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Trace Elements in Parenteral Nutrition: A Practical Guide for Dosage and Monitoring for Adult Patients Theresa A. Fessler Nutr Clin Pract 2013 28: 722 originally published online 25 October 2013 DOI: 10.1177/0884533613506596 The online version of this article can be found at: http://ncp.sagepub.com/content/28/6/722
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research-article2013
NCPXXX10.1177/0884533613506596Nutrition in Clinical PracticeFessler
Techniques & Procedures
Trace Elements in Parenteral Nutrition: A Practical Guide for Dosage and Monitoring for Adult Patients
Nutrition in Clinical Practice Volume 28 Number 6 December 2013 722–729 © 2013 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533613506596 ncp.sagepub.com hosted at online.sagepub.com
Theresa A. Fessler, MS, RDN, CNSC
Abstract Parenteral nutrition (PN) is a life-sustaining therapy for hundreds of thousands of people who have severe impairment of gastrointestinal function. Trace elements are a small but very important part of PN that can be overlooked during busy practice. Serious complications can result from trace element deficiencies and toxicities, and this is especially problematic during times of product shortages. Practical information on parenteral trace element use can be gleaned from case reports, some retrospective studies, and very few randomized controlled trials. A general knowledge of trace element metabolism and excretion, deficiency and toxicity symptoms, products, optimal dosages, and strategies for supplementation, restriction, and monitoring will equip practitioners to provide optimal care for their patients who depend on PN. (Nutr Clin Pract. 2013;28:722-729)
Keywords micronutrients; trace elements; nutritional support; home parenteral nutrition; parenteral nutrition
It is estimated that more than 337,000 hospitalized patients and over 39,000 home patients in the United States depend on parenteral nutrition (PN).1 To effectively manage PN therapy, practitioners must be aware of trace element (TE) requirements, toxicity and deficiency risks, and how to supplement or restrict TE content in PN. Of the 9 known essential TEs—chromium, copper, fluoride, iodine, iron, manganese, molybdenum, selenium, and zinc2—only 5 (chromium, copper, manganese, zinc, and selenium) have been routinely used in PN in the United States. 3 The numerous and complex physiologic functions of the TEs are reviewed in detail in other publications.2,4,5 Parenteral multiple trace element (multi-TE) products in the United States were developed using 1979 American Medical Association guidelines.6 Since then, complications from TE toxicities and deficiencies with PN use have made monitoring and dosage adjustment necessary, and a plan for reformulation of the multi-TE products is under way.3 Parenteral individual TE products are also available (on an inconsistent basis recently). Since 2011, the United States has had critical shortages and, by 2013, periods of complete lack of parenteral TE products.7,8 In May 2013, the U.S. Food and Drug Administration approved the importation and temporary use of a European parenteral multi-TE product to remedy this situation,9 and in some cases, oral TE supplements are useful. This article reviews information on adult parenteral TE needs and prevention of TE toxicities and deficiencies for patients who rely on PN. Oral and parenteral TE requirements and dosage amounts in standard multi-TE products are outlined in Table 1. Parenteral TE product information is in Table 2. Table 3 contains suggestions for monitoring TE status in PN-dependent patients, and
Table 4 provides strategies for optimal use of the different TE products when available and during severe product shortages. Information on TE deficiencies and toxicities in patients using PN was found by a search of the literature using OVID MEDLINE from 1960 to current, using the terms trace elements or copper, chromium, manganese, selenium, zinc, iron, iodine, fluoride, molybdenum, and parenteral nutrition, and limited to “human” and the English language; a Google search was also used.
Selenium (Se) Selenium (Se) is a constituent of several selenoproteins with many functions, including defense against oxidative stress, regulation of thyroid hormone activity, and reductases that regulate regeneration of vitamin C from oxidized metabolites, as well as some functions yet undiscovered. Oral Se is more than 90% absorbed, and it is excreted mainly in the urine. Body stores of Se are in selenomethionine and liver glutathione peroxidase.4
From Morrison Healthcare/University of Virginia Health System, Charlottesville, Virginia. Financial disclosure: None declared. This article originally appeared online on October 25, 2013. Corresponding Author: Theresa A. Fessler, MS, RD, CNSC, Nutrition Support Specialist, Morrison Healthcare/University of Virginia Health System, Charlottesville, VA 22908, USA. Email: [email protected].
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Table 1. Oral and Parenteral Trace Element Requirements and Dosage Guidelines for Adults. One Daily Dose of Multi-TE Productsa
TE
Dietary Reference Intakes for Oral Intake
Parenteral Requirement/ Recommended Daily Doses
Addamel N U.S.
Selenium (Se)
55 mcg, 60 mcg (pregnancy), 60 mcg; 100 mcg or more if 0–60 mcg 70 mcg (lactation) RDA deficiency exists Zinc (Zn) 8 mg (F), 11 mg (M, 4 mg; more if large amounts 3–5 mg pregnancy), 12 mg of GI fluid loss (lactation) RDA Copper (Cu) 900 mcg, 1000 mcg 0.3 mg; 0.4–0.5 mg (high GI 1–1.2 mg (pregnancy), 1300 mcg fluid loss); decrease by 0.15 (lactation) RDA mg for severe cholestasis 1 mg to treat deficiency Manganese (Mn) 1.8 mg (F), 2.3 mg (M) 55 mcg; omit if toxicity or 300–800 mcg 2.0 mg (pregnancy), 2.6 mg elevated whole-blood Mn (lactation) AI Chromium (Cr) 25 mcg (F), 35 mcg (M), 10 mcg; consider omitting in 10–12 mcg age 19–50 y, 20 mcg (F), patients with renal failure 30 mcg (M), age ≥51 y 30 and elevated serum Cr mcg (pregnancy), 45 mcg (lactation)AI Iron (Fe) 8 mg (M), 18 mg (F), ages 1 mg, 1.5 mg (menstruation None 19–50 y, 8 mg, age ≥51 or blood loss); up to 2 mg y 9 mg (lactation), 27 mg during pregnancy (pregnancy) None Iodine (I) 150 mcg, 220 mcg 0.1 mg (Europe)b (pregnancy), 290 mcg (lactation) RDA Molybdenum (Mo) 45 mcg, 50 mcg (pregnancy, 20 mcg (Europe)b None lactation) RDA Fluoride (F) 3 mg (F), 4 mg (M) AI 1 mg (Europe)b None
European
5 mL
10 mL
24–70 mcg
16 mcg
32 mcg
3.25–10 mg
3.25 mg
6.5 mg
0.24–1.24 mg
0.65 mg
1.3 mg
100–550 mcg
135 mcg
270 mcg
5–15 mcg
5 mcg
10 mcg
0.55–2 mg
0.55 mg
1.1 mg
0.0015–0.13 mg 0.065 mg
0.13 mg
10–25 mcg
9.5 mcg
19 mcg
0.475–1.45 mg 0.475 mg
0.95 mg
AI, adequate intake; F, female; GI, gastrointestinal; M, male; RDA, recommended dietary allowance; TE, trace element. a Using varied amounts of the available multi-TE products. Refer to Vanek et al3 and the following websites for information on dosage content of multiTE and individual TE products: American Regent (www.americanregent.com) and Fresenius-Kabi’s Addamel product information site (http://www. apppharma.com/images/documents/our-products/DHCP_Addamel_N_vF_May_29_2013.pdf). b ESPEN Guidelines on Parenteral Nutrition: Surgery (http://espen.info/documents/0909/Surgery.pdf).
From 1979–2003, numerous case reports described Se deficiency in adults and children who used PN lacking in Se for periods ranging from months to years.10-12 Effects of Se deficiency include cardiomyopathy (in some cases fatal), skeletal myopathy, muscle weakness, macrocytosis, whitened nail beds, loss of pigmentation of hair and skin,10,11 and, in infants, alopecia and growth retardation.12 The literature contains no reports of Se toxicity in patients using PN. In the United States, Se has been included in some of the adult but not in any of the pediatric or neonatal multi-TE products.3 Se has been found as a contaminant, at 21 mcg/2 L of PN.13 Parenteral doses of 60–100 mcg/d Se are sufficient for most adults, yet do not maintain ideal serum levels in all patients.14,15 Se needs are higher in malnutrition, critical illness, and burn injury and vary with genetic differences.16,17 Serum and plasma Se tests are used in practice,18,19 with concentrations below normal in patients with Se deficiency
and/or with no Se in PN.4,10-12,20 Plasma Se decreases during stress and inflammatory response, and concurrent tests of C-reactive protein can be helpful in interpreting laboratory results.16,21 Plasma Se is contained mostly in Selenoprotein P and extracellular glutathione peroxidase.16 In red blood cells, Se and glutathione peroxidase activity can be maintained for up to 3 and 6 months, respectively in patients receiving Se-deficient PN, and thus serum Se is a better indicator of recent intake.22
Zinc (Zn) Zinc (Zn) is a cofactor in numerous enzymatic reactions involved in the metabolism of protein, fat, and carbohydrates, and it is essential for growth and development, immune function, the structure of some proteins and enzymes, and regulation of gene expression. More than 85% of body Zn is in skeletal muscle and
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Table 2. Adult Parenteral Trace Element Products. Product Multitrace-4a Multitrace-4 Concentratea 4-Trace Elementsb Multitrace-5a Multitrace-5 Concentratea Addamel Nc Desired “ideal” content
Volume, Zinc Copper Manganese Chromium Selenium mL (Zn), mg (Cu), mg (Mn), mcg (Cr), mcg (Se), mcg
Iron Molybdenum (Fe), mg (Mo), mcg
Iodine (I), mg
Fluoride (F), mg
1 1
1 5
0.4 1
100 500
4 10
0 0
— —
— —
— —
— —
5 1 1
4 1 5
1 0.4 1
800 100 500
10 4 10
0 20 60
— — —
— — —
— — —
— — —
1.3 0.3– 0.5
270 55
10 0–1
32 60–100
1.1 0–1
19 ?
0.13 ?
0.95 ?
10 5
6.5 5
Individual trace elements (TEs) are also available for Cu,a,b Zn,a,b, Mn,a,b Cr,a,b Se,a and Mo.a Fe is available as a separate infusion: Injectafer ferric carboxymaltose,a Dexferrum iron dextran,a InfeD iron dextrose,d Venofer iron sucrose,a and Ferrlecit sodium ferric gluconate.e,3 a American Regent, Shirley, NY (www.americanregent.com)—multi-TE products are no longer widely available at time of this writing; individual element TE products are available on an inconsistent basis. b Hospira, Lake Forest, IL (http://www.hospira.com/search?q=trace+metal&fq=on)—multi-TE products are no longer available, and some individual element TE products may become available on an inconsistent basis. c Fresenius-kabi, various locations worldwide, corporate headquarters Bad Homburg, Germany (www.fresenius-kabi.us and http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM355392.pdf). d Watson Pharmaceuticals (now Actavis) Parsippany, NJ (http://www.infed.com/index.asp). e Ferrlecit sodium ferric gluconate complex in sucrose injection (sanofi-aventis U.S. LLC, Sanofi U.S. Bridgewater, NJ www.ferrlecit.com/default.aspx).
Table 3. Suggestions for Trace Element Monitoring for Patients Using PN. Trace Element
Monitoring Guidelines
Selenium (Se) Zinc (Zn) Copper (Cu)
Watch for signs of deficiency every 1–3 months. Check serum Se if deficiency suspected or symptoms are present. Watch for signs of deficiency every 1–3 months. If PN does not contain Cu, watch for deficiency symptoms monthly. Check serum Cu every 6 months if standard multi-TE product is used in patients with cholestasis or liver dysfunction or if deficiency is suspected. Manganese (Mn) If standard multi-TE products are used, watch for signs of Mn toxicity every 1–3 months. Check whole-blood Mn if symptoms of toxicity are present, or every 3–4 months, or monthly for patients with significant cholestasis. Chromium (Cr) If providing standard multi-TE products on a daily basis, consider checking serum Cr every 6 months in patients with renal insufficiency. Iron (Fe) Monitor serum ferritin and iron studies every 3 months. PN, parenteral nutrition; TE, trace element.
bone, and only 0.1% is in the plasma, bound primarily to serum albumin. Zn is absorbed mainly in the jejunum, with higher efficiency in a Zn-deficient state.5 Zn is secreted into the intestine and excreted in feces, with less than 10% lost in urine, and smaller amounts lost from skin, hair, and body fluids.2,5 A typical PN dose of 3–5 mg Zn meets estimated adult parenteral needs of 2.5–5 mg/d.3 Zn has been found to contaminate PN at about 1.1 mg/2 L.13 The recommendation to replace 17 mg of Zn per kilogram of stool or ileostomy output and 12 mg of Zn per kilogram of duodenal or jejunal fistula drainage comes from 1 study by Wolman et al,23 in which Zn losses were dependent on amounts of gastrointestinal (GI) fluid lost, with significantly less Zn in the GI fluids from patients who had massive small bowel resection. Patients without diarrhea had a positive Zn balance with 3 mg/d Zn in PN. Zn needs may be increased as high as 40 mg/d for patients with major burns of >20% body surface area.24
Many cases of Zn deficiency with use of PN lacking in Zn were documented mostly in the 1970s, before routine use of TEs in PN. Deficiency can occur from 14 days to 3 months or more.25-27 The main manifestation of Zn deficiency is skin lesions (acrodermatitis enteropathica); other symptoms include alopecia, stomatitis, glossitis, perioral ulcers, periungual lesions,25,26 and, in 1 case, intractable vomiting.27 Zn toxicity with PN has been documented only in instances of large dosage errors (hyperamylasemia in 6 patients who received around 50–75 mg/d Zn28) and 1 report of death after a massive overdose of 1.7 g elemental Zn in PN.29 Plasma Zn is low in severe deficiency,25 yet blood tests are not always reliable, since plasma Zn is tightly regulated and maintained in the normal range until Zn restriction is prolonged and severe, and plasma Zn is decreased during physiologic stress, trauma, and infection.5
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Table 4. Utilization and Rationing Guidelines for Parenteral TE Products. Parenteral individual TE products ➢ Use along with other individual TE products for cases in which multi-TE product is omitted. ➢ Selenium can be used in conjunction with standard 4-element multi-TE products. ➢ To treat specific deficiencies—selenium, zinc, and copper. ➢ Individual manganese and chromium products are usually not necessary. ➢ Separate IV iron infusion is to be used for iron deficiency that cannot be treated with oral iron. Parenteral multi-TE products ➢ Omit use for patients with risk for or symptoms of manganese or copper toxicity or with elevated serum copper or whole-blood manganese concentrations. ➢ Consider omitting or decrease dose in PN for patients with renal dysfunction and elevated serum chromium. ➢ Use iron-containing products in lipid-free PN admixtures until/unless more stability information is available for use with PN admixtures in the United States. During times of parenteral TE shortage or product unavailability ➢ Ration parenteral selenium and other TE products for preferential use in neonatal and pediatric PN. ➢ Ration 1 standard multi-TE dose 3 times per week or, if necessary, one-half dose 3 times per week. ➢ Seek supplies of zinc, selenium, and copper (for which deficiencies are more likely). ➢ Use various oral multivitamin-mineral supplements (that include specific TEs needed) or use separate oral trace element supplements whenever possible for patients with sufficient GI absorptive capacity. ➢ Read product labels—some multivitamin-mineral supplements do not contain both selenium and zinc. ➢ Keep in mind the DRIs for oral TE needs and increase dosages for patients with short bowel or malabsorption. ➢ Keep ongoing watch on storeroom inventory, supplier availability, manufacturer updates, and the following websites: U.S. Food and Drug Administration—“Drug shortages”: http://www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm. American Society of Health-System Pharmacists Drug Shortages Resource Center: http://www.ashp.org/shortages?WT.ac=hp%5FP opLinks%5FDrug%5FShortages American Society of Parenteral and Enteral Nutrition (A.S.P.E.N.) Drug Shortages Update: http://www.nutritioncare.org/ Professional_Resources/Drug_Shortages_Update/ DRI, Dietary Reference Intake; GI, gastrointestinal; IV, intravenous; PN, parenteral nutrition; TE, trace element.
Copper (Cu) Copper (Cu) is a component of several metalloenzymes that function as oxidases in numerous reactions, including deactivation of histamine, degradation of serotonin, catecholamine metabolism, and oxidation of ferrous iron for binding to transferrin. Cu is also necessary for the development of connective tissues, melanin synthesis, energy production, and defense against oxidative damage.5 Nearly two-thirds of the body’s Cu is in the skeleton and muscle, and 60%−95% of plasma Cu is bound to ceruloplasmin. Intestinal absorption of Cu varies from 5 mg/d to >50% with an intake 90% is excreted in urine. In an adult’s body, 70%−80% of I is in the thyroid gland, and it functions as a part of thyroid hormones (thyroxine and triiodothyronine). In I deficiency, the thyroid gland enlarges (goiter), thyroglobulin elevates, and urinary I decreases.58 The most serious effects of I deficiency are during pregnancy and in childhood—fetal death, cretinism, abnormal growth, and mental retardation.2 F is needed for bone health, and about 99% of the F in the body is in bones and teeth. Intestinal absorption of F is 50%, and it is excreted in urine. Urinary excretion of F is greater for adults than for children.2 Studies are needed to determine if parenteral F prevents PN-associated osteopenia or if it might even be detrimental to bone health for adults.59 Researchers in France found that patients received greater than recommended
amounts of F from the amount provided in their PN along with F from orally ingested mineral water and tea, and they expressed concern for possible F toxicity risk.60
General Considerations Laboratory testing for TE status is expensive and of limited practicality, and thus blood tests should be limited to those patients who are at high risk or manifest symptoms of toxicity or deficiency and who will be using PN for 4 months or more. Reference ranges for blood TE concentrations differ among different laboratories.18,19 Blood samples for TE tests are often sent out to larger regional laboratories. Many healthcare workers are not familiar with TE blood tests, so it is important to communicate clearly the particular test needed as well as the specific requirements for it, such as special collection tubes, and techniques to avoid sample contamination.18,19 Separate IV infusions of pharmacologic TE doses of up to 500 mcg Se, 4 mg Cu, and 40 mg Zn have been recommended for use in critically ill burn patients since some studies have shown association of these high doses with improved wound healing and a significant reduction in the incidence of nocosomial pneumonia.17,24,61 In these cases, Se, Cu, and Zn were given as separate IV infusions and not associated with PN use. More study is needed on this subject, and of course, the use of large doses of parenteral TEs is not feasible or recommended during periods of nationwide TE product shortages. During severe shortage or unavailability of parenteral TE products, oral TE supplements are available over the counter, in various forms, dosages, and brands, and can be used for patients who have some GI absorptive capacity. Fe, Se, Zn, Cu, Cr, I, and Mo can be obtained in oral tablet, capsule, and liquid formulas. Fe, Zn, Cr, and I are also available in oral lozenges. Many oral multivitamin-mineral supplements also contain TEs in various amounts and combinations.
Summary Trace elements are a very important part of PN therapy both in the hospital and in long-term home care. Knowledge gained from the literature and in clinical practice is useful in gleaning practical guidelines for TE use in PN. Information about TE products, requirements, metabolism, toxicities and deficiencies, and monitoring can equip practitioners to provide optimal care for their patients who use PN.
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multivitamin and multi-trace element products. Nutr Clin Pract. 2012;27: 440-491. 4. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academies Press; 2000. 5. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2001. 6. American Medical Association Department of Foods and Nutrition. Guidelines for essential trace element preparations for parenteral use: a statement by an expert panel. JAMA. 1979;241(19):2051-2054. 7. Mirtallo JM, Holcombe B, Kochevar M. Parenteral nutrition product shortages: the A.S.P.E.N. strategy. Nutr Clin Pract. 2012;27:385-391. 8. American Society for Parenteral and Enteral Nutrition. Parenteral nutrition trace element product shortage considerations. May 19, 2011. http:// www.nutritioncare.org/News/Parenteral_Nutrition_Trace_Element_ Product_Shortage_Considerations/. Accessed June 29, 2013. 9. Fresenius Kabi USA, LLC. Adult multi-trace element availability. http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/ UCM355392.pdf 10. Yusef SW, Rehman Q, Casscells W. Cardiomyopathy in association with selenium deficiency: a case report. JPEN J Parenter Enteral Nutr. 2002;26(1):63-66. 11. Ishida T, Himeno K, Torigoe Y, et al. Selenium deficiency in a patient with Crohn’s disease receiving long-term total parenteral nutrition. Intern Med. 2003;42(2):154-157. 12. Masumoto K, Nagata K, Higashi M, et al. Clinical features of selenium deficiency in infants receiving long-term nutritional support. Nutrition. 2007;23(11-12):782-787. 13. Pluhator-Murton M, Fedorak RN, Audete RJ, Marriage BJ, Yatscoff RW, Gramlich LM. Trace element contamination of total parenteral nutrition: 1. Contribution of component solutions. JPEN J Parenter Enteral Nutr. 1999;23:222-227. 14. Forbes GM, Forbes A. Micronutrient status in patients receiving home parenteral nutrition. Nutrition. 1997;13:941-944. 15. Btaiche I, Carver L, Welch KB. Dosing and monitoring of trace elements in long-term home parenteral nutrition patients. JPEN J Parenter Enteral Nutr. 2011;35:736-747. 16. Shenkin A. Selenium in intravenous nutrition. Gastroenterology. 2009;137(5)(suppl):S61-S69. 17. Hardy G, Hardy I, Manzanares W. Selenium supplementation in the critically ill. Nutr Clin Pract. 2012;27(1):21-33. 18. Fischback FT, Dunning MB. Appendix D: minerals in human nutrition. In: Manual of Laboratory and Diagnostic Tests. 8th ed. Philadelphia, PA: Wolters Kluwer Health, Lippincott Williams & Wilkins; 2009. 19. Quest Diagnostics Test Center. http://www.questdiagnostics.com/testcenter/TestCenterHome.action. Accessed July 28, 2013. 20. Rannem T, Ladefoged K, Hylander E, Hegnhoj J, Staun M. Selenium depletion in patients with gastrointestinal diseases: are there any predictive factors? Scand J Gastroenterol. 1998;33(10):1057-1061. 21. Maehira F, Luyo G, Miyagi I, et al. Alterations of serum selenium concentrations in the acute phase of pathological conditions. Clin Chim Acta. 2002;316:137-146. 22. Hatanaka N, Nakaden H, Yamamoto Y, Matsuo S, Fujikawa T, Matsusue S. Selenium kinetics and changes in glutathione peroxidase activities in patients receiving long-term parenteral nutrition and effects of supplementation with selenite. Nutrition. 2000;16:22-26. 23. Wolman SL, Anderson GH, Marliss EB, Jeejeebhoy KN. Zinc in total parenteral nutrition: requirements and metabolic effects. Gastroenterology. 1979;76:458-467. 24. Berger MM, Shenkin A. Trace element requirements in critically ill burned patients. J Trace Elem Med Biol. 2007;21(suppl 1):44-48.
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in chronic idiopathic intestinal pseudoobstruction. Nutrition. 1998;14: 291-295. 47. Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, Bruce-Robertson A. Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition. Am J Clin Nutr. 1977;30:531-538. 48. Leung FY, Galbraith LV. Elevated serum chromium in patients on total parenteral nutrition and the ionic species of contaminant chromium. Biol Trace Elem Res. 1995;50(3):221-228. 49. Moukarzel A. Chromium in parenteral nutrition: too little or too much? Gastroenterology. 2009;137(5)(suppl):S18-S28. 50. Khaodhiar L, Keane-Ellison M, Tawa NE, Thibault A, Burke PA, Bistrian BR. Iron deficiency anemia in patients receiving home total parenteral nutrition. JPEN J Parenter Enteral Nutr. 2002;26(2):114-119. 51. Forbes A. Iron and parenteral nutrition [published correction appears in Gastroenterology. 2010;139(1):360]. Gastroenterology. 2009;137(5) (suppl):S47-S54. 52. Auerbach M, Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety. Hematology Am Soc Hematol Educ Program. 2010;2010:338-347. 53. Shenkin A, Fraser WD, McLelland AJD, Fell GS, Garden OJ. Maintenance of vitamin and trace element status in intravenous nutrition using a complete nutritive mixture. JPEN J Parenter Enteral Nutr. 1987;11:238-242.
54. Iliano L, Delanghe M, van Den Baviere H, Lauwers A. Effect of electrolytes in the presence of some trace elements on the stability of all-inone emulsion mixtures for total parenteral nutrition. J Clin Hosp Pharm. 1984;9:87-93. 55. Burns DL, Mascioli EA, Bistrian B. Effect of iron-supplemented total parenteral nutrition in patients with iron deficiency anemia. Nutrition. 1996;12(6):411-415. 56. MacKay M, Rusho W, Jackson D, McMillin G, Winther B. Physical and chemical stability of iron sucrose in parenteral nutrition. Nutr Clin Pract. 2009;24(6):733-737. 57. Abumrad NN, Schneider AJ, Steel D, Rogers LS. Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdate therapy. Am J Clin Nutr. 1981;34:2551-2559. 58. Zimmerman MB. Iodine: it’s important in patients that require parenteral nutrition. Gastroenterology. 2009;137(5):S36-S46. 59. Nielsen FH. Micronutrients in parenteral nutrition: boron, silicon, and fluoride. Gastroenterology. 2009;135(5)(suppl):S55-S60. 60. Boulétreau PH, Bost M, Fontanges E, et al. Fluoride exposure and bone status in patients with chronic intestinal failure who are receiving home parenteral nutrition. Am J Clin Nutr. 2006;83:1429-1437. 61. Berger MM, Eggimann P, Heyland DK, et al. Reduction of nosocomial pneumonia after major burns by trace element supplementation: aggregation of two randomized trials. Crit Care. 2006;10:R153.
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Trace Elements in Parenteral Nutrition: A Practical Guide for Dosage and Monitoring for Adult Patients Theresa A. Fessler Nutr Clin Pract 2013 28: 722 originally published online 25 October 2013 DOI: 10.1177/0884533613506596 The online version of this article can be found at: http://ncp.sagepub.com/content/28/6/722
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506596
research-article2013
NCPXXX10.1177/0884533613506596Nutrition in Clinical PracticeFessler
Techniques & Procedures
Trace Elements in Parenteral Nutrition: A Practical Guide for Dosage and Monitoring for Adult Patients
Nutrition in Clinical Practice Volume 28 Number 6 December 2013 722–729 © 2013 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533613506596 ncp.sagepub.com hosted at online.sagepub.com
Theresa A. Fessler, MS, RDN, CNSC
Abstract Parenteral nutrition (PN) is a life-sustaining therapy for hundreds of thousands of people who have severe impairment of gastrointestinal function. Trace elements are a small but very important part of PN that can be overlooked during busy practice. Serious complications can result from trace element deficiencies and toxicities, and this is especially problematic during times of product shortages. Practical information on parenteral trace element use can be gleaned from case reports, some retrospective studies, and very few randomized controlled trials. A general knowledge of trace element metabolism and excretion, deficiency and toxicity symptoms, products, optimal dosages, and strategies for supplementation, restriction, and monitoring will equip practitioners to provide optimal care for their patients who depend on PN. (Nutr Clin Pract. 2013;28:722-729)
Keywords micronutrients; trace elements; nutritional support; home parenteral nutrition; parenteral nutrition
It is estimated that more than 337,000 hospitalized patients and over 39,000 home patients in the United States depend on parenteral nutrition (PN).1 To effectively manage PN therapy, practitioners must be aware of trace element (TE) requirements, toxicity and deficiency risks, and how to supplement or restrict TE content in PN. Of the 9 known essential TEs—chromium, copper, fluoride, iodine, iron, manganese, molybdenum, selenium, and zinc2—only 5 (chromium, copper, manganese, zinc, and selenium) have been routinely used in PN in the United States. 3 The numerous and complex physiologic functions of the TEs are reviewed in detail in other publications.2,4,5 Parenteral multiple trace element (multi-TE) products in the United States were developed using 1979 American Medical Association guidelines.6 Since then, complications from TE toxicities and deficiencies with PN use have made monitoring and dosage adjustment necessary, and a plan for reformulation of the multi-TE products is under way.3 Parenteral individual TE products are also available (on an inconsistent basis recently). Since 2011, the United States has had critical shortages and, by 2013, periods of complete lack of parenteral TE products.7,8 In May 2013, the U.S. Food and Drug Administration approved the importation and temporary use of a European parenteral multi-TE product to remedy this situation,9 and in some cases, oral TE supplements are useful. This article reviews information on adult parenteral TE needs and prevention of TE toxicities and deficiencies for patients who rely on PN. Oral and parenteral TE requirements and dosage amounts in standard multi-TE products are outlined in Table 1. Parenteral TE product information is in Table 2. Table 3 contains suggestions for monitoring TE status in PN-dependent patients, and
Table 4 provides strategies for optimal use of the different TE products when available and during severe product shortages. Information on TE deficiencies and toxicities in patients using PN was found by a search of the literature using OVID MEDLINE from 1960 to current, using the terms trace elements or copper, chromium, manganese, selenium, zinc, iron, iodine, fluoride, molybdenum, and parenteral nutrition, and limited to “human” and the English language; a Google search was also used.
Selenium (Se) Selenium (Se) is a constituent of several selenoproteins with many functions, including defense against oxidative stress, regulation of thyroid hormone activity, and reductases that regulate regeneration of vitamin C from oxidized metabolites, as well as some functions yet undiscovered. Oral Se is more than 90% absorbed, and it is excreted mainly in the urine. Body stores of Se are in selenomethionine and liver glutathione peroxidase.4
From Morrison Healthcare/University of Virginia Health System, Charlottesville, Virginia. Financial disclosure: None declared. This article originally appeared online on October 25, 2013. Corresponding Author: Theresa A. Fessler, MS, RD, CNSC, Nutrition Support Specialist, Morrison Healthcare/University of Virginia Health System, Charlottesville, VA 22908, USA. Email: [email protected].
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Table 1. Oral and Parenteral Trace Element Requirements and Dosage Guidelines for Adults. One Daily Dose of Multi-TE Productsa
TE
Dietary Reference Intakes for Oral Intake
Parenteral Requirement/ Recommended Daily Doses
Addamel N U.S.
Selenium (Se)
55 mcg, 60 mcg (pregnancy), 60 mcg; 100 mcg or more if 0–60 mcg 70 mcg (lactation) RDA deficiency exists Zinc (Zn) 8 mg (F), 11 mg (M, 4 mg; more if large amounts 3–5 mg pregnancy), 12 mg of GI fluid loss (lactation) RDA Copper (Cu) 900 mcg, 1000 mcg 0.3 mg; 0.4–0.5 mg (high GI 1–1.2 mg (pregnancy), 1300 mcg fluid loss); decrease by 0.15 (lactation) RDA mg for severe cholestasis 1 mg to treat deficiency Manganese (Mn) 1.8 mg (F), 2.3 mg (M) 55 mcg; omit if toxicity or 300–800 mcg 2.0 mg (pregnancy), 2.6 mg elevated whole-blood Mn (lactation) AI Chromium (Cr) 25 mcg (F), 35 mcg (M), 10 mcg; consider omitting in 10–12 mcg age 19–50 y, 20 mcg (F), patients with renal failure 30 mcg (M), age ≥51 y 30 and elevated serum Cr mcg (pregnancy), 45 mcg (lactation)AI Iron (Fe) 8 mg (M), 18 mg (F), ages 1 mg, 1.5 mg (menstruation None 19–50 y, 8 mg, age ≥51 or blood loss); up to 2 mg y 9 mg (lactation), 27 mg during pregnancy (pregnancy) None Iodine (I) 150 mcg, 220 mcg 0.1 mg (Europe)b (pregnancy), 290 mcg (lactation) RDA Molybdenum (Mo) 45 mcg, 50 mcg (pregnancy, 20 mcg (Europe)b None lactation) RDA Fluoride (F) 3 mg (F), 4 mg (M) AI 1 mg (Europe)b None
European
5 mL
10 mL
24–70 mcg
16 mcg
32 mcg
3.25–10 mg
3.25 mg
6.5 mg
0.24–1.24 mg
0.65 mg
1.3 mg
100–550 mcg
135 mcg
270 mcg
5–15 mcg
5 mcg
10 mcg
0.55–2 mg
0.55 mg
1.1 mg
0.0015–0.13 mg 0.065 mg
0.13 mg
10–25 mcg
9.5 mcg
19 mcg
0.475–1.45 mg 0.475 mg
0.95 mg
AI, adequate intake; F, female; GI, gastrointestinal; M, male; RDA, recommended dietary allowance; TE, trace element. a Using varied amounts of the available multi-TE products. Refer to Vanek et al3 and the following websites for information on dosage content of multiTE and individual TE products: American Regent (www.americanregent.com) and Fresenius-Kabi’s Addamel product information site (http://www. apppharma.com/images/documents/our-products/DHCP_Addamel_N_vF_May_29_2013.pdf). b ESPEN Guidelines on Parenteral Nutrition: Surgery (http://espen.info/documents/0909/Surgery.pdf).
From 1979–2003, numerous case reports described Se deficiency in adults and children who used PN lacking in Se for periods ranging from months to years.10-12 Effects of Se deficiency include cardiomyopathy (in some cases fatal), skeletal myopathy, muscle weakness, macrocytosis, whitened nail beds, loss of pigmentation of hair and skin,10,11 and, in infants, alopecia and growth retardation.12 The literature contains no reports of Se toxicity in patients using PN. In the United States, Se has been included in some of the adult but not in any of the pediatric or neonatal multi-TE products.3 Se has been found as a contaminant, at 21 mcg/2 L of PN.13 Parenteral doses of 60–100 mcg/d Se are sufficient for most adults, yet do not maintain ideal serum levels in all patients.14,15 Se needs are higher in malnutrition, critical illness, and burn injury and vary with genetic differences.16,17 Serum and plasma Se tests are used in practice,18,19 with concentrations below normal in patients with Se deficiency
and/or with no Se in PN.4,10-12,20 Plasma Se decreases during stress and inflammatory response, and concurrent tests of C-reactive protein can be helpful in interpreting laboratory results.16,21 Plasma Se is contained mostly in Selenoprotein P and extracellular glutathione peroxidase.16 In red blood cells, Se and glutathione peroxidase activity can be maintained for up to 3 and 6 months, respectively in patients receiving Se-deficient PN, and thus serum Se is a better indicator of recent intake.22
Zinc (Zn) Zinc (Zn) is a cofactor in numerous enzymatic reactions involved in the metabolism of protein, fat, and carbohydrates, and it is essential for growth and development, immune function, the structure of some proteins and enzymes, and regulation of gene expression. More than 85% of body Zn is in skeletal muscle and
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Table 2. Adult Parenteral Trace Element Products. Product Multitrace-4a Multitrace-4 Concentratea 4-Trace Elementsb Multitrace-5a Multitrace-5 Concentratea Addamel Nc Desired “ideal” content
Volume, Zinc Copper Manganese Chromium Selenium mL (Zn), mg (Cu), mg (Mn), mcg (Cr), mcg (Se), mcg
Iron Molybdenum (Fe), mg (Mo), mcg
Iodine (I), mg
Fluoride (F), mg
1 1
1 5
0.4 1
100 500
4 10
0 0
— —
— —
— —
— —
5 1 1
4 1 5
1 0.4 1
800 100 500
10 4 10
0 20 60
— — —
— — —
— — —
— — —
1.3 0.3– 0.5
270 55
10 0–1
32 60–100
1.1 0–1
19 ?
0.13 ?
0.95 ?
10 5
6.5 5
Individual trace elements (TEs) are also available for Cu,a,b Zn,a,b, Mn,a,b Cr,a,b Se,a and Mo.a Fe is available as a separate infusion: Injectafer ferric carboxymaltose,a Dexferrum iron dextran,a InfeD iron dextrose,d Venofer iron sucrose,a and Ferrlecit sodium ferric gluconate.e,3 a American Regent, Shirley, NY (www.americanregent.com)—multi-TE products are no longer widely available at time of this writing; individual element TE products are available on an inconsistent basis. b Hospira, Lake Forest, IL (http://www.hospira.com/search?q=trace+metal&fq=on)—multi-TE products are no longer available, and some individual element TE products may become available on an inconsistent basis. c Fresenius-kabi, various locations worldwide, corporate headquarters Bad Homburg, Germany (www.fresenius-kabi.us and http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM355392.pdf). d Watson Pharmaceuticals (now Actavis) Parsippany, NJ (http://www.infed.com/index.asp). e Ferrlecit sodium ferric gluconate complex in sucrose injection (sanofi-aventis U.S. LLC, Sanofi U.S. Bridgewater, NJ www.ferrlecit.com/default.aspx).
Table 3. Suggestions for Trace Element Monitoring for Patients Using PN. Trace Element
Monitoring Guidelines
Selenium (Se) Zinc (Zn) Copper (Cu)
Watch for signs of deficiency every 1–3 months. Check serum Se if deficiency suspected or symptoms are present. Watch for signs of deficiency every 1–3 months. If PN does not contain Cu, watch for deficiency symptoms monthly. Check serum Cu every 6 months if standard multi-TE product is used in patients with cholestasis or liver dysfunction or if deficiency is suspected. Manganese (Mn) If standard multi-TE products are used, watch for signs of Mn toxicity every 1–3 months. Check whole-blood Mn if symptoms of toxicity are present, or every 3–4 months, or monthly for patients with significant cholestasis. Chromium (Cr) If providing standard multi-TE products on a daily basis, consider checking serum Cr every 6 months in patients with renal insufficiency. Iron (Fe) Monitor serum ferritin and iron studies every 3 months. PN, parenteral nutrition; TE, trace element.
bone, and only 0.1% is in the plasma, bound primarily to serum albumin. Zn is absorbed mainly in the jejunum, with higher efficiency in a Zn-deficient state.5 Zn is secreted into the intestine and excreted in feces, with less than 10% lost in urine, and smaller amounts lost from skin, hair, and body fluids.2,5 A typical PN dose of 3–5 mg Zn meets estimated adult parenteral needs of 2.5–5 mg/d.3 Zn has been found to contaminate PN at about 1.1 mg/2 L.13 The recommendation to replace 17 mg of Zn per kilogram of stool or ileostomy output and 12 mg of Zn per kilogram of duodenal or jejunal fistula drainage comes from 1 study by Wolman et al,23 in which Zn losses were dependent on amounts of gastrointestinal (GI) fluid lost, with significantly less Zn in the GI fluids from patients who had massive small bowel resection. Patients without diarrhea had a positive Zn balance with 3 mg/d Zn in PN. Zn needs may be increased as high as 40 mg/d for patients with major burns of >20% body surface area.24
Many cases of Zn deficiency with use of PN lacking in Zn were documented mostly in the 1970s, before routine use of TEs in PN. Deficiency can occur from 14 days to 3 months or more.25-27 The main manifestation of Zn deficiency is skin lesions (acrodermatitis enteropathica); other symptoms include alopecia, stomatitis, glossitis, perioral ulcers, periungual lesions,25,26 and, in 1 case, intractable vomiting.27 Zn toxicity with PN has been documented only in instances of large dosage errors (hyperamylasemia in 6 patients who received around 50–75 mg/d Zn28) and 1 report of death after a massive overdose of 1.7 g elemental Zn in PN.29 Plasma Zn is low in severe deficiency,25 yet blood tests are not always reliable, since plasma Zn is tightly regulated and maintained in the normal range until Zn restriction is prolonged and severe, and plasma Zn is decreased during physiologic stress, trauma, and infection.5
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Table 4. Utilization and Rationing Guidelines for Parenteral TE Products. Parenteral individual TE products ➢ Use along with other individual TE products for cases in which multi-TE product is omitted. ➢ Selenium can be used in conjunction with standard 4-element multi-TE products. ➢ To treat specific deficiencies—selenium, zinc, and copper. ➢ Individual manganese and chromium products are usually not necessary. ➢ Separate IV iron infusion is to be used for iron deficiency that cannot be treated with oral iron. Parenteral multi-TE products ➢ Omit use for patients with risk for or symptoms of manganese or copper toxicity or with elevated serum copper or whole-blood manganese concentrations. ➢ Consider omitting or decrease dose in PN for patients with renal dysfunction and elevated serum chromium. ➢ Use iron-containing products in lipid-free PN admixtures until/unless more stability information is available for use with PN admixtures in the United States. During times of parenteral TE shortage or product unavailability ➢ Ration parenteral selenium and other TE products for preferential use in neonatal and pediatric PN. ➢ Ration 1 standard multi-TE dose 3 times per week or, if necessary, one-half dose 3 times per week. ➢ Seek supplies of zinc, selenium, and copper (for which deficiencies are more likely). ➢ Use various oral multivitamin-mineral supplements (that include specific TEs needed) or use separate oral trace element supplements whenever possible for patients with sufficient GI absorptive capacity. ➢ Read product labels—some multivitamin-mineral supplements do not contain both selenium and zinc. ➢ Keep in mind the DRIs for oral TE needs and increase dosages for patients with short bowel or malabsorption. ➢ Keep ongoing watch on storeroom inventory, supplier availability, manufacturer updates, and the following websites: U.S. Food and Drug Administration—“Drug shortages”: http://www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm. American Society of Health-System Pharmacists Drug Shortages Resource Center: http://www.ashp.org/shortages?WT.ac=hp%5FP opLinks%5FDrug%5FShortages American Society of Parenteral and Enteral Nutrition (A.S.P.E.N.) Drug Shortages Update: http://www.nutritioncare.org/ Professional_Resources/Drug_Shortages_Update/ DRI, Dietary Reference Intake; GI, gastrointestinal; IV, intravenous; PN, parenteral nutrition; TE, trace element.
Copper (Cu) Copper (Cu) is a component of several metalloenzymes that function as oxidases in numerous reactions, including deactivation of histamine, degradation of serotonin, catecholamine metabolism, and oxidation of ferrous iron for binding to transferrin. Cu is also necessary for the development of connective tissues, melanin synthesis, energy production, and defense against oxidative damage.5 Nearly two-thirds of the body’s Cu is in the skeleton and muscle, and 60%−95% of plasma Cu is bound to ceruloplasmin. Intestinal absorption of Cu varies from 5 mg/d to >50% with an intake 90% is excreted in urine. In an adult’s body, 70%−80% of I is in the thyroid gland, and it functions as a part of thyroid hormones (thyroxine and triiodothyronine). In I deficiency, the thyroid gland enlarges (goiter), thyroglobulin elevates, and urinary I decreases.58 The most serious effects of I deficiency are during pregnancy and in childhood—fetal death, cretinism, abnormal growth, and mental retardation.2 F is needed for bone health, and about 99% of the F in the body is in bones and teeth. Intestinal absorption of F is 50%, and it is excreted in urine. Urinary excretion of F is greater for adults than for children.2 Studies are needed to determine if parenteral F prevents PN-associated osteopenia or if it might even be detrimental to bone health for adults.59 Researchers in France found that patients received greater than recommended
amounts of F from the amount provided in their PN along with F from orally ingested mineral water and tea, and they expressed concern for possible F toxicity risk.60
General Considerations Laboratory testing for TE status is expensive and of limited practicality, and thus blood tests should be limited to those patients who are at high risk or manifest symptoms of toxicity or deficiency and who will be using PN for 4 months or more. Reference ranges for blood TE concentrations differ among different laboratories.18,19 Blood samples for TE tests are often sent out to larger regional laboratories. Many healthcare workers are not familiar with TE blood tests, so it is important to communicate clearly the particular test needed as well as the specific requirements for it, such as special collection tubes, and techniques to avoid sample contamination.18,19 Separate IV infusions of pharmacologic TE doses of up to 500 mcg Se, 4 mg Cu, and 40 mg Zn have been recommended for use in critically ill burn patients since some studies have shown association of these high doses with improved wound healing and a significant reduction in the incidence of nocosomial pneumonia.17,24,61 In these cases, Se, Cu, and Zn were given as separate IV infusions and not associated with PN use. More study is needed on this subject, and of course, the use of large doses of parenteral TEs is not feasible or recommended during periods of nationwide TE product shortages. During severe shortage or unavailability of parenteral TE products, oral TE supplements are available over the counter, in various forms, dosages, and brands, and can be used for patients who have some GI absorptive capacity. Fe, Se, Zn, Cu, Cr, I, and Mo can be obtained in oral tablet, capsule, and liquid formulas. Fe, Zn, Cr, and I are also available in oral lozenges. Many oral multivitamin-mineral supplements also contain TEs in various amounts and combinations.
Summary Trace elements are a very important part of PN therapy both in the hospital and in long-term home care. Knowledge gained from the literature and in clinical practice is useful in gleaning practical guidelines for TE use in PN. Information about TE products, requirements, metabolism, toxicities and deficiencies, and monitoring can equip practitioners to provide optimal care for their patients who use PN.
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