Gastroenterology
Volume 137, Issue 5, Supplement , Pages S1-S6, November 2009

Micronutrients in Parenteral Nutrition: Too Little or Too Much? The Past, Present, and Recommendations for the Future

  • Alan L. Buchman

      Affiliations

    • Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, Evanston, Illinois
    • Corresponding Author InformationCorrespondence Address correspondence to: Alan L. Buchman, MD, MSPH, Division of Gastroenterology, Feinberg School of Medicine, Northwestern University, 676 N. St. Clair St., Suite 1400, Chicago, Illinois 60611. fax: (312) 695-3999
    • ,
  • Lyn J. Howard

      Affiliations

    • Albany Medical College, Oley Foundation, Albany, New York
    • ,
  • Peggi Guenter

      Affiliations

    • American Society for Parenteral and Enteral Nutrition, Silver Spring, Maryland
    • ,
  • Reid A. Nishikawa

      Affiliations

    • Nutrishare, Inc, Elk Grove, California
    • ,
  • Charlene W. Compher

      Affiliations

    • School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania
    • ,
  • Kelly A. Tappenden

      Affiliations

    • University of Illinois at Urbana-Champaign, Urbana, Illinois

Article Outline

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?

Abbreviations used in this paper: AGA, American Gastroenterological Associate, AMA, American Medical Association, ASPEN, American Society for Parenteral and Enteral Nutrition, FDA, Food and Drug Administration, NAG, Nutrition Advisory Group, PN, parenteral nutrition, RDA, Recommended Dietary Allowance

 

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.1, 2, 3, 4 Many have now survived over 20 years on home PN, and a few have reached 40 years on this therapy.5 Some of the early patients on long-term PN.1 developed micronutrient deficiency syndromes, emphasizing the importance of a complete nutritional formula.6, 7, 8, 9, 10, 11, 12, 13

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).19 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 concentrations20 and functional tests21 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.22, 23, 24, 25 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.26 For reasons that are not clear, these vitamin changes recommended in 1985 were not mandated by the FDA until 2000.17 In the 1988 update of research and clinical experience of pediatric parenteral requirements,18 the 1975 NAG-AMA guidelines appeared also to be appropriate except in preterm infants in whom vitamin A concentrations were deficient,27 causing a potential increased risk of bronchopulmonary dysplasia.28 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 1. Summary of Parenteral Multivitamin Regulation in the United States
1972FDA 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.”14
1975NAG-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.15, 16 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 2000.17
1988Pediatric 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.18

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 JAMA29 and presented in summary form in the Journal of Parenteral and Enteral Nutrition.30 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.35 In 1981, copper balance studies were published in stable patients on long-term PN,36 suggesting a much lower dose was needed than that published in the original guideline.29 In 1982, there was a second review of parenteral trace elements, and selenium was added and copper doses were significantly reduced.31

Table 2. Changes Over Time in Parenteral Trace Elements for Adults
Published guidelinesZinc (mg)aCopper (mg)bManganese (μg)cChromium (μg)cSelenium (μg)c
NAG-AMA, 197929, 302.5–40.5–1.5150–80010–15—
AMA, New York Academy of Medicine, 1984312.5–40.3–0.5400–80010–2050–60
Modern Nutrition in Health & Disease, 9th ed, 1994322.5–40.3–0.560–10010–1540–80

A.S.P.E.N., 199833

A.S.P.E.N., 200634

2.5–40.3–0.560–10010–1520–60

aIncrease with abnormal intestinal loss.

bDecrease or omit with increasing cholestasis.

cDecrease of omit with increasing renal dysfunction.

In 1988, pediatric parenteral trace element requirements were reevaluated by the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition.18 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.37 In addition, in the late 1990s, neurotoxicity from excessive manganese was reported in children.38, 39 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.40 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.31, 32, 33, 34 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 3. Intravenous Multivitamin Formulations Available in North America
ProductContent perADEB1B2B3B5B6B12CBiotinFolic acidK1Other content
(distributor)(IU)(IU)(IU)(mg)(mg)(mg)(mg)(mg)(μg)(mg)(μg)(mg)(μg)(how supplied)
MVI-12 Injection (Hospira)5 mL3300200D210a33.6401545100600.40In 2 vial sets: vial 1b (5-mL single dose or 50-mL multiple dose) and vial 2c (5-mL single dose or 50-mL multiple dose)
MVI Pediatric (Hospira)5 mL2300400D27a1.21.41751180200.1200Mannitol 375 mg/in single- and multiple-dose vialsd
Cernevit-12 (Baxter)5 mL3500200D311.23.54.144617.254.535.5125600.405-mL single-dose vials
Infuvite Adult (Baxter)10 mL (after combining vials)3300200D31063.640156520060600150Polysorbate 90/in two 5-mL vials to be combined together
Infuvite Pediatric (Baxter)5 mL (after combining vials)2300400D371.21.4175118020140200Polysorbate 90/in 2 vials (4 mL and 1 mL to be combined together)
B-Complex 100 Bioniche Pharma1 mL 100210022 30-mL multiple-dose vial

aAs dL-α-tocopheryl acetate.

bWith propylene glycol, EDTA, and 1% benzyl alcohol.

cWith propylene glycol, polysorbate 80, and polysorbate 20.

dWith propylene glycol.

Table 4. Intravenous Single Vitamin Formulations Available in North America
Vitamin (distributor)ConcentrationHow supplied
Thiamine (various)100 mg/mL as HCl1- and 2-mL Tubex, 2-mL multi-dose vials, 1-mL vial
Pyridoxine (various)100 mg/mL as HCl1-mL vials
Cyanocobalamin (various)100 mg/mL30-mL multi-dose vials
Cyanocobalamin (various)1000 mg/mL10- and 30-mL multi-dose vials, 1-mL vial
Ascorbic acid (various)500 mg/mL50-mL multi-dose vials
Ascorbic acid (various)500 mg/mL1-mL ampule
Ascorbic acid (various)1000 mg/mL2-mL ampule
Folic acid (various)5 mg/mL10-mL multi-dose vial
Vitamin A (Hospira)50,000 U/mL as palmitate2-mL vials (intramuscular)
Calcitriol (aaiPharma/Abbott)1 μg/mL1-mL viala sodium chloride, EDTA
Calcitriol (aaiPharma)2 μg/mL1-mL viala sodium chloride, EDTA
Paricalcitol (Abbott)2 μg/mL1-mL vial
Paricalcitol (Abbott)5 μg/mL1- and 2-mL vial
Doxercalciferol (Genzyme)2 μg/mL2-mL ampuleb
Phytonadione (K1) (Hospira)10 mg/mL1-mL ampule
Phytonadione (K1) (Hospira)2 mg/mL0.5-mL ampule

aWith 4 mg polysorbate 20, 1.5 mg sodium chloride, 10 mg sodium ascorbate, 7.6 mg dibasic sodium phosphate, anhydrous, and EDTA.

bEach 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.

Table 5. Intravenous Multi-trace Element Formulations Available in North America
Product (distributor)Zinc (as sulfate) (mg)Copper (as sulfate) (mg)Chromium (as chloride) (μg)Manganese (as sulfate) (mg)Selenium (as selenious acid) (μg)How supplied
Multiple Trace Element Neonatal (American Regent)1.50.10.850.02502-mL vials
NeoTrace-4 (American Pharmaceutical Partners) 02-mL vials
PTE-4 (American Pharmaceutical Partners)10.110.02503-mL vials
4 Trace Elements (Hospira)1.67a0.4260.37a05-mL vials
Multiple Trace Element w/Selenium (American Regent)10.440.1203-, 10-, and 30-mL vialsb
Multiple Trace Element w/Selenium Concentrated (American Regent)51100.5601-mL single-dose and 10-mL multiple-dose vialsb

NOTE. Contents are per milliliter of solution.

aAs chloride.

bWith 0.9% benzyl alcohol.

Table 6. Intravenous Single Trace Element Formulations Available in North America
Trace element (distributor)ConcentrationHow supplied
Zinc sulfate (various)1 mg/mL (as zinc sulfate)10-mL and 30-mL vials
Zinc sulfate (various)5 mg/mL (as zinc sulfate)5- and 10-mL vials
Zinc chloride (various)1 mg/mL (as zinc chloride)10-mL vials
Copper (Hospira)0.4 mg/mL (as cupric Cl)10-mL vials
Cupric sulfate (various)0.4 mg/mL (as copper sulfate)10- and 30-mL vials
Cupric sulfate (various)2 mg/mL (as cupric sulfate)10-mL vials
Chromium (various)4 μg/mL (as chromic chloride hexahydrate)10- and 30-mL vials
Chromic chloride (various)20 μg/mL10-mL vials
Selenium (various)40 μg/mL (as selenious acid)10- and 30-mL vials
Manganese chloride (various)0.1 mg/mL10-mL vials
Manganese sulfate (various)0.1 mg/mL10- and 30-mL vials
Molybdenum (various)25 μg/mL (as ammonium molybdate tetrahydrate)10-mL vials
Iodine (American Pharmaceutical Partners)100 μg/mL (as sodium iodide)10-mL vials

NOTE. Contents are per milliliter of solution.

Table 7. Parenteral Multivitamin Products Available in Europe
Product (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 ampules
Cernevit (Baxter)5 mL3500220 D31144.14617.34.5612569045-mL single-dose vials; excipients glycine, glycocholic acid, soybean phosphates, sodium hydroxide, hydrochloric acid
Vitalipid Infant (Fresenius Kabi)10-mL2300400 D27000000000200In 10-mL liquid in ampules
Table 8. Parenteral Multi-trace Metal Products Available in Europe
Product (distributor)Zinc (as sulfate) (mg)Copper (as sulfate) (mg)Chromium (as chloride) (μg)Manganese (as sulfate) (mg)Selenium (as selenious acid) (μg)How supplied
Additrace (Fresenius Kabi)6.51.3100.273210-mL liquid ampules
Peditrace (Fresenius Kabi)0.250.0200.01210-mL liquid vials
Decan (Baxter)100.48150.27040-mL liquid vials

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.

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References 

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 Conflicts of interest Dr Buchman shares in the intellectual property rights to intravenous choline licensed to Bioniche Pharma USA. Dr Buchman declares no other relationship with Bioniche Pharma. The remaining authors disclose no conflicts.

PII: S0016-5085(09)01560-1

doi:10.1053/j.gastro.2009.09.001

Refers to erratum:

  • Correction , 08 February 2010

    Gastroenterology April 2010 (Vol. 138, Issue 4, Page 1633)

Gastroenterology
Volume 137, Issue 5, Supplement , Pages S1-S6, November 2009

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