Download Pharmacy Issues in Multivitamin Infusion An Update

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