Hypoprothrombinemia

ABSTRACT. The newly amended requirements by the Food and Drug Administration (FDA) for an effective adult parenteral multivitamin drug product increase the amounts of vitamins B1, B6, C, and folic acid currently in the product to better meet estimated needs, and specifies the inclusion of 150 [mu]g of vitamin K. Infuvite Adult Multiple Vitamins for Infusion is the first adult parenteral multivitamin product to meet the revised FDA requirements. The inclusion of vitamin K in adult parenteral multivitamin products is intended to afford patients a consistent daily supply of vitamin K approximating usual levels of intake. This is a change to clinical practice in the United States, where vitamin K has not been included in adult parenteral vitamin preparations, and physicians prescribe vitamin K separately. The reformulation of adult parenteral multivitamins required by the FDA raises questions about the potential impact that inclusion of vitamin K will have on patient management. One clinical practice change is that patients on parenteral nutrition receiving Infuvite Adult should no longer need weekly subcutaneous (SC) or intramuscular (IM) vitamin K injections. In addition, the consistent and modest level of vitamin K provided by the reformulated adult parenteral multivitamins may make it easier for physicians to maintain the desired level of hypoprothrombinemia (low levels of prothrombin) in those patients also on anticoagulant therapy with warfarin. However, for physicians accustomed to administering vitamin K separately, it is important to highlight that it may be more difficult to titrate anticoagulant therapy, especially among patients receiving dual feeding or vitamin K from another source. If marketed globally, these clinical practice issues may be more pronounced outside of the United States, where dual feeding is common, and patients may receive vitamin K from other sources. (Journal of Parenteral and Enteral Nutrition 27:220-224, 2003)

Infuvite Adult Multiple Vitamins for Infusion (Sabex Inc, Montreal, Canada) is the first parenteral multiple vitamin product formulated to meet the newly amended requirements of the Food and Drug Administration (FDA) for adult parenteral multivitamin drug products published in the Federal Register in 2000.1 The new adult parenteral multivitamin formulation requirements are based on recommendations proposed by a public workshop held in August 1985 that was sponsored by the FDA's Division of Metabolic and Endocrine Drug Products and the American Medical Association's (AMA) Division of Personal and Public Health Policy, and included an expert panel of clinicians such as founding members and a past president of the American Society of Parenteral and Enteral Nutrition (A.S.P.E.N.). Compared with the 1975 formulation recommended by the Nutritional Advisory Group (NAG) of the AMA,2 the new parenteral multivitamin formulation recommendations include increased amounts of vitamins B1, B6, C, and folic acid, and for the first time, include vitamin K. Reasons for the unusually long time period between the 1985 workshop recommendations and the publication of the revised formulation requirements by the FDA are unclear but may be related to the multiple national shortages of adult and pediatric parenteral vitamins that occurred in the late 1980s and 1990s. The reformulation of adult parenteral multivitamins raises questions among healthcare practitioners concerning the potential impact that inclusion of vitamin K will have on patient management.

VITAMIN K

Biologically Active Forms of Vitamin K

Vitamin K occurs in several molecular forms. All have a 2-methyl-1,4-naptholquinone ring, but they differ in the structure of the side-chain at the 3-position. Phylloquinone (old nomenclature: vitamin K1) occurs naturally in plants. The menaquinones (vitamin K2), of which there are several forms, are synthesized by bacteria in the intestinal tract and are categorized based on the number of repeating unsaturated 5-carbon (prenyl) units. The menaquinones, usually abbreviated as MK-n, bind tightly to the bacterial cytoplasmic membrane and are lipophilic. Nevertheless, the finding that 90% of the human liver vitamin K content is menaquinones suggests that the microfloral synthesis makes a significant contribution to human vitamin K stores.3 Menadione (vitamin K3) is a synthetic vitamin K compound. In the intestinal tract, menadione is converted to the menaquinone form.4

Physiologic Role of Vitamin K

Vitamin K is an essential cofactor for the synthesis of blood coagulation factors II (prothrombin), VII, IX, and X and is required for the synthesis of the coagulation inhibitors, proteins C and S. The association between vitamin K deficiency and bleeding abnormalities is well-established,5,6 particularly in malnourished patients receiving antibiotics that interfere with the intestinal microflora and the production of menaquinone.32 Easy bruisability and mucosal bleeding are symptoms of vitamin K deficiency and the related reduction in vitamin K-dependent coagulation factors. More recently, it has been recognized that vitamin K is also necessary for the synthesis of a diverse group of proteins involved in calcium homeostasis.7 Osteocalcin, one of these vitamin K-dependent proteins, is found in the extracellular matrix of bone and is important to both early skeletal development and the maintenance of healthy mature bone. Recent epidemiologic association between mild vitamin K insufficiency and increased risk of fractures has been noted in healthy populations.8,9 Experimentally, short-term depletion of vitamin K has been shown to increase bone turnover.10 Vitamin K supplementation for patients on parenteral nutrition may be particularly critical because metabolic bone disorders are common in this patient group. Several studies have shown that a high percentage (42% to 100%) of patients on long-term parenteral nutrition develop either histologic features of bone disease or diminished axial bone mineral density.11 Bone metabolism disorders have been shown to be directly related to the duration of parenteral nutrition therapy.12 The cause of bone disease associated with parenteral nutrition is most likely multifactorial and related to the patients underlying disease and the parenteral nutrition therapy. Cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor [alpha] are known to influence bone resorption, and if induced by parenteral nutrition, may be factors in the hypercalciuria and reduced bone mineralization seen in patients on parenteral nutrition therapy.13

Vitamin K is also involved in such diverse physiologic activities as regulation of glucose metabolism, antiarteriosclerosis, and induction of cell differentiation.14 New understanding of how vitamin K-dependent proteins bind to tyrosine kinase receptors and affect cell replication, cell transformation, and cell survival underscore a previously unrecognized role for vitamin K in cell signaling.15

Vitamin K is primarily concentrated in the liver but is also found in the adrenal glands, lungs, bone marrow, kidney, pancreas, spleen, and lymph nodes. The plasma transport of vitamin K seems to be mediated by triglyceride-rich lipoproteins.16 Because vitamin K is not stored in significant quantities in the body, a regular supply is required.

Vitamin K Deficiencies

The phylloquinone form of vitamin K is widely distributed in food, with particularly high levels in green leafy vegetables, soybeans, and certain vegetable oils. Menaquinones have more limited dietary sources, with significant amounts occurring only in animal livers and some fermented foods such as cheese. Parenteral lipid emulsions made from soybean oil contain significant amounts of vitamin K, with approximately 0.3 [mu]g/mL in 10% emulsion and 0.6 [mu]g/mL in 20% emulsion and about one-half this amount in the 50:50 soybean:safflower mixture.17 This translates into approximately 30 [mu]g of vitamin K in 10 g of soybean oil. Green tea, egg yolks, and whole wheat are also good dietary sources of vitamin K. As previously noted, the resident bacterial flora in the anterior portion of the gut provide another source of vitamin K. The intrinsic synthesis of vitamin K and the wide distribution of vitamin K in food make primary vitamin K deficiency sufficient to cause bleeding rare among healthy adults. Indications for vitamin K supplementation include patients with coagulation disorders related to vitamin K, malabsorption syndromes, and patients who are unable to maintain an adequate oral intake of vitamin K. The latter also includes situations that stress the body's metabolic demands such as surgery and extensive burns. Newborns have a greater likelihood of spontaneous vitamin K deficiency because of poor placental transfer and limited dietary intake of vitamin K, which puts them at risk of developing hemorrhagic disease of the newborn (HDN), a bleeding disorder characterized by cutaneous, gastrointestinal (GI), intrathoracic, or in the worst cases, intracranial bleeding. Neonates are routinely given a prophylactic IM vitamin K injection or oral vitamin K supplements to prevent HDN.

Parenteral nutrition may cause a silent deficiency of vitamin K. If patients receiving parenteral nutrition are given an antibiotic that inhibits the hepatic vitamin K cycle (eg, certain cephalosporins), they may develop severe or fatal bleeding.18,19 As a result, vitamin K is routinely given to patients on parenteral nutrition.

Drug Inhibition of Vitamin K

Certain other drugs also interfere with vitamin K and decrease blood clotting times. For example, salicylates, such as aspirin, increase the need for vitamin K. Coumarin anticoagulants, such as warfarin, compete with vitamin K at its active sites and reduce the formation of prothrombin. Anticoagulant therapy with warfarin is commonly used to reduce the risk of thromboembolism in patients who have had strokes, heart attacks, valvular heart disease, cardiac arrhythmias, thrombophlebitis, or pulmonary embolism, or who are at risk for any of these conditions. Injections of vitamin K can rapidly reverse overdoses of anticoagulant drugs.

Vitamin K Requirements in Patients on Parenteral Nutrition

In otherwise healthy individuals, a daily adequate intake (AI) for vitamin K of 90 [mu]g for women and 120 [mu]g for men has been established20 or about 30 and 40 g of soybean oil emulsion per day, respectively. Because toxic manifestations have not been reported for vitamin K even when large amounts are ingested over extended periods of time, no upper limit (UL) has been established on daily vitamin K intake.

Patients on total parenteral nutrition (TPN) have increased need for vitamin K because of liver disorders, increased consumption of clotting factors, and a lack of dietary vitamin K intake.21,33 If not given supplemental vitamin K, patients on parenteral nutrition show prolonged prothrombin times.22 The AMA originally recommended a single weekly dose of 2 to 4 mg of vitamin K in for patients on parenteral nutrition not receiving anticoagulants.23 More recently, studies have shown that adequate plasma vitamin K concentrations can be maintained at parenteral vitamin K doses below the AMA recommendations. Hands et al showed that 140 [mu]g of vitamin K once weekly, a level significantly less than the weekly dose of 10 mg frequently given to patients on parenteral nutrition, was sufficient for patients receiving TPN.24 In patients receiving both TPN and anticoagulation therapy with warfarin, the usual policy has been to avoid supplemental vitamin K and to adjust warfarin dosage rather than provide this very large weekly dose of vitamin K. With the availability on a daily basis of physiologic amounts of vitamin K from this new formulation, it should be anticipated that warfarin doses for anticoagulation may therefore be somewhat higher than previously provided. In home TPN, patients receiving so-called minidose warfarin of 1 to 2 mg/d, which provides some protection against catheter-associated thrombosis while not prolonging prothrombin times,25 further study will be required to determine whether a change in warfarin dose will be necessary to achieve the same level of protection. The reformulated adult parenteral multiple vitamins for infusion contain 150 [mu]g of vitamin K, a level much closer to the AI established for vitamin K. Current vitamin K requirements relate only to the coagulation function of vitamin K. Better understanding of vitamin K's role in bone metabolism and cell differentiation may require redefinition of vitamin K requirements in both healthy adults and patients receiving TPN.

Routes of Administration

Supplemental vitamin K may be given orally, but oral vitamin K preparations are not well absorbed without the presence of bile salts and pancreatic juices. As a result, the intramuscular (IM) or subcutaneous (SC) routes are generally used for patients with impaired or unpredictable gut absorption. Disadvantages to IM and SC administration of vitamin K are that they require a nurse to administer and they can be painful for the patient. IM injections are also difficult for those patients on parenteral nutrition that have decreased fat or muscle layers. Vitamin K may be administered by the IV route and is preferentially given by the IV route to patients in severe hemorrhagic states and to patients who fail to respond to other routes of administration.26

CLINICAL CONSIDERATIONS FOR REFORMULATED PARENTERAL MULTIPLE VITAMINS

Differences From Previous Formulations

The newly amended requirements of the FDA for adult parenteral mutivitamin drug products increase the amounts of vitamins B1, B6, C, and folic acid currently in the products and specify the inclusion of 150 [mu]g of vitamin K. A comparison of the 1975 formulation issued by the NAG of the AMA and current FDA requirements is shown in Table I.

Safety and Efficacy of Administering Vitamin K With Parenteral Nutntion Solutions

Vitamin K is compatible with TPN solutions as determined by high-pressure liquid chromatography (HPLC), and the inclusion of vitamin K in TPN has not been associated with adverse reactions.27,28 Major adverse reactions have been reported in patients receiving 5 to 10 mg of vitamin K by the IV route over short periods of time (10 to 45 minutes); however, when administered over longer periods of time, the IV route is as safe as IM administration.29 A study comparing IV and IM vitamin K administration in 60 patients using parenteral nutrition found that patients receiving vitamin K by the IV route over 8 to 12 hours had no more adverse reactions than patients receiving IM vitamin K. The study also found that the IV and IM routes of vitamin K administration were equally effective as measured by correction of the prothrombin and activated partial thromboplastin times.

Benefits of Inclusion of Vitamin K in Adult Parenteral Multivitamins

Previous parenteral multivitamin formulations that lacked vitamin K allowed clinicians to choose which patients received supplemental vitamin K. Inclusion of vitamin K in the parenteral multivitamin product eliminates a clinician's ability to make this choice and has raised questions about the impact of daily vitamin K infusions on patients being treated with anticoagulants such as warfarin. Although it is well known that the amount of vitamin K patients consume through their diet may affect therapy with anticoagulants, a consistent intake of vitamin K does not adversely affect the efficacy of anticoagulant therapy. The makers of Coumadin (warfarin; Bristol-Myers Squibb, Princeton, NJ) do not recommend patients eliminate all vitamin K containing foods from their diets.30 Instead, they recommend that patients eat a normal, balanced diet and maintain a consistent intake of vitamin K. They recommend patients avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables, which might cause vitamin K intake to fluctuate and affect the level of hypoprothrombinemia induced by the anticoagulant. All patients on anticoagulant therapy need frequent prothrombin time measurements and adjustments of their dose of drug until the desired level of anticoagulation is achieved. Once the patient is at the desired level of hypoprothrombinemia (low levels of prothrombin), the consistent amount of vitamin K provided by the reformulated adult parenteral multivitamins may aid in maintaining this level. Maintaining anticoagulation levels in the therapeutic range is essential to good patient outcomes.

Another benefit of including low levels of vitamin K in parenteral multivitamins is that it allows for more physiologic dosing. With single, weekly bolus injections, the daily bioavailability of vitamin K can vary widely depending on the patient's clinical condition and amount of body fat stores. The consistent supply of vitamin K provided by the reformulated adult parenteral multivitamins more closely matches the liver's constant requirement for vitamin K to support the production of coagulation factors. Daily vitamin K supplementation has been reported to result in low fluctuations in serum levels and an improvement of the synthesis of coagulation factors.31

The consistent daily supply of vitamin K provided by the reformulated adult parenteral multivitamins better mimics the normal dietary intake of vitamin K and thus may facilitate patients' transitioning from an enterai diet to a parenteral diet and vice versa.

A practical benefit of infusing vitamin K with the TPN solution is that it eliminates the need for a weekly vitamin K injection. This not only spares patients the discomfort of an SC or IM injection, but also saves nursing and pharmacy time. However, despite these many putative benefits, it is recommended that clinicians pay close attention to anticoagulant status when initially confronted with patients receiving this new parenteral vitamin therapy and warfarin anticoagulation therapy. Obviously, the FDA believes that there are more advantages than disadvantages to the inclusion of vitamin K in parenteral multivitamins. Given the difference in nutrition therapy practices throughout the world, it will be interesting to see whether the rest of the world adopts these new recommendations or creates a separate committee to evaluate adult parenteral vitamin formulations. Infuvite is the first vitamin available to meet the new FDA guidelines.

CONCLUSIONS

Vitamin K is a necessary nutrient with important roles in the maintenance of hemostasis and bone health and newly uncovered roles in cell proliferation and cell signaling. The inclusion of vitamin K in paren teral multivitamin products, as the FDA has specified, is safe and effective and ensures that patients receiving TPN will receive a consistent level of vitamin K. Infuvite Adult Multiple Vitamins for Infusion is the first parenteral multiple vitamin product to meet the new FDA Advisory Committee recommendations for the increased amounts of vitamins B1, B6, C, and folic acid, and the inclusion of vitamin K. In addition to ensuring patients receive sufficient vitamin K, use of the reformulated adult parenteral multivitamins may spare patients a weekly, painful IM vitamin K injection and provide patients with a more physiologic dosing of this vitamin. Because vitamin K is widely available in the diet, the inclusion of vitamin K in parenteral multivitamins may facilitate the transition of patients on to or off of parenteral nutrition. Patients on parenteral nutrition who are also on Coumadin (warfarin) anticoagulants initially will need periodic prothrombin time tests to ensure they are receiving the appropriate dose of drug given the competitive nature of vitamin K intake and warfarin dose. Once patients have achieved a stable level of hypoprothrombinemia, the consistent and low vitamin K intake provided by the reformulated adult parenteral multivitamins may aid in maintaining the desired level of anticoagulation by eliminating fluctuations in vitamin K intake that are known to interfere with anticoagulant therapy. Other vitamin preparations available throughout the world continue to be reviewed as safe and effective and conform to local standards of practice for separate administration of vitamin K.

ACKNOWLEDGMENTS

This study was supported in part by a grant from Baxter Healthcare.

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Cynthia J. Helphingstine, PhD*; and Bruce R. Bistrian, MD, PhD[dagger] From the *Biotron Group, Inc., Highland Park, Illinois; and [dagger]Laboratory of Nutrition/Infection, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Received for publication, May 21, 2002.

Accepted for publication, January 31, 2003.

Correspondence: Cynthia J. Helphingstine, PhD, The Biotron Group, 396 Vine Avenue, Highland Park, IL 60035-2043.

Copyright American Society for Parenteral and Enteral Nutrition May/Jun 2003
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