Introduction
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 parenteral 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
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
Photodegradation is directly influenced by luminous intensity. In accordance with Planck’s Theory, wavelength is inversely proportional to photon energy or light intensity (i.e., 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.6,7 Its loss can contribute to a clinically evident deficiency.8
Sorption Losses
Sorption is the loss of chemical compounds (e.g., 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
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.9Sulfite antioxidants such as sodium or potassium salts of bisulfite, hydrosulfite or metabisulfite are contained in varying quantities and to varying degrees in commerical amino acid formulations and are important reactive species that may result in the hydrolytic cleavage of thiamine to yield inactive products.710Recently, 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 life threatening hazards of precipitation, including calcium phosphate precipitates, was issued in 1994.
Recommendations included 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 malnutrition and in those requiring long-term parenteral 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 supplementation5,14or with inadequate supplementation.5Thiamine 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.5,13During 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 parenterally 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 admixtures intended 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.
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 include16:
- One should not await the clinical signs of vitamin deficiency before initiating vitamin therapy.
- 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.
- 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 (RDA) of the National Academy of Sciences/National Research Council (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.
M.V.I.® is contraindicated in patients with a known hypersensitivity to any of the vitamins in the M.V.I. ® preparations or in patients with preexisting hypervitaminosis. 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.
For complete M.V.I.-12® prescribing information, click here (requires Adobe pdf).
Safety Issues for Multivitamin Infusions
Aseptic Technique
All multivitamin infusion solutions should be prepared under sterile conditions. If available, preparation under a laminar flow hood is recommended. A multivitamin formulation can be added to a TPN admixture with a single injection. In contrast, the addition of multiple single-vitamin solutions can increase the risk of extrinsic contamination due to an excessive number of violations to the entry port of the infusion container.
Absence of Order for Multivitamin Infusion
If the nutrition support pharmacist notices the omission of multivitamins on the TPN order sheet, he or she should notify either the physician writing the order or a member of the nutrition support team. Most patients receiving TPN are candidates for multivitamin infusion. Such omissions, therefore, should be considered erroneous until further explained by appropriate clinical personnel.
Using an FDA-Approved Product
The use of a complete product that conforms to the NAGAMA guidelines and has received FDA approval makes the management of multivitamin supplementation easier and safer for the practitioner. The use of individual vitamin products or incomplete formulations may heighten the risk of untoward clinical outcomes.
Summary
Patients receiving parenteral nutrition therapy have increased vitamin needs. Daily infusion of a multivitamin formulation that is based on the NAG-AMA recommendations can maintain serum vitamin levels within normal parameters, meet the vitamin needs of the patient, and protect the patient against clinically significant vitamin losses. In most cases, the daily use of a multivitamin product obviates the need to speculate on the status of individual vitamin nutriture.
The nutrition support pharmacist’s combined knowledge of pharmacokinetics, drug-drug interactions, and drug-nutrient interactions is a valuable component of nutritional support. Of further help is the pharmacist’s knowledge of pharmaceutics with respect to the stability and physicochemical compatibility of various infusion mixtures. Patients who are receiving TPN therapy are likely to benefit from a comprehensive formulation review of their regimens by the nutrition support pharmacist.
References
1. American Society for Parenteral and Enteral Nutrition. Standards for nutrition support
pharmacists. Nutr Clin Pract. 1993;8:124-127.
2. Special Report. Safe Practices for Parenteral Nutrition Formulations. J Parenter Enteral Nutr. 1998;22:49-66.
3. Zaloga GP, Bortenschlager L. Vitamins. In: Zaloga GP, ed. Nutrition in Critical Care. St Louis, Mo: Mosby Year Book. 1993:217-242.
4. Zak J, Burns D, Lingenfelser T, et al. Dry beriberi: unusual complication of prolonged
parenteral nutrition. J Parenter Enteral Nutr. 1991;15:200-201.
5. Velez RJ, Myers B, Guber MS. Severe acute metabolic acidosis (acute beri-beri): an avoidable complication of total parenteral nutrition. J Parenter Enteral Nutr. 1985;9:216-219.
6. Newton DW. Physicochemical determinants of incompatibility and instability in injectable drug solutions and admixtures. Am J Hosp Pharm. 1978;35:1213-1222.
7. Smith JL, Canham JE, Wells PA. Effect of phototherapy light, sodium bisulfite, and pH on vitamin stability in total parenteral nutrition admixtures. JParenter Enteral Nutr. 1988;12:394-402.
8. Howard L, Chu R, Feman S, Mintz H, Ovesen L, Wolf B. Vitamin A deficiency from long-term parenteral nutrition. Ann Intern Med. 1980;93:576-577.
9. Schiano TD, Klang MG, Quesada E. Scott F, Tao Y, Shike M. Thiamine status in patients
receiving long-term home parenteral nutrition. Am J Gastroenterol. 1996;91:2555-2 5 5 9 .
10. Scheiner JM, Araujo MM, DeRitter E. Thiamine destruction by sodium bisulfite in infusion solutions. Am J Hosp Pharm. 1981;38:1911-1913.
11. Das Gupta V. Stability of vitamins in total parenteral nutrient solutions. Am J Hosp Pharm. 1986;43:2132. Letter.
12. Lumpkin MM, Burlington DB. Safety alert: hazards of precipitation associated with parenteral nutrition. Am J Hosp Pharm. 1994;51:1427-1428.
13. Van Way CW. Vitamins and trace elements. In: Van Way CW III, ed. Handbook of Surgical Nutrition. Philadelphia, Pa: JB Lippincott Co; 1992:56-69.
14. Anon. Deaths associated with thiamine-deficient total parenteral nutrition. Morb Mortal Wkly Rep. 1989;38:43-46.
15. McCormick DB. Thiamine. In: Shils ME, Young VR, eds. Modern
Nutrition in Health and Disease. Philadelphia, Pa: Lea & Febiger; 1988:355-361.
16. American Medical Association Department of Foods and Nutrition. Multivitamin preparations for parenteral use. A statement by the Nutrition Advisory Group. J Parenter Enteral Nutr.1979;3:258-262.
17. Shils ME, 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. J Parenter Enteral Nutr.1985;9:179-188.
The American Medical Association (AMA) may be found on the Web at http://www.ama-assn.org/.
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