition. 33. Forbes A. Iron and parenteral nutrition. Gastroenterology. 2009;137(5) Gastroenterology. 2009;137(5)(suppl):S7-S12. (suppl):S47-S54. 13. Certain injectable multiple vitamin preparations, drugs for human use; 34. Hardy G. Manganese in parenteral nutrition: who, when, and why should drug efficacy study implementation. Fed Reg. 1972;37:15027. we supplement? Gastroenterology. 2009;137(5)(suppl):S29-S35. 14. American Medical Association. Guidelines for Multivitamin Prepara- 35. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Dietary Reference tions for Parenteral Use. Chicago, IL: Department of Foods and Nutrition, Intakes for Vitamin D and Calcium. Washington, DC: National Academies American Medical Association; 1975. Press; 2010. http://books.nap.edu/catalog/13050.html. Accessed July 7, 15. Multivitamin preparations for parenteral use: a statement by the Nutrition 2011. Advisory Group. JPEN J Parenter Enteral Nutr. 1979;3:258-262. 36. Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, 16. Parenteral multivitamin products; drugs for human use; drug efficacy study Selenium, and Carotenoids. Washington, DC: National Academies Press; implementation; amendment. Fed Reg. 2000;65:21200-21201. 2000. http://books.nap.edu/openbook.php?record_id=9810&page=192. 17. Guidelines for the use of vitamins, trace elements, calcium, magnesium, Accessed July 7, 2011. phosphorus in infants and children receiving total parenteral nutrition: 37. Singer P, Berger M, Van den Berghe G, et al. ESPEN guidelines on paren- report of the Subcommittee on Pediatric Parenteral Nutrient Requirements teral nutrition: intensive care. Clin Nutr. 2009;28:387-400. from the Committee on Clinical Practice Issues of the American Society 38. Greene HL, Hambidge M, Schanler R, Tsang R. Guidelines for the use of for Clinical Nutrition. Am J Clin Nutr. 1988;48:1324-1342. vitamins, trace elements, calcium, magnesium, and phosphorus in infant 18. Guidelines for essential trace element preparations for parenteral use. and children receiving total parenteral nutrition: report of the Subcommit- JAMA. 1979;24:2051-2054. tee on Pediatric Parenteral Nutrient Requirements from the Committee on 19. Guidelines for essential trace element preparations for parenteral use: a Clinical Practice Issues of the American Society for Clinical Nutrition. Am statement by the Nutrition Advisory Group. JPEN J Parenter Enteral Nutr. J Clin Nutr. 1988;48:1324-1342. 1979;3:263-267. 39. Tsang R, Uauy R, Koletzko B, Zlotkin SH, eds. Nutrition of the Preterm 20. Shils ME, White PL. Working conference on parenteral trace elements: spon- Infant: Scientific Basis and Practical Guidelines. Cincinnati, OH: Digital sored by NY Acad Med and AMA. Bull NY Acad Med. 1984;60:115-212. Educational Publishing; 2005. 21. Shils ME, Brown RO. Parenteral nutrition. In: Shils ME, Olsen JA, Shike 40. Zimmerman, M. . Endocrine Rev. 2009;30(4):376-409. M, eds. Modern Nutrition in Health and Disease. 9th ed. Philadelphia, PA: 41. Multivitamin preparations for parenteral use. A statement by the Nutrition Lea & Febiger; 1994. Advisory Group. American Medical Association Department of Foods and 22. National Advisory Group on Standards and Practice Guidelines for Paren- Nutrition, 1975. JPEN J Parenter Enteral Nutr. 1979;3:258-262. teral Nutrition. Safe practices for parenteral nutrition formulations. JPEN 42. Ross AC, Manson JE, Abrams SA, et al. The 2011 dietary reference intakes J Parenter Enteral Nutr. 1998;22:49-66. for calcium and vitamin D: what dietetics practitioners need to know. J Am 23. Mirtallo J, Canada T, Johnson D, et al; Task Force for the Revision of Diet Assoc. 2011;111:524-527. Safe Practices for Parenteral Nutrition. Safe practices for parenteral nutri- 43. Compher C, Pazianas M, Benedict S, Brown JC, Kinosian BP, Hise M. tion [published correction appears in JPEN J Parenter Enteral Nutr. Systemic inflammatory mediators and bone homeostasis in intestinal fail- 2006;30:177]. JPEN J Parenter Enteral Nutr. 2004;28(6):S39-S70. ure. JPEN J Parenter Enteral Nutr. 2007;31:142-147. 24. Buchman AL, Howard LJ, Guenter P, Nishikawa RA, Compher CW, Tap- 44. Corey B, Ackerman K, Allen P, Sceery N, Rafoth C. Vitamin D status of penden KA. Micronutrients in parenteral nutrition: too little or too much? New England home TPN patients—a snapshot of practice [abstract]. Nutr The past, present, and recommendations for the future. Gastroenterology. Clin Pract. 2009;24:110. 2009;137(5)(suppl):S1-S6. 45. Thomson P, Duerksen DR. Vitamin D deficiency in patients receiving 25. DeLuca HF. Vitamin D and the parenteral nutrition patient. Gastroenterol- home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2011;35(4): ogy. 2009;137(5)(suppl):S79-S91. 499-504.

Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 490 Nutrition in Clinical Practice 27(4)

46. Boullata J, Compher C, Schiavone P, et al. Oral vitamin D repletion in 66. Ito Y, Alcock NW, Shils ME. Chromium content of parenteral nutrition patients with parenteral nutrition–dependent intestinal failure [abstract]. solutions. JPEN J Parenter Enteral Nutr. 1990;14:610-614. Nutr Clin Pract. 2009;24(1):138-139. 67. Smith JL, Goos SM. Selenium nutriture in TPN: intake levels. JPEN J 47. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, Parenter Enteral Nutr. 1980;4:23-26. and prevention of vitamin D deficiency: an Endocrine Society clinical 68. Koo WWK, Kaplan LA, Bendon R, et al. Aluminum in parenteral nutrition practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930. solution—sources and possible alternative. JPEN J Parenter Enteral Nutr. 48. Boullata JI. Vitamin D supplementation: a pharmacologic perspective. 1986;10:591-595. Curr Opin Clin Nutr Metab Care. 2010;13(6):677-684. 69. Sedman AB, Klein GL, Merritt RJ, et al. Evidence of aluminum loading in 49. Koo WW, Sherman R, Succop P, Ho M, Buckley D, Tsang RC. Serum infants receiving . N Engl J Med. 1985;312:1337-1343. vitamin D metabolites in very low birth weight infants with and without 70. U.S. Department of Health and Human Services. Aluminum in large and rickets and fractures. J Pediatr. 1989;114(6):1017-1022. small volume parenterals used in total parenteral nutrition; amendment; 50. Cederblad G, Svenningsen N. Plasma carnitine and breast milk carnitine delay of effective date. Fed Reg. 2002;67:70691. intake in premature infants. J Pediatr Gastroenterol Nutr. 1986;5(4): 71. Buchman AL, Neely M, Grossie VB, et al. Organ heavy-metal accumula- 616-621. tion during parenteral nutrition is associated with pathologic abnormalities 51. Cairns PA, Stalker DJ. Carnitine supplementation of parenterally fed neo- in rats. Nutrition. 2001;17:600-606. nates. Cochrane Database Syst Rev. 2000;(4):CD000950. 72. Wolman SL, Anderson GH, Marliss EB, et al. Zinc in total parenteral 52. U.S. Food and Drug Administration. Sec. 412. [21 USC §350a]. Require- nutrition: requirements and metabolic effects. Gastroenterology. 1979;76: ments for infant formulas. http://www.fda.gov/RegulatoryInformation/ 458-467. Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChap- 73. Berger MM, Cavadini C, Bart A, et al. Cutaneous copper and zinc losses in terIVFood/ucm107864.htm. Accessed March 1, 2012. burns. Burns. 1992;18(5):373-380. 53. Dickerson RN. Manganese intoxication and parenteral nutrition. Nutrition. 74. Angstwurm MW, Engelmann L, Zimmermann T, et al. Selenium in 2001;15:689-693. intensive care (SIC): results of a prospective randomized, placebo-con- 54. Hardy IJ, Gillanders L, Hardy G. Is manganese an essential supplement trolled, multiple-center study in patients with severe systemic inflam- for parenteral nutrition? Curr Opin Clin Nutr Metab Care. 2008;11: matory response syndrome, sepsis, and septic shock. Crit Care Med. 289-296. 2007;35(1):118-126. 55. Howard L, Ashley C, Lyon D, Shenkin A. Autopsy tissue trace elements 75. Berger MM, Binnert C, Chiolero RL, et al. Trace element supplementation in 8 long-term parenteral nutrition patients who received the current U.S. after major burns increases burned skin trace element concentrations and Food and Drug Administration formulation. JPEN J Parenter Enteral modulates local protein metabolism but not whole-body substrate metabo- Nutr. 2007;31:388-396. lism. Am J Clin Nutr. 2007;85(5):1301-1306. 56. Milatovic D, Yin Z, Gupta RC, et al. Manganese induces oxidative impair- 76. Forceville X. Effects of high doses of selenium, as sodium selenite, in ment in cultured rat astrocytes. Toxicol Sci. 2007;98(1):198-205. septic shock patients a placebo-controlled, randomized, double-blind, 57. Blaszyk H, Wild PJ, Oliveira A, et al. Hepatic copper in patients receiv- multi-center phase II study—selenium and sepsis. J Trace Elem Med Biol. ing long-term total parenteral nutrition. J Clin Gastroenterol. 2005;39: 2007;21(suppl 1):62-65. 318-320. 77. Mishra V, Baines M, Perry SE, et al. Effect of selenium supplementation 58. Shearer CA, Bozian RC. Availability of trace elements in intravenous on biochemical markers and outcome in critically ill patients. Clin Nutr. hyperalimentation solutions. Drug Intell Clin Pharm. 1977;11:465-469. 2007;26(1):41-50. 59. Hauer EC, Kaminski MB. Trace metal profile of parenteral nutrition solu- 78. Andrews PJ, Avenell A, Noble DW, et al. Randomised trial of , tions. Am J Clin Nutr. 1978;31:264-268. selenium, or both, to supplement parenteral nutrition for critically ill 60. van Caillie M, Luijendijk I, Degenhart H, et al. Zinc content of intravenous patients. BMJ. 2011;342:d1542. solutions. Lancet. 1978;2:200-201. 79. Takagi Y, Okada A, Sando K, et al. Evaluation of indexes of in vivo manga- 61. Boddapati S, Yang K, Murty R. Intravenous solution compatibility and nese status and the optimal intravenous dose for adult patients undergoing filter-retention characteristics of trace element preparation. Am J Hosp home parenteral nutrition. Am J Clin Nutr. 2002;75:112-118. Pharm. 1981;38:1731-1736. 80. Bertinet DB, Tinivella M, Balzola FA, et al. Brain manganese deposition 62. Pluhator-Murton MM, Fedorak RN, Audette RJ, et al. Trace element con- and blood levels in patients undergoing home parenteral nutrition. JPEN J tamination of total parenteral nutrition, 1: contribution of component solu- Parenter Enteral Nutr. 2000;24(4):223-227. tions. JPEN J Parenter Enteral Nutr. 1999;23:222-227. 81. Mason KE. A conspectus of research on copper metabolism and require- 63. Hoffman RP, Ashby DS. Trace element concentrations in commercially ments of man. J Nutr. 1979;109:1979-2066. available solutions. Drug Intell Clin Pharm. 1976;10:74-76. 82. Shike M, Roulet M, Kurian R, et al. Copper metabolism and requirements 64. Jetton MM, Sullivan JF, Burch RE. Trace element contamination of intra- in total parenteral nutrition. Gastroenterology. 1981;81:290-297. venous solutions. Arch Intern Med. 1976;136:782-784. 83. Monasterio RP, Lascalea GE, Martínez LD, Wuilloud RG. Determination 65. Kurkus J, Alcock NW, Shils ME. Manganese content of large volume par- of Cr(VI) and Cr(III) species in parenteral solutions using a nanostructured enteral solutions and of nutrient additives. JPEN J Parenter Enteral Nutr. material packed-microcolumn and electrothermal atomic absorption 1984;8:254-257. spectrometry. J Trace Elem Med Biol. 2009;23:157-166.

Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013 A.S.P.E.N. Position Paper / Vanek et al 491

84. Leung FY. Elevated serum chromium in patients on total parenteral nutri- 95. Koto I, Vogelman JH, Dilman V, et al. Effect of supplementation with tion and the ionic species of contaminant chromium. Biol Trac Elem Res. chromium picolinate on titers to 5-hydroxymethyl uracil. Eur J 1995;50:221-228. Epidemiol. 1998;14:621-626. 85. Leung FY, Grace DM, Alfieri MA, et al. Abnormal trace elements in a 96. Hathcock JN. Vitamins and minerals: efficacy and safety. Am J Clin Nutr. patient on total parenteral nutrition with normal renal function. Clin Bio- 1997;66:427-437. chem. 1995;28:297-302. 97. Moukarzel A, Song MK, Buchman AL, et al. Excessive chromium intake 86. Mouser JF, Hak EB, Helms RA, et al. Chromium and zinc concentrations in children receiving total parenteral nutrition. Lancet. 1992;339:385-388. in pediatric patients receiving long-term parenteral nutrition. Am J Health 98. Via M, Scurlock C, Raikhelkar J, Di Luozzo G, Mechanick JI. Chromium Syst Pharm. 1999;56:1950-1956. infusion reverses extreme insulin resistance in a cardiothoracic ICU 87. Bougle D, Bureau F, Deschrevel G, et al. Chromium and parenteral nutri- patient. Clin Pract. 2008;23:325. tion in children. J Pediatr Gastroenterol Nutr. 1993;17:72-74. 99. Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, Bruce-Robertson 88. Food and Nutrition Board, Institute of Medicine. Chromium. In: Dietary A. , glucose intolerance, and neuropathy reversed Reference Intakes for Vitamin A, Vitamin K, Boron, Chromium, Copper, by chromium supplementation in a patient receiving long-term total par- Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and enteral nutrition. Am J Clin Nutr. 1977;30:531-538. Zinc. Washington, DC: National Academies Press, 2001:197-223. 100. Freund H, Atamian S, Fischer JE. Chromium deficiency during total par- 89. Marker M, Grübl A, Riedl O, Heinze G, Pohanka E, Kotz R. Metal- enteral nutrition. JAMA. 1979;241:496-498. on-metal hip implants: do they impair renal function in the long-term? 101. Brown RO, Forloines-Lynn S, Cross RE, Heizer WD. Chromium deficiency A 10-year follow-up study. Arch Orthop Trauma Surg. 2008;128: after long-term total parenteral nutrition. Dig Dis Sci.1986;31:661-664. 915-919. 102. Harraki B, Guiraud P, Rochat MH, et al. Influence of copper, iron, and 90. Albarracin CA, Fuqua BC, Evans JL, Goldfine ID. Chromium picolinate zinc on the physicochemical properties of parenteral admixture. J Par- and biotin combination improves glucose metabolism in treated, uncon- enter Sci Technol. 1993;47(5):199-204. trolled overweight to obese patients with . Diabetes Metab 103. Ganzoni AM. Intravenous iron-dextran: therapeutic and experimental pos- Res Rev. 2008;24:41-51. sibilities. Schweiz Med Wochensch. 1970;100:301-303. 91. Wasser WG, Feldman NS, D’Agati VD. Chronic renal failure after ingestion 104. Cicalese MP, Bruzzese E, Guarino A, Spagnuolo MI. Requesting iodine of over-the-counter chromium picolinate. Ann Intern Med. 1997;126:410. supplementation in children on parenteral nutrition. Clin Nutr. 2009; 92. Curulli J, Grabe DW, Gauthier I, et al. Chromium picolinate toxicity. Ann 28:256-259. Pharmacother. 1998;32:428-431. 105. Below H, Behrens-Baumann W, Bernhardt C, Völzke H, Kramer A, 93. Wani S, Weskamp C, Marple J, et al. Acute tubular necrosis associated Rudolph P. Systemic iodine absorption after preoperative antisepsis using with chromium picolinate–containing . Ann Pharmoco- povidone-iodine in cataract surgery—an open controlled study. Derma- ther. 2006;40:563-566. tology. 2006;212(suppl 1):41-46. 94. Stearns DM, Wise JP, Patierno SR, et al. Chromium (III) picolinate pro- 106. Howard L, Ament M, Fleming CR, Shike M, Steiger E. Current use and duces damage in Chinese hamster ovary cells. FASEB J. clinical outcome of home parenteral and enteral nutrition therapies in the 1995;9:1643-1648. United States. Gastroenterology. 1995;109:355-365.

Downloaded from ncp.sagepub.com by Karrie Derenski on April 1, 2013