Micronutrients in Parenteral Nutrition: Too Little or Too Much? The Past, Present, and Recommendations for the Future
2009; Elsevier BV; Volume: 137; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2009.09.001
ISSN1528-0012
AutoresAlan L. Buchman, Lyn Howard, Peggi Guenter, Reid A. Nishikawa, Charlene Compher, Kelly A. Tappenden,
Tópico(s)Intestinal Malrotation and Obstruction Disorders
ResumoThis research workshop in 2009 grew out of a concern in the United States, Europe, and other countries with advanced medicine that it was time to revisit the parenteral requirements for a number of micronutrients. Critical questions sought to be answered included the following: Were there micronutrients not routinely added that should be part of a parenteral nutrition (PN) formula? Were other micronutrients present but in inappropriate amounts? How are various micronutrient requirements altered in the critically or chronically ill? This research workshop in 2009 grew out of a concern in the United States, Europe, and other countries with advanced medicine that it was time to revisit the parenteral requirements for a number of micronutrients. Critical questions sought to be answered included the following: Were there micronutrients not routinely added that should be part of a parenteral nutrition (PN) formula? Were other micronutrients present but in inappropriate amounts? How are various micronutrient requirements altered in the critically or chronically ill? Parenteral nutrition (PN) became an established hospital therapy in the 1960s. In the early 1970s, a few academic centers started sending stable patients with short-bowel syndrome home to live on this therapy indefinitely.1Jeejeebhoy K.N. Zohrab W.J. Langer B. et al.Total parenteral nutrition at home for 23 months, without complications and with good rehabilitation.Gastroenterology. 1973; 65: 811-820PubMed Google Scholar, 2Broviac J.N. Scribner B.H. Prolonged parenteral nutrition in the home.Surg Gynecol Obstet. 1974; 139: 24-28PubMed Google Scholar, 3Fleming C.R. McGill D.B. Berkerer S. Home parenteral nutrition as primary therapy in patients with extensive Crohn's disease of the bowel and malnutrition.Gastroenterology. 1977; 73: 1077-1081PubMed Google Scholar, 4Ladefoged K. Jaum S. Long term parenteral nutrition.Br Med J. 1978; 2: 262-266Crossref PubMed Scopus (31) Google Scholar Many have now survived over 20 years on home PN, and a few have reached 40 years on this therapy.5The Oley Foundation for Home Parenteral & Enteral Nutrition Web siteOley Patient Profiles.www.oley.org/oley_profilesGoogle Scholar Some of the early patients on long-term PN.1 developed micronutrient deficiency syndromes, emphasizing the importance of a complete nutritional formula.6Okada A. Takagi Y. IIeakura T. et al.Skin lesions during intravenous hyperalimentation: zinc deficiency.Surgery. 1976; 80: 629-635PubMed Google Scholar, 7Kay R.G. Tasman-Jones C. Pybus J. et al.A syndrome of acute zinc deficiency during total parenteral alimentation in man.Ann Surg. 1976; 183: 331-340Crossref PubMed Scopus (180) Google Scholar, 8Heller R.M. Kirchner S.A. O'Neill Jr, J.A. et al.Skeletal changes of copper deficiency in infants receiving prolonged parenteral nutrition.J Pediatr. 1978; 92: 947-949Abstract Full Text PDF PubMed Scopus (84) Google Scholar, 9Karpel J.T. Peden V.H. Copper deficiency in long term parenteral nutrition.J Pediatr. 1972; 80: 32-36Abstract Full Text PDF PubMed Scopus (184) Google Scholar, 10Vilter R.W. Bozian R.C. Hess E.V. et al.Manifestations of copper deficiency in patient with systemic sclerosis on intravenous hyperalimentation.N Engl J Med. 1974; 29: 188-193Crossref Scopus (78) Google Scholar, 11Jeejeebhoy K.N. Chu R.C. Marliss E.B. et al.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: 535-538Google Scholar, 12Freund H. Atamian J. Fisher J.E. Chromium deficiency during total parenteral nutrition.JAMA. 1979; 241: 496-498Crossref PubMed Scopus (231) Google Scholar, 13van Rij A.M. Thompson C.D. McKenzie J.M. et al.Selenium deficiency in total parenteral nutrition.Am J Clin Nutr. 1979; 32: 2076-2085Crossref PubMed Scopus (301) Google Scholar Table 1 summarizes the history of parenteral multivitamin regulation in the United States. The 1975 guidelines recommended to the Food and Drug Administration (FDA) by the Nutrition Advisory Group of the American Medical Association (NAG-AMA) were based on research and clinical observations underpinning the oral Recommended Dietary Allowance (RDA).19National Research Council, Food and Nutrition BoardRecommended dietary allowances.8th ed. National Academy Science, Washington, DC1974Google Scholar Most of the parenteral water-soluble vitamins were double the RDA dose for a specific age group to take into account greater utilization associated with illness and an increased rate of excretion due to systemic rather than portal delivery. The fat-soluble vitamins were reduced 30%–50% from the RDA to take into account their partial absorption and potential toxicity. Over time, these NAG-AMA vitamin recommendations have held up fairly well, as judged by blood concentrations20Shils M.E. Baker H. Frank O. Blood vitamin levels of long term adult home total parenteral nutrition patients: the efficacy of the AMA-FDA parenteral multivitamin formulation.JPEN J Parenter Enteral Nutr. 1985; 9: 179-188Crossref PubMed Scopus (42) Google Scholar and functional tests21Howard L. Bigaouette J. Chu R. et al.Water soluble vitamin requirements in home parenteral nutrition patients.Am J Clin Nutr. 1983; 37: 421-428PubMed Google Scholar in stable adults on long-term PN. However, in more depleted patients receiving the NAG-AMA 1979 formula, there were several reports of inadequate vitamin restitution.22Labadarios D. O'Keefe S. Dicker J. et al.Plasma vitamin levels in patients on prolonged total parenteral nutrition.JPEN J Parenter Enteral Nutr. 1988; 12: 205-211Crossref PubMed Scopus (26) Google Scholar, 23Dempsey D.T. Mullen J.L. Rombeau J.L. et al.Treatment effects of parenteral vitamins in total parenteral nutrition patients.JPEN J Parenter Enteral Nutr. 1987; 11: 229-237Crossref PubMed Scopus (18) Google Scholar, 24Inculet R.I. Norton J.A. Nichoalds G.E. et al.Water-soluble vitamins in cancer patients on parenteral nutrition: a prospective study.JPEN J Parenter Enteral Nutr. 1987; 11: 243-249Crossref PubMed Scopus (27) Google Scholar, 25Stromberg P. Shenkin A. Campbell R.A. et al.Vitamin status during total parenteral nutrition.JPEN J Parenter Enteral Nutr. 1981; 5: 295-299Crossref PubMed Scopus (26) Google Scholar In 1985, the FDA and AMA cosponsored a workshop on parenteral multivitamins, and increased doses of ascorbic acid, thiamine, pyridoxine, and folate were recommended. It was also suggested that 100 μg of vitamin K (phylloquinone) be added to the adult formula to provide a consistent and modest level of vitamin K, perhaps making it easier to sustain the desired level of hypoprothrombinemia in patients on anticoagulant therapy with warfarin.26Hands L.J. Royle G.T. Kettlewell M.G. Vitamin K requirements in patients receiving total parenteral nutrition.Br J Surg. 1985; 72: 665-667Crossref PubMed Scopus (13) Google Scholar For reasons that are not clear, these vitamin changes recommended in 1985 were not mandated by the FDA until 2000.17Federal Register. April 20, 2000.Google Scholar In the 1988 update of research and clinical experience of pediatric parenteral requirements,18Guidelines for the use of vitamins, trace elements, calcium, magnesium, phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Practice issues of the American Society for Clinical Nutrition.Am J Clin Nutr. 1988; 48: 1324-1342PubMed Google Scholar the 1975 NAG-AMA guidelines appeared also to be appropriate except in preterm infants in whom vitamin A concentrations were deficient,27Greene H.L. Phillips B.L. Franck L. et al.Persistently low blood retinol levels during and after parenteral feeding of very low birth weight infants: examination of losses into intravenous administration sets and a method of prevention by addition to a lipid emulsion.Pediatrics. 1987; 79: 894-900PubMed Google Scholar causing a potential increased risk of bronchopulmonary dysplasia.28Shenai J.P. Chytil F. Stahlman M.T. Vitamin A status of neonates with bronchopulmonary dysplasia.Pediatr Res. 1985; 19: 185-187Crossref PubMed Scopus (185) Google Scholar Because of concern that preterm infants may not metabolize polysorbate and propylene glycol, used as emulsifiers of fat-soluble vitamins, the suggestion was made that for preterm infants, fat-soluble vitamins be provided separate from the water-soluble vitamins in the parenteral lipid emulsion.Table 1Summary of Parenteral Multivitamin Regulation in the United States1972FDA declared parenteral multivitamin preparations as “ineffective as currently formulated” because “they lack certain essential vitamins and some vitamins were present in too high or too low dose.”14Federal Register. July 27, 172.Google Scholar1975NAG-AMA proposed guidelines for 9 water-soluble (ascorbic acid, thiamin, riboflavin, niacin, pyridoxine, pantothenic acid, folate, cobalamin, and biotin) and 4 fat-soluble (vitamins A [retinol], D [cholecalciferol/ergocalciferol], E [α-tocopherol], and K [phylloquinone] vitamins for adult and pediatric age groups.15Department of Foods and Nutrition, American Medical Association. Guidelines for multivitamin preparations for parenteral use. Chicago, IL: Department of Foods and Nutrition, American Medical Association.Google Scholar, 16Multivitamin preparations for parenteral use A statement by the Nutrition Advisory Group.JPEN J Parenter Enteral Nutr. 1979; 3: 258-262Crossref PubMed Scopus (97) Google Scholar The FDA accepted the adult formulation in 1979 and the pediatric formulation in 1981.1985FDA and AMA cosponsored a workshop on parenteral multivitamins; increases in doses of ascorbic acid, thiamine, pyridoxine, and folate were recommended plus addition of vitamin K to the adult formula. These changes were not mandated until 2000.17Federal Register. April 20, 2000.Google Scholar1988Pediatric parenteral vitamin requirements were reevaluated by the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition and modified according to input from the American Academy of Pediatrics and National Institute of Child Health and Development.18Guidelines for the use of vitamins, trace elements, calcium, magnesium, phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Practice issues of the American Society for Clinical Nutrition.Am J Clin Nutr. 1988; 48: 1324-1342PubMed Google Scholar Open table in a new tab While current parenteral vitamin doses appear to be satisfactory for relatively stable patients on PN, 2 vitamin-like nutrients, choline (a quaternary amine) and carnitine (a quaternary amino acid), appear also to be required for stable adults and children (choline) and infants (carnitine), so these data were reviewed at the workshop. Much less is known about vitamin, choline, and carnitine requirements in critically ill, trauma, and burn patients. However, new information is available on the antioxidant vitamins ascorbic acid and vitamin E in critically ill patients, so these topics were therefore selected for the workshop. In addition, there are newly recognized metabolic functions of vitamins D and K, so these vitamins were also presented. Turning to parenteral trace elements, Table 2 shows the daily doses recommended for adults and how they were modified as new research information became available. In 1977, NAG-AMA convened an expert panel to review parenteral trace element requirements. In 1978, NAG-AMA submitted guidelines to the FDA for daily doses of zinc, copper, manganese, and chromium salts appropriate for adults and children. In 1979, these guidelines were published in JAMA29Guidelines for essential trace element preparations for parenteral use.JAMA. 1979; 24: 2051-2054Google Scholar and presented in summary form in the Journal of Parenteral and Enteral Nutrition.30Guidelines for essential trace element preparations for parenteral use A statement by the Nutrition Advisory Group.JPEN J Parenter Enteral Nutr. 1979; 3: 263-267Crossref PubMed Google Scholar Parenteral sources of the other trace elements known to be essential—iron, iodine, and cobalt as vitamin B12—were already commercially available. Selenium was not firmly established as essential for humans until 1979, when Chinese scientists had a highly successful selenium intervention trial in Keshan disease.35Keshan Disease Research GroupObservations on effect of sodium selenite in prevention of Keshan disease.Chin Med J. 1979; 92: 471-476PubMed Google Scholar In 1981, copper balance studies were published in stable patients on long-term PN,36Skike M. Roule M. Kurian R. et al.Copper metabolism and requirement in total parenteral nutrition.Gastroenterology. 1981; 81: 290-297PubMed Google Scholar suggesting a much lower dose was needed than that published in the original guideline.29Guidelines for essential trace element preparations for parenteral use.JAMA. 1979; 24: 2051-2054Google Scholar In 1982, there was a second review of parenteral trace elements, and selenium was added and copper doses were significantly reduced.31Shils M.E. White P.L. Working conference on parenteral trace elements: sponsored by NY Acad Med and AMA.Bull N Y Acad Med. 1984; 60: 115-212PubMed Google ScholarTable 2Changes Over Time in Parenteral Trace Elements for AdultsPublished guidelinesZinc (mg)aIncrease with abnormal intestinal loss.Copper (mg)bDecrease or omit with increasing cholestasis.Manganese (μg)cDecrease of omit with increasing renal dysfunction.Chromium (μg)cDecrease of omit with increasing renal dysfunction.Selenium (μg)cDecrease of omit with increasing renal dysfunction.NAG-AMA, 197929Guidelines for essential trace element preparations for parenteral use.JAMA. 1979; 24: 2051-2054Google Scholar, 30Guidelines for essential trace element preparations for parenteral use A statement by the Nutrition Advisory Group.JPEN J Parenter Enteral Nutr. 1979; 3: 263-267Crossref PubMed Google Scholar2.5–40.5–1.5150–80010–15—AMA, New York Academy of Medicine, 198431Shils M.E. White P.L. Working conference on parenteral trace elements: sponsored by NY Acad Med and AMA.Bull N Y Acad Med. 1984; 60: 115-212PubMed Google Scholar2.5–40.3–0.5400–80010–2050–60Modern Nutrition in Health & Disease, 9th ed, 199432Shils M.E. Brown R.O. Parenteral nutrition.in: Shils M.E. Olsen J.A. Shike M. Modern nutrition in health and disease. 9th ed. Lea & Febiger, Philadelphia, PA1994Google Scholar2.5–40.3–0.560–10010–1540–80A.S.P.E.N., 199833Safe practices for parenteral nutrition.JPEN J Parenter Enteral Nutr. 1998; 22: 49-66Crossref PubMed Scopus (145) Google ScholarA.S.P.E.N., 200634Revision of safe practices for parenteral nutrition.JPEN J Parenter Enteral Nutr. 2006; 30: 177Crossref Google Scholar2.5–40.3–0.560–10010–1520–60a Increase with abnormal intestinal loss.b Decrease or omit with increasing cholestasis.c Decrease of omit with increasing renal dysfunction. Open table in a new tab In 1988, pediatric parenteral trace element requirements were reevaluated by the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition.18Guidelines for the use of vitamins, trace elements, calcium, magnesium, phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Practice issues of the American Society for Clinical Nutrition.Am J Clin Nutr. 1988; 48: 1324-1342PubMed Google Scholar They believed that only zinc supplementation was needed if PN was for less than 4 weeks. In stable infants and children on long-term PN, they made a case for a multi-trace element solution providing zinc, copper, selenium, chromium, manganese, molybdenum, and iodine. The routine addition of iron posed issues about stability after 18 hours at room temperature. Although there had been previous data with regard to contamination of parenteral fluids during the manufacturing process with some of the very elements that needed to be provided, it was not until the early 1990s when potential chromium toxicity, related to contamination in various PN components, was described as a cause for PN-associated nephropathy in humans.37Moukarzel A.A. Song M.K. Buchman A.L. et al.Excessive chromium intake in children receiving total parenteral nutrition.Lancet. 1992; 339: 385-388Abstract PubMed Scopus (66) Google Scholar In addition, in the late 1990s, neurotoxicity from excessive manganese was reported in children.38Fell J.M. Reynolds A.P. Meadows N. et al.Manganese toxicity in children receiving long term parenteral nutrition.Lancet. 1996; 347: 1218-1221Abstract PubMed Scopus (193) Google Scholar, 39Reynolds C.R. Manganese requirement and toxicity in patients on home parenteral nutrition.Clin Nutr. 1998; 17: 227-230Abstract Full Text PDF PubMed Scopus (46) Google Scholar This led to a drastic reduction in the parenteral manganese recommendation; however, no official changes were forthcoming from the FDA with regard to maximum acceptable contamination or dosing for either manganese or chromium. A recent study on autopsy tissues of 8 patients who lived on PN for 2–21 years receiving the NAG-AMA 1979 formula confirmed very high concentrations of hepatic copper, manganese, and chromium.40Howard L. Ashley C. Lyon D. et al.Autopsy tissue trace elements in 8 long-term parenteral nutrition patients who received the current U.S. Food and Drug Administration Formulation.JPEN J Parenter Enteral Nutr. 2007; 31: 388-396Crossref PubMed Scopus (64) Google Scholar There was close agreement among the experts for a need to reduce copper, manganese, and chromium from the original trace element guideline. It was not clear why the FDA has not updated the 1979 guidelines despite strong recommendations from several expert conferences.31Shils M.E. White P.L. Working conference on parenteral trace elements: sponsored by NY Acad Med and AMA.Bull N Y Acad Med. 1984; 60: 115-212PubMed Google Scholar, 32Shils M.E. Brown R.O. Parenteral nutrition.in: Shils M.E. Olsen J.A. Shike M. Modern nutrition in health and disease. 9th ed. Lea & Febiger, Philadelphia, PA1994Google Scholar, 33Safe practices for parenteral nutrition.JPEN J Parenter Enteral Nutr. 1998; 22: 49-66Crossref PubMed Scopus (145) Google Scholar, 34Revision of safe practices for parenteral nutrition.JPEN J Parenter Enteral Nutr. 2006; 30: 177Crossref Google Scholar Currently available vitamin and trace metal formulations available in the United States are listed in Table 3, Table 4 as well as Table 5, Table 6, respectively, and those formulas available in Europe are listed in Table 7, Table 8, respectively (kindly researched and provided by Reid Nishikawa, PharmD, Nutrishare, Inc, Elk Grove, CA).Table 3Intravenous Multivitamin Formulations Available in North AmericaProductContent perADEB1B2B3B5B6B12CBiotinFolic acidK1Other content(distributor)(IU)(IU)(IU)(mg)(mg)(mg)(mg)(mg)(μg)(mg)(μg)(mg)(μg)(how supplied)MVI-12 Injection (Hospira)5 mL3300200 D210aAs dL-α-tocopheryl acetate.33.6401545100600.40In 2 vial sets: vial 1bWith propylene glycol, EDTA, and 1% benzyl alcohol. (5-mL single dose or 50-mL multiple dose) and vial 2cWith propylene glycol, polysorbate 80, and polysorbate 20. (5-mL single dose or 50-mL multiple dose)MVI Pediatric (Hospira)5 mL2300400 D27aAs dL-α-tocopheryl acetate.1.21.41751180200.1200Mannitol 375 mg/in single- and multiple-dose vialsdWith propylene glycol.Cernevit-12 (Baxter)5 mL3500200 D311.23.54.144617.254.535.5125600.405-mL single-dose vialsInfuvite Adult (Baxter)10 mL (after combining vials)3300200 D31063.640156520060600150Polysorbate 90/in two 5-mL vials to be combined togetherInfuvite Pediatric (Baxter)5 mL (after combining vials)2300400 D371.21.4175118020140200Polysorbate 90/in 2 vials (4 mL and 1 mL to be combined together)B-Complex 100 Bioniche Pharma1 mL10021002230-mL multiple-dose viala As dL-α-tocopheryl acetate.b With propylene glycol, EDTA, and 1% benzyl alcohol.c With propylene glycol, polysorbate 80, and polysorbate 20.d With propylene glycol. Open table in a new tab Table 4Intravenous Single Vitamin Formulations Available in North AmericaVitamin (distributor)ConcentrationHow suppliedThiamine (various)100 mg/mL as HCl1- and 2-mL Tubex, 2-mL multi-dose vials, 1-mL vialPyridoxine (various)100 mg/mL as HCl1-mL vialsCyanocobalamin (various)100 mg/mL30-mL multi-dose vialsCyanocobalamin (various)1000 mg/mL10- and 30-mL multi-dose vials, 1-mL vialAscorbic acid (various)500 mg/mL50-mL multi-dose vialsAscorbic acid (various)500 mg/mL1-mL ampuleAscorbic acid (various)1000 mg/mL2-mL ampuleFolic acid (various)5 mg/mL10-mL multi-dose vialVitamin A (Hospira)50,000 U/mL as palmitate2-mL vials (intramuscular)Calcitriol (aaiPharma/Abbott)1 μg/mL1-mL vialaWith 4 mg polysorbate 20, 1.5 mg sodium chloride, 10 mg sodium ascorbate, 7.6 mg dibasic sodium phosphate, anhydrous, and EDTA. sodium chloride, EDTACalcitriol (aaiPharma)2 μg/mL1-mL vialaWith 4 mg polysorbate 20, 1.5 mg sodium chloride, 10 mg sodium ascorbate, 7.6 mg dibasic sodium phosphate, anhydrous, and EDTA. sodium chloride, EDTAParicalcitol (Abbott)2 μg/mL1-mL vialParicalcitol (Abbott)5 μg/mL1- and 2-mL vialDoxercalciferol (Genzyme)2 μg/mL2-mL ampulebEach milliliter contains 4 mg polysorbate 20, 1.5 mg sodium chloride, 10 mg sodium ascorbate, 7.6 mg sodium phosphate dibasic, 1.8 mg sodium phosphate monobasic, and 1.1 mg EDTA.Phytonadione (K1) (Hospira)10 mg/mL1-mL ampulePhytonadione (K1) (Hospira)2 mg/mL0.5-mL ampulea With 4 mg polysorbate 20, 1.5 mg sodium chloride, 10 mg sodium ascorbate, 7.6 mg dibasic sodium phosphate, anhydrous, and EDTA.b Each milliliter contains 4 mg polysorbate 20, 1.5 mg sodium chloride, 10 mg sodium ascorbate, 7.6 mg sodium phosphate dibasic, 1.8 mg sodium phosphate monobasic, and 1.1 mg EDTA. Open table in a new tab Table 5Intravenous Multi-trace Element Formulations Available in North AmericaProduct (distributor)Zinc (as sulfate) (mg)Copper (as sulfate) (mg)Chromium (as chloride) (μg)Manganese (as sulfate) (mg)Selenium (as selenious acid) (μg)How suppliedMultiple Trace Element Neonatal (American Regent)1.50.10.850.02502-mL vialsNeoTrace-4 (American Pharmaceutical Partners)02-mL vialsPTE-4 (American Pharmaceutical Partners)10.110.02503-mL vials4 Trace Elements (Hospira)1.67aAs chloride.0.4260.37aAs chloride.05-mL vialsMultiple Trace Element w/Selenium (American Regent)10.440.1203-, 10-, and 30-mL vialsbWith 0.9% benzyl alcohol.Multiple Trace Element w/Selenium Concentrated (American Regent)51100.5601-mL single-dose and 10-mL multiple-dose vialsbWith 0.9% benzyl alcohol.NOTE. Contents are per milliliter of solution.a As chloride.b With 0.9% benzyl alcohol. Open table in a new tab Table 6Intravenous Single Trace Element Formulations Available in North AmericaTrace element (distributor)ConcentrationHow suppliedZinc sulfate (various)1 mg/mL (as zinc sulfate)10-mL and 30-mL vialsZinc sulfate (various)5 mg/mL (as zinc sulfate)5- and 10-mL vialsZinc chloride (various)1 mg/mL (as zinc chloride)10-mL vialsCopper (Hospira)0.4 mg/mL (as cupric Cl)10-mL vialsCupric sulfate (various)0.4 mg/mL (as copper sulfate)10- and 30-mL vialsCupric sulfate (various)2 mg/mL (as cupric sulfate)10-mL vialsChromium (various)4 μg/mL (as chromic chloride hexahydrate)10- and 30-mL vialsChromic chloride (various)20 μg/mL10-mL vialsSelenium (various)40 μg/mL (as selenious acid)10- and 30-mL vialsManganese chloride (various)0.1 mg/mL10-mL vialsManganese sulfate (various)0.1 mg/mL10- and 30-mL vialsMolybdenum (various)25 μg/mL (as ammonium molybdate tetrahydrate)10-mL vialsIodine (American Pharmaceutical Partners)100 μg/mL (as sodium iodide)10-mL vialsNOTE. Contents are per milliliter of solution. Open table in a new tab Table 7Parenteral Multivitamin Products Available in EuropeProduct (distributor)Content perA (IU)D (IU)E (IU)B1 (mg)B2 (mg)B3 (mg)B5 (mg)B6 (mg)B12 (μg)C (mg)Biotin (μg)Folic acid (mg)K1 (μg)Other content (how supplied)Solivito N (Fresenius Kabi)10 mL00033.64015451006000In 10-mL freeze-dried vials. Contains only water-soluble vitamins. Can be dissolved in Vitalipid N Adult. For adults.Vitalipid Adult (Fresenius Kabi)10 mL3300200 D210000000000150In 10-mL liquid ampulesCernevit (Baxter)5 mL3500220 D31144.14617.34.5612569045-mL single-dose vials; excipients glycine, glycocholic acid, soybean phosphates, sodium hydroxide, hydrochloric acidVitalipid Infant (Fresenius Kabi)10-mL2300400 D27000000000200In 10-mL liquid in ampules Open table in a new tab Table 8Parenteral Multi-trace Metal Products Available in EuropeProduct (distributor)Zinc (as sulfate) (mg)Copper (as sulfate) (mg)Chromium (as chloride) (μg)Manganese (as sulfate) (mg)Selenium (as selenious acid) (μg)How suppliedAdditrace (Fresenius Kabi)6.51.3100.273210-mL liquid ampulesPeditrace (Fresenius Kabi)0.250.0200.01210-mL liquid vialsDecan (Baxter)100.48150.27040-mL liquid vialsNOTE. Contents are per milliliter of solution. Open table in a new tab NOTE. Contents are per milliliter of solution. NOTE. Contents are per milliliter of solution. NOTE. Contents are per milliliter of solution. The current research workshop brought together a panel of 14 international scientists with specific expertise on a particular vitamin, a trace metal, or other potentially needed micronutrients. These scientists and 6 additional experts in the field formed a discussion panel. The larger audience was invited to join the discussion once the panel exchange was complete. This supplement includes the reports provided by the presenters, each ending with a summary of clinical recommendations and their suggested research priorities. A transcription of the discussion, redacted by the 2 chairpersons, Drs Alan Buchman and Lyn Howard, follows each report. There was broad agreement about the need for the FDA to require some level of control of trace element contamination in all components of the parenteral formula. This issue has been emphasized for 30 years. Even if it is not feasible to remove all contaminants, at a minimum, a label should be required that describes the level of contamination that would allow clinicians to modify added trace element supplements accordingly. There was agreement to add 70–150 μg/day of iodine to a basic adult formula, given the decreased use of cutaneous povidone-iodine, and 1 mg of iron if stability and compatibility issues can be resolved for the latter. A case can also be made for the potential addition of molybdenum, boron, and silicon, depending on the amounts present as contaminants. The addition of 150 μg of vitamin K to the adult formula appears to meet the requirement for γ-carboxylation status of noncoagulation Gla proteins. It was pointed out, however, that lipid emulsions contain variable amounts of vitamin K (soybean oil, 150–300 μg/100 g; safflower oil, 6–12 μg/100 g), so despite a baseline vitamin K dose, this can make warfarin treatment erratic. Both vitamin K and vitamin D have metabolic effects that were largely unknown at the time of the original vitamin recommendations. The requirement for vitamin D will increase as the adequate intake is adjusted (under current review). In addition, the development of lypholized vitamins, which are rehydrated and added to lipid emulsions, may avoid the potential toxicity problems with polysorbate and propylene glycol, which are used as fat-soluble vitamin vehicles. Choline appears to be important for the preservation of normal hepatic function and may reduce catheter thrombosis. It is now considered a required nutrient in the diet (and therefore in PN as well). Additional studies, however, will be necessary to determine optimal dosing, especially for neonates. Carnitine, although not clearly required in the adult, appears to be conditionally essential in the neonate; however, more data are required before specific recommendations can be made. Additional data are needed for neonatal vitamin and trace element dosing and for adults and children with severe burns, critical illness, and other specific situations. It was noted, however, during the workshop that the novel use of mega doses of antioxidant vitamins (ascorbic acid, α-tocopherol) to restore normal plasma vitamin concentrations in critically ill, trauma, or burn patients may have important benefits, such as the prevention of circulatory shock. One further issue that needs to be addressed is the valid assessment of micronutrient status. Earlier dosing recommendations were based on “normal” serum or erythrocyte concentrations. The use of blood concentrations for nutrient assessment is a widely used technique, particularly because a more physiologic test, namely the measurement of nutrient function, is available for only a few nutrients and very often the functional test is limited to a research setting. Blood concentrations (whole blood, serum, plasma) often show no correlation with total body micronutrient balance data in patients who require PN. Those concentrations may simply reflect the exogenous infusion rather than true adequacy of the nutrient. In addition, meticulous sampling, handling, and measurement techniques are required to avoid contamination. Studies are needed to determine how long a particular intravenously infused nutrient must be withheld to ensure a blood value is interpretable. Several newer and more sensitive assessment techniques were presented at the workshop, particularly for vitamins D and K. We hope this research workshop will lead to FDA-required multivitamin and multi-trace element reformulations, as well as the availability of safer commercial products. In fact, a highly desirable outcome would be parenteral micronutrient formulas that meet international acceptance, because there are a limited number of commercial producers of parenteral vitamins and trace elements and sudden shortages in production can drastically affect the PN patient population. Parenteral micronutrients are a relatively small item in the large world of pharmaceutical products, and the number of companies that produces them is also small. It would seem desirable to develop an international consensus about necessary products and doses so that all producers could potentially extend their current market. This could help to avoid future crises of the kind that occurred in the United States with an acute parenteral multivitamin shortage from April 1997 to June 1999. Perhaps parenteral micronutrients could be the prototype for the introduction of international pharmaceutical standards, although that will require a significant change in the current culture of European and American regulatory authorities. This research workshop was made possible by a conference grant (U13 DK064190) from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, to the American Society for Parenteral and Enteral Nutrition (ASPEN). Additional supporting grants for the 2009 Micronutrient Workshop were received from the American Gastroenterological Associate (AGA) Institute, the European Society for Parenteral and Enteral Nutrition, the North American Society for Pediatric Gastroenterology Nutrition and Hepatology, and the Oley Foundation for Home Parenteral and Enteral Nutrition. Unrestricted educational grants were received from Baxter Healthcare Corporation, Fresenius Kabi Deutschland GmbH, Hospira Worldwide, Apria Healthcare/Coram Inc Specialty Infusion Services, Walgreens-OptionCare, American Regent, and Nutrishare, Inc. The annual ASPEN Research Workshop has been a successful and scientifically respected conference since 1985. As the convening organization, and in conjunction with other organizations and sponsors, ASPEN has fostered the idea of a multi-organizational meeting on a single research subject. This research workshop provides a venue for interactive thinking between acknowledged experts from basic to clinical nutrition science areas on a topic related to nutrition support. The topics addressed in recent research workshops included subjects such as inflammation, intestinal failure, regulation of food intake, nutrition in renal disease, and hyperglycemia in the critically ill. These presentations and question and answer sessions provide the substance and direction for future research efforts. CorrectionGastroenterologyVol. 138Issue 4PreviewBuchman AL, Howard LJ, Guenter P, et al. Micronutrients in parenteral nutrition: too little or too much? The past, present, and recommendations for the future. Gastroenterology 2009;137(5 Suppl):S1–S6. Full-Text PDF
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