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Pharmacy Issues in Multivitamin Infusion An Update Editorial by David F. Driscoll, PhD Senior Researcher, Nutrition/Infection Laboratory Beth Israel Deaconess Medical Center Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts Introduction Physicochemical Mechanisms of Vitamin Loss During total parenteral nutrition (TPN) therapy, vitamin losses can occur through 1 of 4 principal chemical degradation pathways. They are: photodegradation/oxidation, sorption into plastic matrices, hydrolysis, and co-precipitation from degradation products of various hydrolytic and oxidation reactions. Several physicochemical factors—such as fat emulsions, temperature, light intensity, and pharmaceutical adjuvants—may influence the rate of vitamin degradation. 6,7 Photodegradation/Oxidation Reactions The nutrition support pharmacist plays a critical role in the overall management of patients receiving parenteral nutrition and multivitamin infusion. According to the pharmacy practice standards established by the American Society for Parenteral and Enteral Nutrition (A.S.P. E.N.) in 1993, the pharmacist is an active participant in nutritional assessment, development, and implementation of the therapeutic plan, as well as monitoring of the patient’s progress.1 More recently, the details of these activities have been delineated in a Special Report from A.S.P.E.N. entitled Safe Practices for Parenteral Nutrition Formulations.2 In patients receiving long-term and short-term parenter al nutrition support, vitamins constitute an essential component of nutrition therapy. Vitamins are necessary to maintain normal metabolic function. Often, multivitamins are viewed as a daily additive that completes a parenteral nutrition regimen, and assuming all other essential nutrients are present, meets the definition of balanced nutrition support. During states of abnormal body metabolism, vitamin requirements increase as a result of inadequate intake, greater utilization, or both.3 Because vitamins are important cofactors in numerous metabolic pathways, vitamin deficiencies can have a rate-limiting effect on healing and tissue repair. In certain cases, however, the absence of multivitamins in a parenteral nutrition admixture can have serious consequences.4,5 Photodegradation is directly influenced by luminous intensity. In accordance with Planck’s Theory, wavelength is inversely proportional to photon energy or light intensity (ie, as the wavelength decreases, its energy increases). Therefore, within the electromagnetic spectrum, a wavelength ranging from 380 to 780 nm (visible light spectrum) is less damaging to vitamins contained in a TPN bag than if the same TPN bag is exposed to ultraviolet light or to fluorescent light with wavelengths ranging from 320 to 380 nm. Vitamin A is particularly susceptible to photodegradation.7 Its loss can contribute to a clinically evident deficiency.8 Light intensity of shorter wavelength (UV fluorescent) causes greater photochemical damage than visible light. Sorption Losses Sorption is the loss of chemical compounds (eg, drugs, vitamins) into semipermeable plastic parenteral containers. Polyvinyl chloride TPN bags constructed with the plasticizer diethylhexylphthalate (DEHP) facilitate the sorptive loss process. The plasticizer acts as a solvent that promotes the sorption of vitamin A into the plastic matrix of the infusion container. The combined processes of photodegradation and sorption account for the substantial losses of vitamin A in DEHP-containing TPN bags, and can eventually lead to a clinically significant deficiency in susceptible patients.8 Hydrolysis Reactions Thiamine stability can be significantly degraded in the presence of sodium bisulfite. Hydrolytic degradation reactions often result in the splitting of one chemical constituent into 2 or more degradation products that have little or no pharmacological or nutritional actions of the parent compound. In the case of vitamins, thiamine stability can be significantly altered in the presence of the antioxidant sodium bisulfite. Sodium bisulfite is a common pharmaceutical adjuvant used in many parenteral products, including commercial amino acid formulations.9 Sulfite antioxidants such as sodium or potassium salts of bisulfite, hydrosulThiamine stability can be fite or metabisulfite significantly degraded in the are contained in presence of sodium bisulfite. varying quantities a n d t o va r y in g degrees in commerical amino acid formulations and are important reactive species that may result in the hydrolytic cleavage of thiamine to yield inactive products.7,10 Recently, however, some manufacturers have reformulated their amino acid products and either reduced or removed entirely sulfite antioxidants. Co-precipitation From Degradation Products A less known and unfavorable chemical reaction occurs when the degradation of a compound forms insoluble precipitates in a TPN admixture. For example, ascorbic acid can undergo a series of decomposition reactions to form oxalic acid. Calcium gluconate is a common daily additive in TPN admixtures, and free calcium readily reacts with oxalic acid to form the insoluble calcium oxalate.11 Important physicochemical factors involved in this reaction include the concentration of ascorbic acid and calcium gluconate, as well as pH and the order of mixing. An FDA Safety Alert concerning the potentially lifethreatening hazards of precipitation, including calcium phosphate precipitates, was issued in 1994. Recommendationsincluded use of air-elimination filters.12 Metabolic and Biochemical Factors That Contribute to Vitamin Deficiency Thiamine Status in TPN Thiamine is a critical component of carbohydrate metabolism.13 A deficiency of thiamine can develop quite rapidly in patients with significant malA deficiency in thiamine n u t rition and in can develop quite rapidly those requiring longin susceptible patients. t e r m p a r e n t er a l nutrition support. Chronic thiamine deficiency may manifest itself as a neurologic deficit with symptoms characteristic of peripheral neuritis known as dry beriberi. In rare cases, cardiac dysfunction from high-output failure can also occur and is referred to as wet beriberi.4 Clinical thiamine deficiency can occur in patients receiving TPN without thiamine supplementation5,14 or with inadequate supplementation.5 Thiamine requirements become greater as carbohydrate intake or metabolic rate increases.15 The occurrence of severe thiamine deficiency in patients receiving TPN demonstrates the need to ensure that all parenteral nutrition formulations contain thiamine in adequate quantities. Vitamin C Vitamin C (ascorbic acid) has numerous functions in the body, both at the cellular and subcellular levels. It plays an essential role in the production and maintenance of collagen.3,13 During periods of physiological stress, the urinary excretion of vitamin C is increased. There is a need, therefore, for vitamin C supplementation in patients with burns and severe trauma.13 In doses exceeding the amounts typically provided in daily parenteral multivitamins, vitamin C should be administered separate from the TPN admixture because of the compatibility reasons discussed above.7 Deficiencies of Other Vitamins Patients with inflammatory bowel disease, intestinal malabsorption, pancreatic disease, and biliary disease may be at increased risk for low serum levels of vitamins B12, A, D, and E. Therefore they may have increased susceptibility of adverse effects associated with vitamin deficiencies. Vitamin K is not a component of parenteral multivitamin mixtures in adults. Hypoprothrombinemia may result over several weeks of hospitalization if some supplementation of vitamin K is not given and the patient remains nil per os (NPO).13 The rapid development of vitamin K deficiency in acutely ill patients is often related to the lack of routine supplementation and to the destruction (by broad-spectrum antibiotics) of gut bacteria that normally synthesize endogenous vitamin K. Generally, if patients are hospitalized for 1 week or more and are NPO, weekly supplementation of 1 to 2 mg vitamin K subcutaneously is sufficient to prevent acute deficiency of this micronutrient.13 However, vitamin K supplementation should be carefully evaluated in patients with thromboembolic disease and/or in those receiving coumarin anticoagulant therapy. Prevention of Iatrogenic Vitamin Loss There are several important considerations when preparing a multivitamin solution for infusion. During the preparation of TPN admixtures, vitamins should be infused within 24 hours. Vitamins should not be included in TPN a dmixtures Vitamins should not be included intended for proin the TPN admixtures intended longed storage for prolonged storage. because vitamin losses can result from sorption or from degradative processes that form either inactive or even dangerous insoluble products. In all cases, parenteral multivitamins should be aseptically added to an admixture just prior to infusion. NAG-AMA Guidelines The need for multivitamin supplementation as part of comprehensive TPN therapy has been recognized by the Nutrition Advisory Group of the Department of Foods and Nutrition of the American Medical Association (NAG-AMA). The NAG-AMA adopted a number of statements regarding formulations and uses for parenteral multivitamin preparations that include 16: M.V.I. is contraindicated in patients with a known h y p e r s e n s i t i v i t y to any of the vitamins in the M.V.I. preparations or in patients with preexisting hypervitaminosis. • One should not await the clinical signs of vitamin deficiency before initiating vitamin therapy. Patients with multiple vitamin deficiencies or with markedly increased requirements may be given multiples (1.5 to 3 times) of the daily dosage for a period of time as indicated by clinical status. When multiple doses of the formulation are used for more than a few weeks, vitamins A and D should be monitored occasionally to ensure that an excess accumulation of these vitamins is not occurring. • Multivitamin preparations for intravenous administration are essential for use in long-term TPN therapy for maintenance of good nutritional status and nutritional rehabilitation of patients. The Table shows a comparison of adult RDA changes and recommended concentrations for intravenous multivitamin formulations. The critically ill patient may have an • Multivitamin preparations should be available for easy integration into TPN systems and should be utilized on a routine basis to assure that the solutions used are nutritionally complete. The NAG-AMA also issued specific suggestions for adult intravenous multivitamin formulations. The suggestions are based on the recommended daily allowances A 10-mL daily dose (RDA) of the National ® of M.V.I. -12 (multi-vitaAcademy of Sciences/ min infusion) matches National Research Council NAG-AMA guidelines. (NAS/NRC). Fat-soluble vitamins administered intravenously do not encounter the absorption barriers of orally administered fat-soluble vitamins; therefore, a lower dose is used. In addition, the NAG-AMA recognized that the amounts of water-soluble vitamins in multivitamin combinations may need to be in excess of the RDA in order to meet the needs of patients with the clinical conditions for which TPN is used. M.V.I.-12 matches the NAG-AMA guidelines for parenteral multivitamins in a 10-mL dose.16 This formulation makes available a combination of important fat- and water-soluble vitamins in an aqueous solution formulated specifically for incorporation into intravenous solutions. M.V.I.-12 is indicated as a daily multivitamin maintenance dosage for adults and children (11 years of age or older) who require parenteral nutrition. It is also indicated in other situations in which administration by the intravenous route is required. Such situations include surgery, extensive burns, fractures and other trauma, severe infectious diseases, and comatose states. These conditions may promote a stress situation with profound alterations in the body’s metabolic demands and consequent tissue depletion of nutrients. Comparison of Daily Recommended Dietary Allowance (RDA) and NAG-AMA Guidelines for Intravenous Multivitamin Formulations Vitamin Intravenous Concentration RDA (Daily) NAG-AMA (Daily) M.V.I.-12 (10 mL, Daily) A 4000-5000 IU 3300 IU 3300 IU D 400 IU 200 IU 200 IU E a b c 12-15 IU 10 IU 10 IU C (Ascorbic acid) 45 mg 100 mg 100 mg Folic acid 400 mcg 400 mcg 400 mcg Niacin 12-20 mg 40 mg 40 mg B1 (Thiamine) 1.0-1.5 mg 3.0 mg 3.0 mg e B2 (Riboflavin) 1.1-1.8 mg 3.6 mg 3.6 mg f B6 (Pyridoxine) 1.6-2.0 mg 4.0 mg 4.0 mg d B12 (Cyanocobalamin) 3 mcg 5 mcg 5 mcg Pantothenic acid 5-10 mg 15 mg 15 mg Biotin 150-300 mcg 60 mcg 60 mcg a as 1 mg retinol b as 5 mcg ergocalciferol c as 10 mg di-alpha tocopheryl acetate d as niacinamide g e as HCl f as riboflavin-s-phospahe sodium g as dexpanthenol Adapted from American Medical Association Department of Foods and Nutrition. J Parenter Enteral Nutr. 1979;3:260.16 increased micronutrient demand to fuel the augmented enzymatic processes associated with high metabolic stress; therefore, it is important to supplement the TPN formula with a standard multivitamin solution at least once daily. Shils et al studied the ability of a multivitamin preparation (that meets the NAG-AMA guidelines) to maintain normal serum concentrations in long-term home TPN patients.17 Their results are based on observations of vitamin levels in 16 long-term stable TPN patients for a period of 5 to 8 months. The multivitamin formulation maintained plasma and whole blood levels of its 11 constituent vitamins and vitamin D metabolites for the