DOI: 10.1002/jpen.

2306

REVIEW

Parenteral nutrition compatibility and stability: A

comprehensive review

Joseph I. Boullata PharmD, RPh1 Jay M. Mirtallo MS, RPh2,3

Gordon S. Sacks PharmD4 Genene Salman PharmD5 Kathleen Gura PharmD6,7
Todd Canada PharmD8 Angela Maguire PharmD9 the ASPEN Parenteral Nutrition
Safety Committee2
1
Clinical Nutrition Support Services, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
2
American Society for Parenteral and Enteral Nutrition, Silver Spring, Maryland, USA
3
College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
4
Medical Affairs for PN Market Unit, Fresenius Kabi USA, LLC, Lake Zurich, Illinois, USA
5
Department of Pharmacy Practice, College of Pharmacy, Marshall B. Ketchum University, Fullerton, California, USA
6
Pharmacy Clinical Research Program, Boston Children’s Hospital, Boston, Massachusetts, USA
7
Harvard Medical School, Boston, Massachusetts, USA
8
University of Texas MD Anderson Cancer Center, Houston, Texas, USA
9
BJC HomeCare Infusions, Overland, Missouri, USA

Correspondence
Jay M. Mirtallo, 2921 Braumiller Rd, Delaware, Abstract
OH 43015, USA.
Email: jaym@nutritioncare.org
Several guidance documents support best practices across the stages of the parenteral
nutrition (PN) use process to optimize patient safety. The critical step of PN order ver-
ification and review by the pharmacist requires a contextual assessment of the com-
patibility and stability implications of the ordered PN prescription. This article will
provide working definitions, describe PN component characteristics, and present a
wide-ranging representation of compatibility and stability concerns that need to be
considered prior to preparing a PN admixture. This paper has been approved by the
American Society for Parenteral and Enteral Nutrition (ASPEN) Board of Directors.

KEYWORDS
compatibility, parenteral nutrition, stability

INTRODUCTION
Parenteral nutrition (PN) therapy continues to be a valued clinical
intervention for many patients across care settings. It is considered
a high-alert medication, meaning that its use requires safety-focused
policies, procedures, practices, and systems to limit patient risk. From
the first use of PN, pharmacists were called upon to design and pre-
pare safe formulations taking into account sterility, compatibility, and
stability.1 Numerous national guidance documents promote the safety
and efficacy of PN therapy.2–5 Among the guidance documents are
those that specifically address the review of the PN prescription.3 In
this critical step of the PN use process, a pharmacist reviews each PN

© 2022 American Society for Parenteral and Enteral Nutrition

JPEN J Parenter
J Parenter Enteral
Enteral Nutr. 2022;46:273–299.
Nutr. 2022;1–27. wileyonlinelibrary.com/journal/jpen
wileyonlinelibrary.com/journal/jpen 273
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2 BOULLATA ET AL .
prescription for completeness, clinical appropriateness, and formula-
tion safety, communicating any concerns with the prescriber.6,7 This is
inherently understood to require the pharmacist to apply their knowl-
edge of pharmaceutical science and ensure the likelihood of a safe PN
formulation.
This comprehensive review fills an identified void on the topic with
a deeper look behind isolated tables or lists of PN compatibility and
stability. The article aims to reinforce the pharmacist’s appreciation of
the complexity of PN formulation review by defining and then describ-
ing the major compatibility and stability pitfalls that need to be rec-
ognized to limit the risk of infusing a potentially unsafe PN. A phar-
macist specializing in nutrition support uses their knowledge, skill, and
experiences to verify the safety of PN regimens recommended or pre-
scribed by others. This article also serves as a resource for other clini-
cians involved in recommending or prescribing a specific PN regimen to
better appreciate the pharmacist’s foundation and rationale. A follow-
up article will provide practical steps to help clinicians recommend or
prescribe safe PN formulations with compatibility and stability in mind,
and a third article will describe methodology for evaluating PN compat-
ibility and stability.
These recommendations do not constitute medical or other pro-
fessional advice and should not be taken as such. To the extent that
the information published herein may be used to assist in the care
of patients, this is the result of the sole professional judgment of the
attending healthcare professional whose judgment is the primary com-
ponent of quality medical care. The information presented is not a sub-
stitute for the judgment by the healthcare professional. Circumstances
in clinical settings and patient indications may require actions differ-
ent from those recommended in this document, and in those cases,
the judgment of the treating professional should prevail. The American
Society for Parenteral and Enteral Nutrition (ASPEN) does not endorse
any particular brand of products mentioned herein. This paper has been
approved by the ASPEN Board of Directors.
Pharmacy science
The pharmaceutical sciences often refer to the broad, interdisciplinary
foundational sciences and the unique knowledge underpinning phar-
macy practice.8 This is not just a collection of science for its own end,
but one that ultimately supports the safe and effective use of medica-
tions. This knowledge allows both qualitative and quantitative appli-
cation of scientific principles to patient care—for example, applying
known data on the physical properties and chemical properties of sub-
stances to best predict solubility, compatibility, stability, formulation
design, and physiologic action, among others. Pharmaceutical science
disciplines include pharmaceutics, pharmacokinetics, and pharmaco-
dynamics, which are each incorporated into the clinical care of the
patient.8 It is the unique responsibility of the pharmacist in general to
ensure that prepared medications dispensed for patient use are safe
and effective. This obligation includes ensuring the integrity of any pre-
pared parenteral dosage form, not least being the compatibility and
stability of PN—arguably the most complex drug in routine clinical use.
This requires the pharmacist reviewing their patient’s PN formulation
to be knowledgeable in pharmaceutics, a responsibility already empha-
sized in the literature.9–12
Chemical compounds (eg, drugs, nutrients) are formulated into
dosage forms by manufacturers to create a product to be administered
to patients. For intravenous (IV) administration, this requires sterile,
low-particulate (within compendial limits) dosage forms formulated as
solutions—usually aqueous, but they may often include some nonaque-
ous solvents. The exception are those products formulated as oil-in-
water emulsions (eg, lipid injectable emulsions [ILEs]). Physicochemi-
cal properties (eg, solubility, ionization constants) are accounted for in
the formulation of each manufactured IV product. Each product may
include substances beyond the active ingredient(s), including excipi-
ents intended for a specific role (eg, to maintain sterility, solubility, sta-
bility). Combining individual IV drug products (ie, components) into a
single preparation is referred to as an IV admixture. The pharmacy asep-
tically prepares these IV admixtures (also known as compounded ster-
ile preparations). The most complex such admixture, containing over 50
chemical components, is PN. Throughout this paper, the compounded
sterile PN, as a preparation available for administration, is referred to
as an admixture (ie, PN admixture) regardless of whether it contains
ILEs (ie, 3-in-1, total nutrient admixture [TNA]) or not (ie, 2-in-1).
Inevitably, the admixture is less stable than its individual compo-
nent products, with risk for incompatibilities. Risk for incompatibility
and instability is ever-present and an issue long recognized with PN but
less well appreciated in recent years.4,13 Compatibility and stability are
at least as important as sterility in determining a beyond-use date for
PN admixtures, whether preparing the admixtures for immediate use
in acute care or for a 7-day supply in the home care setting.
Compatibility
Compatibility refers to the uneventful physical and chemical coexis-
tence of two or more components over time after being combined.14–16
Combining substances at any point prior to or during administration
holds the potential for physical and chemical reactivity. The term incom-
patibility therefore indicates an interaction between two or more sub-
stances (active ingredients, excipients, and/or materials [eg, packaging,
containers, infusion sets]) over time in a specific environment. These
may be physical incompatibilities (eg, complexation or leaching or des-
orption) or chemical incompatibilities. The latter involve reactants of
intermolecular and interionic forces as might be seen with the Mail-
lard reaction and calcium and phosphate insolubility. The manifestation
of an incompatibility may be a change in color, pH, osmolality or vis-
cosity, formation of gas, or yielding of a precipitate (whether visible or
not) altering the admixture. The result may ultimately limit therapeutic
effect of one or more active components or increase the risk for toxicity
including that from the infusion of precipitates.
Incompatibility is generally preventable, often dependent on pro-
portional concentrations of ingredients, requiring some knowledge
of chemical structures, solubilities, pKa values for ionizable ingre-
dients, and the pH of each component to anticipate and avoid
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION
incompatibilities. The potential incompatibilities may or may not
already be defined in the literature but are less likely described for
multicomponent admixtures such as PN. If an incompatibility is already
reported, the pharmacist will need to be able to decipher the cause to
prevent similar recurrence in formulating a PN admixture. Multiple and
overlapping forces may affect a PN admixture. For example, the pH of
the final admixture may influence the solubility as well as the stability
of ingredients. Consider that a pH difference of 2 units represents a
100-fold change, since the scale is logarithmic not linear. Each PN com-
ponent product is manufactured at a pH at which the active ingredient
is most soluble and stable. The pH of each component can vary con-
siderably from other component products and is a critical characteris-
tic that needs to be considered when combining components in a PN
admixture to avoid incompatibility and instability related to the overall
pH of the final PN admixture.
Stability
The term stability refers to the maintenance of the chemical integrity
of each active ingredient or the physical integrity of the dosage
form/system over time in a given environment.14–16 Instability there-
fore indicates the irreversible decomposition/degradation of active
ingredients or the dosage form/system as a result of pH, tempera-
ture, light, oxygen, solvents, and/or reactants. These may be physical
(eg, crystallization, adsorption, broken emulsion) or chemical (eg,
hydrolysis, oxidation). Oxidation reactions may occur in the presence
of oxygen (auto-oxidation) or additionally in the presence of light
(photo-oxidation). The environment in which PN preparation—as well
as storage and administration—takes place involves exposure to air
and light. Instability may manifest as increased particulate matter, a
visible haze, visible oil, or other color change but, in most cases, may
only be identified using appropriate methodology. The rates of degra-
dation or reaction vary with the reactants and the environment. The
ultimate result is that instability can take away from biological activity
of the degraded component or generate risk from toxic by-products or
particulate matter, including large lipid droplets.
The physical instability of ILE refers to increases in lipid droplet
size. However, chemical instability of ILE may include peroxide forma-
tion and pH change without necessarily affecting physical stability.17
Combining substances at any point prior to intravascular infusion holds
the potential to alter chemical structure of a substance or the phys-
ical state of the admixture. For example, ILE physical instability may
occur not only in a TNA but also with Y-site administration.18 Any
change beyond acceptable parameters (eg, maintaining at least 90%
of the labeled amount or initial concentration of an active ingredient
throughout infusion) indicates instability with the risk of altering thera-
peutic effect. Although individual minerals—including electrolytes and
trace elements—do not undergo decomposition, they do possess prop-
erties (ie, ionization, valence states) that invite compatibility concerns
or stability concerns for the organic components in the PN admixture
or the emulsion itself. Instability is not reversible; the degradation can
be slowed but not stopped.
275
3
Application to practice
Whether a PN formulation is completely customized to a patient’s
macronutrient and micronutrient needs or begins with a standard-
ized, commercially available PN product, variation of just one compo-
nent has the potential to influence the final admixture. The complex-
ity of a PN admixture is quickly recognized when acknowledging the
many ingredients that are eventually in the patient’s infusion container.
Newer products and updated compatibility and stability study meth-
ods and data may even supplant older information. Furthermore, with
each new product introduced to the market and included as a PN com-
ponent, or as clinical practice evolves to better customize the PN to
meet patient needs, recalibration of our understanding of compatibil-
ity and stability is needed. This has happened over time, whether it
was the introduction of TNAs into practice,19,20 including the newer
ILE products,21 or evaluating new drugs administered by Y-site with
PN.22,23 The importance of compatibility and stability is heightened
for the patients who will receive a 7-day supply of PN admixtures at
home.24 Incompatibility or instability of an admixture is seldom obvi-
ous to the unaided eye but can be determined experimentally using val-
idated methods or can be predicted based on known physicochemical
properties of all the components. Unfortunately, significant harm and
fatality can occur when available data are not taken into account or
pharmaceutics is not considered.25,26 Pharmacists without the requi-
site knowledge or not applying principles do so at their own peril and
place their patients at risk.
PN COMPONENTS AND RELEVANT PROPERTIES
Numerous product components are used to prepare a PN admix-
ture. As each component has unique physicochemical properties, a
summary of these will be presented. Several aspects relevant to
compatibility and stability will be noted below prior to the discus-
sion of compatibility and stability in PN admixtures in subsequent
sections.
Macronutrients
Amino acids
Commercial amino acid products available in the United States are
listed in Tables 1 and 2.27–36 Most are supplied in plastic containers,
with an overwrap to avoid water loss and subsequent altered concen-
tration. Plastic is now used in preference to glass bottles for ease of
transport and storage, and very little plasticizer is expected to leach
into the amino acid solution from the product’s plastic container dur-
ing storage.
The products vary in the number and concentration of each crys-
talline amino acid, total amino acid, and nitrogen content, as well as
electrolyte content and pH.27–36 As a result, the amino acid prod-
ucts and associated compatibility and stability data are not necessarily
276
4 BOULLATA ET AL .

TA B L E 1 Content and characteristics of AA injection products (pediatric)

Product Aminosyn-PF 10%27 Premasol 10%33 TrophAmine 10%36

Manufacturer ICU Medical Baxter B. Braun
Essential AAs, g/100 ml
Cysteinea 0 <0.016 <0.016
Histidine 0.312 0.48 0.48
Isoleucine 0.76 0.82 0.82
Leucine 1.2 1.4 1.4
Lysine 0.677 0.82 0.82
Methionine 0.18 0.34 0.34
Phenylalanine 0.427 0.48 0.48
Threonine 0.512 0.42 0.42
Tryptophan 0.18 0.2 0.2
a
Tyrosine 0.044 0.24 0.24
Valine 0.673 0.78 0.78
Nonessential AAs, g/100 ml
Alanine 0.698 0.54 0.54
Arginine 1.227 1.2 1.2
Aspartic acid 0.527 0.32 0.32
Glutamic acid 0.82 0.5 0.5
Glycine 0.385 0.36 0.36
Proline 0.812 0.68 0.68
Serine 0.495 0.38 0.38
Taurine 0.07 0.025 0.025
Electrolytes, mmol/L
Acetate 46 94 96.2
Phosphate None NR NR
Sodium None NR 5
Chloride None <3 <3
Other
Na Metabisulfite NF, mg/L 0 0 <50b
Water for injection, USP qs qs qs
pH (range) 5.5 (5.0–6.5) 5.5 (5.0–6.0) 5.5 (5.0–6.0)
Osmolarity, mOsm/L 788 865 875
Total AAs, g/L 100 100 100
Nitrogen, g/L 15.2 15.5 15.5

Abbreviations: AA, amino acid; NR, not reported; USP, United States Pharmacopeia.
a
Conditionally essential.
b
The product packaged in plastic is sulfite-free, compared with the product packaged in glass.
qs: the amount which is enough or sufficient to result in an accurate final volume of the product.

interchangeable. Therefore, a cautious approach to determining com-
patibility and stability data is needed to ensure the evidence is specific
to the product in question. Historically, these solutions contained chlo-
ride salts of some of the amino acids, but they currently contain some
acetate salts or acetic acid buffering depending on the amino acid con-
tent, with consequent pH differences between products. The different
products contain both essential (indispensable) and nonessential (dis-
pensable) amino acids at varying proportions in compatible mixtures
from the manufacturer and are expected to remain stable in their orig-
inal container during storage. Storage of amino acids should avoid light
exposure to maintain stability up to the expiration date. Adult prod-
ucts typically do not contain cysteine or taurine or glutamine. Products
intended for pediatric patients contain lower concentrations of alanine,
arginine, and lysine. Electrolytes may also be found in amino acid solu-
tions, again varying with the product, and need to be considered for
compatibility and total clinical dose.
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION 277
5

TA B L E 2 Content and characteristics of AA injection products (adult)

Product Aminosyn II 15%28 Clinisol 15%29 Plenamine 15%32 ProSol 20%34 Travasol 10%35
Manufacturer ICU Medical Baxter B. Braun Baxter Baxter
Essential AAs, g/100 ml
Cysteinea None None None None None
Histidine 0.45 0.894 0.894 1.18 0.48
Isoleucine 0.99 0.749 0.749 1.08 0.60
Leucine 1.5 1.04 1.04 1.08 0.73
Lysine 1.575 1.18 1.18 1.35 0.58
Methionine 0.258 0.749 0.749 0.76 0.40
Phenylalanine 0.447 1.04 1.04 1 0.56
Threonine 0.6 0.749 0.749 0.98 0.42
Tryptophan 0.3 0.25 0.25 0.32 0.18
a
Tyrosine 0.405 0.039 0.039 0.05 None
Valine 0.75 0.96 0.96 1.44 0.58
Nonessential AAs, g/100 ml
Alanine 1.49 2.17 2.17 2.76 2.07
Arginine 1.527 1.47 1.47 1.96 1.15
Aspartic acid 1.05 0.434 0.434 0.6 None
Glutamic acid 1.107 0.749 0.749 1.02 None
Glycine 0.75 1.04 1.04 2.06 1.03
Proline 1.083 0.894 0.894 1.34 0.68
Serine 0.795 0.592 0.592 1.02 0.50
Taurine None None None None None
Electrolytes, mmol/L
Acetate 107.6 127 151 140 88
Phosphate None None None None None
Sodium 50 None None None None
Chloride None None None None 40
Other
Na Metabisulfite NF, mg/L 0 0 300 NR
Water for injection, USP qs qs qs qs qs
pH (range) 5.8 (5.0–6.5) 6.0 (5.0–7.0) 5.6 (5.2–6.0) 6.0 (5.5–6.5) 6.0 (5.0–7.0)
Osmolarity, mOsm/L 1270 1357 1383 1835 998
Total AAs, g/L 150 150 150 200 100
Nitrogen, g/L 23 23.7 23.7 32.1 16.5

Abbreviations: AA, amino acid; NR, not reported; USP, United States Pharmacopeia.
a
Conditionally essential.
qs: the amount that is enough or sufficient to result in an accurate final volume of the product.

Each crystalline amino acid in a commercial product is considered
an active pharmaceutical ingredient and meets standards for purity.
Amino acids are amphoteric in nature; therefore, depending on solu-
tion pH, they can react as acids and bases, and they are each least sol-
uble at their isoelectric point (at which ionic charges neutralize each
other), thereby reducing any ionic attraction to water. For example,
tyrosine has low solubility and precipitates at a more acidic pH. The
buffering capacity (titratable acidity) of amino acid solutions is deter-
mined in large part by the proportion of the formulation that is argi-
nine, histidine, and lysine. This buffering capacity will be important to
the overall PN admixture and is more robust at a higher final concen-
tration of amino acids in the PN. Additionally, the ratio of basic to acidic
amino acids may be important to optimal emulsion stability.37
Most products no longer include a sulfite (SO3 2– ) antioxidant
preservative, with its potential to cause hypersensitivity reactions.
To help avoid oxidation, most products are filled under nitrogen
atmosphere or under vacuum. However, unlabeled contaminants are
present in amino acid solutions and include aluminum, cadmium,
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6 BOULLATA ET AL .
chromium, lead, zinc, and possibly manganese.38,39 This contamination
reflects the ability of amino acids to easily form complexes with metals.
The affinity for metals varies with the amino acid, with different kinet-
ics for each complex formation.38 Nonnutrient metals (eg, cadmium,
lead) are most likely to complex with alanine, aspartate, glutamate,
glycine, histidine, methionine, phenylalanine, serine, and threonine.40
Although this likelihood is based on individual amino acid stability con-
stants, the amino acid concentration in a commercial amino acid mix-
ture remains the major determining factor.
Amino acids can complex with macrominerals such as calcium (with
lysine especially) and trace minerals such as copper (with cysteine
especially). In most cases, the chelates of trace metals with amino acids
are expected to maintain the bioavailability of both components.41
However, copper-cysteine complexes are likely to precipitate. The dilu-
tion of copper (elemental) to a concentration <160 mcg/L is expected
to avoid this complexation.42,43 Precipitates (yellow-to-brown) were
noted in pediatric PN admixtures.43 The precipitate was attributed to
an incompatibility between copper (as cupric sulfate [SO4 2– ]) and a
cysteine-containing, lower-pH amino acid solution, which did not recur
when using a different amino acid solution.43 No evaluation was made
to determine whether the precipitate was copper cysteinate, copper
sulfide (S2– ), or both.
Two amino acids are each available as a separate injectable prod-
uct in glass containers: cysteine and arginine. But only cysteine is
intended for PN admixtures when indicated. Cysteine hydrochloride
is available as a 50-mg/ml (34.5 mg/ml cysteine) solution at a pH
of 1.0–2.5. This amino acid may form the insoluble dimeric form
cystine over time. As mentioned above, the complex of cysteine
with copper may precipitate out of solution, decreasing amino acid
concentration.44
Although not an amino acid, L-carnitine is synthesized endogenously
from lysine and methionine. This nutrient is available for inclusion in PN
admixtures when indicated. The product (200 mg/ml) does not contain
a preservative. Hydrochloric acid and sodium hydroxide may be used to
adjust the product pH to 6.0–6.5. As a zwitterion (ie, contains both pos-
itively charged and negatively charged functional groups) with a pKa of
3.8, this very water-soluble primary amine can behave as a basic amino
acid.
Dextrose
Dextrose, or α-D-glucose monohydrate (C6 H12 O6 ⋅H2 O), is a natural
monosaccharide resulting from the hydrolysis of corn starch and is the
predominant source of carbohydrate in PN.45 Each gram of dextrose
monohydrate provides 3.4 kcal or 14 kilojoules (anhydrous dextrose
provides 4 kcal/g). It is a sterile, nonpyrogenic IV solution commercially
available in concentrations ranging from 5% to 70% and contains no
antimicrobial agent. IV dextrose products have a pH range between
3.2 and 6.5, with most solutions in the range of 4–4.5, since the solu-
tion contains no added buffer. Dextrose may convert to anhydrous
glucose in temperatures >40◦ C, so excessive heat exposure is to be
avoided and temperatures of 20–25◦ C are recommended for storage;
freezing is also to be avoided.46–48 Exposure to heat during the ster-
ilization phase of manufacturing results in the degradation products
5-hydroxymethyl-furaldehyde, levulinic acid, and formic acid, which
drive down the pH of sterile dextrose solutions over time.20 The small
amount of the reactive open-chain form of glucose in solution varies
depending on that pH.49
Dextrose has a molecular weight (MW) of 198.17 Da and, at a con-
centration of 5%, is considered isotonic (252 mOsm/L), whereas 70%
is hypertonic with an osmolarity of 3532 mOsm/L (∼50 mOsm/L con-
tributed for every 1% dextrose in solution). Isotonic solutions of dex-
trose 5% have been shown to facilitate growth of Burkholderia cepa-
cia and Serratia marcescens after contamination at 25◦ C.50 Most PN
formulations contain dextrose at a final concentration of 10%–25% in
present-day clinical practice.
The commercially available concentrations of dextrose contain no
more than 25 mcg/L of aluminum or 5 mg/L of di-2-ethylhexyl phtha-
late (DEHP) (in polyvinyl chloride [PVC] bags) within their expiration
periods, which may be of most importance in neonates with chronic
exposure.51 Patients with a known allergy to corn or corn products
should avoid use of dextrose.47,48
Lipid emulsions
ILEs are an essential component in PN as a source of energy and
essential fatty acids and as a therapeutic modality. During the man-
ufacturing process, an egg lecithin–based phospholipid emulsifier is
used to disperse the oil phase into the aqueous phase to ensure a
stable emulsion. ILE products are oil-in-water emulsions consisting
of one or more oils containing triglycerides, a phospholipid emulsifier,
and glycerol and are manufactured to mimic properties of natural
chylomicrons (Table 3).52–58 Sodium hydroxide is added to maintain
a pH range between 6 and 9, and the glycerol is added to improve
tonicity and provide additional energy.59 Nearly 1 million lipid droplets
can be found per milliliter, and the emulsion remains most stable
at pH 8 with a surface potential of at least −35 mV in repulsive
forces.60
The United States Pharmacopeia (USP) Chapter <729> (“Globule Size
Distribution in Lipid Injectable Emulsions”) provides explicit pharma-
copeial specifications to ensure manufacturer product integrity, includ-
ing a mean droplet diameter below 500 nm (0.5 μm) and a large globule
content (percentage of fat globules >5 μm or ‘‘microns’’ [ie, PFAT5 ]) no
greater than 0.05%.61 Additionally, ILEs must possess a free fatty acid
content no greater than 0.07 mEq/g.
These emulsions, however, are inherently unstable systems and,
over time, may undergo various stages of destabilization such as aggre-
gation, creaming, coalescence, and increased particle size. In aggre-
gation, dispersed lipid droplets come together but do not fuse. These
aggregates may be redispersed with gentle agitation and safely admin-
istered to patients. Creaming is the initial stage of emulsion destabiliza-
tion and is one of only two stages that may be detectable by the naked
eye, the other being free oil as the final stage of a broken emulsion.
The lipid particles present in a cream layer are destabilized, but their
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION 279
7

TA B L E 3 Composition and properties of lipid injectable emulsion products

Category Component OO,SO-ILE53 SO-ILE54 SO-ILE55 FO-ILE56 SO,MCT,OO,FO-ILE57

Commercial product concentration 20 20,30 20 10 20
Source oil SO, % 20 100 100 0 30
FO, % 0 0 0 100 15
MCT, % 0 0 0 0 30
OO, % 80 0 0 0 25
Additives Egg phospholipid, g/100 ml 1.2 1.2 1.2 1.2 1.2
Glycerin, g/100 ml 2.25 2.25 2.5 2.5 2.5
α-Tocopherol, mg/100 ml 3.2 0 0 15–30 16.3–22.5
Sodium oleate, g/100 ml 0.03 0 0.03 0.03 0.03
ω-3 Linolenic acid, % 0.5–4.2 4–11 4–11 1.1 (mean) 1.5–3.5
EPA, % 0 0 0 13–26 1–3.5
DHA, % 0 0 0 14–27 1–3.5
ω-6 Linoleic acid, % 13.8–22 44–62 48–58 1.5 (mean) 14–25
Arachidonic acid, % 0 0 0 0.2–2 NR
ω-7 Palmitoleic acid, % 0 0 0 4–10 NR
ω-9 Oleic acid, % 44.3–79.5 19–30 17–30 4–11 23–35
Saturated fatty acids Caprylic acid, % 0 0 0 0 13–24
Capric acid, % 0 0 0 0 5–15
Palmitic acid, % 7.6–19.3 7–14 9–13 4–12 7–12
Stearic acid, % 0.7–5 1.4–5.5 2.5–5 0 1.5–4
Myristic acid, % 0 0 0 2–7 NR
ω-6:ω-3 ratio 9:1 7:1 7:1 1:8 2.5:1
Phytosterols, mg/L 208.8 ± 39.4 422.4 ± 130.5 NR 0 142.2 ± 15.3
Phosphate, mmol/L 15 15 15 15 15
Energy kcal/ml 2 2 2 1.12 2

Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentanoic acid; FO-ILE, fish-oil lipid injectable emulsion (Omegaven, Fresenius Kabi USA); OO,SO-ILE,
olive-oil, soybean-oil lipid injectable emulsion (Clinolipid, Baxter Healthcare Corporation); NR, none reported; SO-ILE, soybean-oil lipid injectable emulsion
(Intralipid, Baxter Healthcare Corporation; Nutrilipid, B. Braun Medical); SO,MCT,OO,FO-ILE, soybean-oil, medium-chain triglycerides, olive-oil, fish-oil lipid
injectable emulsion (Smoflipid, Fresenius Kabi USA).

individual droplet identities are generally preserved. A cream layer is
visible at the surface of the emulsion as a translucent band separate
from the remaining dispersion. With gentle agitation, a creamed emul-
sion may be redispersed and safely administered to a patient. Coales-
cence occurs when there is a fusion of lipid droplets, leading to a fewer
number but an increase in droplet size. This type of emulsion cannot be
redispersed and is unsafe to administer to patients or include in a PN
admixture.62
The stability of ILE is dictated by its zeta potential and the effective-
ness of its emulsifying agent. The emulsifier forms a mechanical bar-
rier around each fat droplet and simultaneously forms an electrostatic
(ionic) barrier with their ionized phosphate groups to separate droplets
from each other and the surrounding water. Emulsifying agents cre-
ate a barrier that prevents droplets from coalescing to form unsafe,
larger globules. The zeta potential is a negative charge created by the
emulsifier that generates repulsive forces that act to separate parti-
cles and work against attractive (van der Waal) forces, thus improv-
ing the stability of the emulsifier. Compatibility and stability of an ILE
are dependent on the emulsifier’s strength and the presence of con-
founders that may counteract the emulsifier’s repulsive properties to
keep oil droplets apart.63 The zeta potential can be negated with the
addition of divalent cations (eg, calcium, magnesium), trivalent cations
(eg, iron), or high concentrations of monovalent cations (eg, potassium,
sodium) or by decreasing the emulsion’s pH. As the pH decreases to
<5, the zeta potential becomes less negative and more neutral, thus
increasing the chance of droplets coalescing and creating larger, unsafe
particles. Optimal ILE stability is achieved at a pH range of 7–8 and
when the zeta potential is high (ie, more negative), at least −35 mV,
as the repulsive forces will exceed the attractive forces. Conversely, all
repulsive forces disappear by a pH of 2.5 and the lipid particles will coa-
lesce, resulting in an unsafe emulsion. Other factors that can disrupt
an emulsion’s integrity include exposure to oxygen, as it will oxidize the
fats within the emulsion. Package design and use of an oxygen absorber
help lessen this risk.64 Even with these protective measures, ILEs will
280
8 BOULLATA ET AL .
destabilize over time as the emulsion’s pH decreases and particle size
increases.
Until recently, only soybean-oil ILEs were available in the United
States. In the past decade, ILEs containing olive oil, fish oil, and medium-
chain triglycerides (MCTs) have become available (Table 3).52 Because
of the differences in chain length associated with these sources of
triglycerides, the same phospholipid emulsifying agent may behave
differently, and emulsion stability may be different depending on the
blend of oils used in an ILE.65 For example, MCTs can improve the sta-
bility of an ILE by displacing long-chain triglycerides (eg, from soybean,
fish, or olive oil) at the droplet surface, thus reducing stress on the
emulsifier because of its shorter chain length.66
For these reasons, compounding a TNA (ie, 3-in-1 PN admixture)
or coadministering parenteral medications with an ILE remains a chal-
lenge. Any time an ILE has another medication or IV fluid mixed with it,
there is a potential for a disruption of the emulsion or coalescence that
creates larger fat globules that may be unsafe to infuse. Some literature
on ILE stability may not utilize the methods specified by USP Chapter
<729> (ie, dynamic light scattering, light obscuration) for determining
the stability of an emulsion. Importantly, both methods must be used
in a complementary fashion to assess the quality of ILEs. Dynamic light
scattering is only a sizing method and provides only semiquantitative
information on the relative droplet size distribution; it does not count
the number of particles or droplets. In contrast, light obscuration both
counts the fat globules present and identifies the size of lipid droplets
(1.3–400 μm), providing “reliable” count values at a size threshold
of 5 μm.
Micronutrients
The micronutrients include electrolytes, trace elements, and vitamins.
Each is a required component in a PN admixture to support a patient’s
metabolic needs. A parenteral micronutrient product may include mul-
tiple electrolytes, multiple trace elements, or multiple vitamins, but
several of these nutrients are also available as single-entity products.
The physicochemical properties of each active ingredient and accom-
panying excipients are important to the issue of PN admixture compat-
ibility and stability. Although some of the mineral salts are organic, the
remainder are inorganic.
Electrolytes
The electrolytes, found as salts in injectable products, that serve as
components for PN admixtures include sodium, potassium, magne-
sium, calcium, and phosphorus. Generally, electrolyte solutions are
mildly acidic with polarity similar to water. This allows the salts to dis-
sociate in aqueous PN admixtures to varying degrees depending on
the salt and concentration. The monovalent electrolytes (sodium and
potassium in their representative salts) are much less likely than the
multivalent electrolytes (calcium, magnesium) to pose compatibility
concerns.
Multielectrolyte additives
Products that contain multiple electrolytes may offer some conve-
nience as a component in preparing PN admixtures. Each product
will vary in the concentration and specific electrolyte salts, often low
in potassium and without phosphorus. As a result, the pH may vary
between products in a range of ∼4–8, often requiring hydrochloric acid
or acetic acid for pH adjustment, and are hypertonic (Hyperlyte CR [B.
Braun] [pH 5.0–5.4], 5500 mOsm/L; TPN Electrolytes [Hospira, Inc] [pH
6.0–7.5], 6200 mOsm/L). These sterile solutions may contain one or
more different sodium salts (acetate, chloride, gluconate), potassium
chloride, magnesium chloride, and often calcium chloride. Incidentally,
magnesium chloride and calcium chloride may be included as part of
standardized, commercially available PN products. When these prod-
ucts are used as a component for preparing a final PN admixture for
a patient, the difference in any included electrolyte salts is important
to note, as chloride salts tend to dissociate to a greater degree and are
available for interaction, with an influence on pH.
Bicarbonate, citrate, and lactate salts should be avoided in PN
admixtures because of incompatibilities. For example, with a pH of
nearly 8, sodium bicarbonate drives precipitation of several salts,
including calcium and magnesium. Cardioplegic solutions, intraperi-
toneal irrigation solutions, or dialysate solutions—which usually con-
tain sodium, magnesium, and calcium as chloride salts, as well as con-
taining potassium chloride in cardioplegic solutions, or other sodium
salts (eg, acetate, bicarbonate, gluconate, or lactate) in irrigation and
dialysate solutions—are not indicated as components to be used for PN
admixtures.
Sodium and potassium chloride or acetate
The chloride salts (sodium chloride, potassium chloride) generally form
neutral aqueous solutions available for use in preparing PN admixtures.
As a weaker conjugate acid anion, the acetate salts (sodium acetate,
potassium acetate) form more alkaline solutions. Despite significant
dissociation of the ions from these salts in solution, the monovalent
minerals are less likely to interact with other components at typical
final admixture concentrations.
Magnesium sulfate or chloride
Aqueous solutions of magnesium are expected to have a pH of 5.5–
7.0; this includes magnesium sulfate products adjusted with sulfu-
ric acid and sodium hydroxide. Magnesium chloride is not typically
available as a separate additive but has been included in combi-
nation products, including the standardized, commercially available
PN products.
Calcium gluconate or chloride
Although calcium gluconate is the preferred salt for use in compound-
ing PN because of its lower risk of precipitation, calcium chloride has
also been used. The pH for calcium gluconate injections ranges from
6.0 to 8.2 and is adjusted with hydrochloric acid and/or sodium hydrox-
ide. Based upon this pH range, this salt is more likely to be mildly alka-
line than acidic. The pH of calcium chloride injections is 5.5–7.5 when
diluted with water for injection, and it may contain hydrochloric acid
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION
and/or sodium hydroxide for pH adjustment. Additionally, calcium chlo-
ride dissociates more extensively in water than does calcium gluconate,
rendering more calcium ions free to complex with phosphate and to
produce calcium phosphate precipitates. Even if the extent of dissoci-
ation was similar, calcium gluconate dissociates into a weak acid (glu-
conic acid) and a strong base (calcium hydroxide), whereas calcium
chloride dissociates into a strong acid (hydrochloric acid) and a strong
base (calcium hydroxide).
Sodium or potassium phosphate
Mixtures of inorganic monobasic (dihydrogen) and dibasic (monohy-
drogen) phosphate salts of sodium and potassium are available for
use in compounding PN in the United States. Although the pH of
each individual phosphate salt is not identified in USP monographs,
the pH of sodium phosphates injection has been reported in the
range of 5.0–6.0, whereas the pH of potassium phosphates injection
has been reported between 6.2 and 7.8. The degree of dissociation
of inorganic phosphate salts into free phosphate anions is largely
dictated by pH. In addition, phosphate may occur in three differ-
ent anionic forms, including H2 PO4 − anion (dihydrogen or monoba-
sic phosphate), HPO4 2− (monohydrogen or dibasic phosphate), and
PO4 3− (tribasic phosphate), all of which may generate insoluble cal-
cium phosphate. The content of aluminum contamination is much
greater in potassium phosphates injection than in sodium phosphates
injection.
Trace elements
In the time since the initial recommendations for including copper,
chromium, manganese, and zinc in PN admixtures,67 and after hospi-
tals had to prepare their own formulations,68 there have been a num-
ber of lessons learned in IV trace element requirements as well as an
evolution in the available products on the market.69–72 Currently, there
are multi–trace element products as well as single-entity trace ele-
ment products available to include in PN admixtures or other carrier
fluids (Table 4).73–76 The multi-element products are commonly used
because of convenience, whereas the single-entity products become
more valuable for long-term use in patients with varying requirements
or for individual-element repletion independent of the PN admixture.
Although rarely observed, certain trace element solutions may exhibit
a slight colored hue.
Products formulated for neonatal and pediatric patients do not con-
tain a preservative, as the commonly used benzyl alcohol is associ-
ated with adverse effects. Most multidose vial products contain no
preservative/bacteriostatic agent. Without a preservative, the vials of
any trace element product have a limited beyond-use date after initial
entry. Of note, the concentration of each trace element is relatively low
in the products, made even lower when added to a PN admixture, cre-
ating a challenge in analysis when close to the limits of detection. Fur-
thermore, most methods of analysis determine mineral concentration
without distinguishing between oxidation states or complexation and
precipitation.
281
9
Multielement additives
Historically, products have contained up to seven trace elements, but
multi–trace element products in the United States currently remain at
four elements in fixed-concentration proportions. The available prod-
ucts vary in concentration of each trace element, the excipients, and
pH. Sulfuric acid and sodium hydroxide may be used to adjust product
pH to 1.5–3.5. Products with excessive copper and manganese content
have been transitioned to products with lower concentrations of these
minerals in keeping with expert recommendations.69,70 Products con-
taining fluoride, iodine, iron, and/or molybdenum may still be available
outside the United States.
Chromium
Chromium can exist in multiple oxidation states, including the toxic
hexavalent chromate form. The chromic (Cr3+ ) ion is the most physio-
logically valuable and the one used in parenteral products, compared
with the chromous (Cr2+ ) form. Chromic chloride is a hydrated salt
(MW = 266.5 Da) containing just under 20% chromium. Hydrochloric
acid and sodium hydroxide may be used to adjust product pH to 1.5–
2.5. Given the amounts of chromium present as a contaminant in other
PN components (eg, amino acid solutions), the requirement for this
trace element as an additive in short-term treatment has been recon-
sidered. Although chromium concentrations can be measured using
neutron activation analysis, atomic absorption spectrophotometry, or
inductively coupled plasma with mass spectrometry (ICP-MS), these
reflect total chromium and may not adequately distinguish oxidation
state of the mineral, which is important to compatibility as well as phys-
iologic activity.
Copper
The oxidized cupric (Cu2+ ) form is more soluble and stable in solution
than the cuprous (Cu1+ ) state. Copper (cupric) sulfate is a hydrated salt
(MW = 249.69 Da) containing just over 25% copper. Sulfuric acid and
sodium hydroxide may be used to adjust product pH to 2.0–3.5. Copper
(cupric) chloride is also available and may contain hydrochloric acid and
sodium hydroxide to adjust product pH to 1.5–2.5. Copper can form
complexes with organic anions, including some amino acids, depending
on the degree of other competing cations available in the admixture.
Some of these copper complexes may have limited solubility. Although
copper concentrations can be measured using atomic absorption spec-
trophotometry or ICP-MS, these reflect total copper content and can-
not distinguish oxidation state or the free form from the complexed
mineral, including insoluble microprecipitates. For example, a PN com-
patibility study that noted no visually apparent copper precipitate
and reported unchanged copper concentration over time using atomic
absorption did not necessarily rule out copper microprecipitate.77
Manganese
Of the several oxidation states of manganese, the divalent (Mn2+ ) form
is most stable in aqueous solutions. This form has been available in both
the chloride and sulfate salts. Manganese sulfate is a hydrated salt (MW
= 169 Da) containing 32.5% manganese. Sulfuric acid may be used
to adjust product pH to 2.0–3.5. Although manganese concentrations
 10
282

TA B L E 4 Trace element products

Multiple-entity product Single-entity product

Pediatric Adult

Multitrace-4 Multitrace-4
Neonatal73 Multrys Pediatric73a Tralement74b Chromium Copper Manganese Selenium Zinc Zinc
(1 ml) (1 ml) (1 ml) (1 ml) (1 ml) (1 ml) (1 ml) (1 ml) (1 ml) (1 ml)
Trace elements
Chromium (as chloride), mcg 0.85 None 1 None 4 None None None None None
Copper (as sulfate), mcg 100 60 100 300 None None None None None None
Copper (as chloride), mcg None None None None None 400 None None None None
Manganese (as sulfate), mcg 25 3 25 55 None None 100 None None None
Selenium (as selenious acid), mcg None 6 0 60 None None None 60 None None
Zinc (as sulfate), mg 1.5 1 1 3 None None None None 3 5
Other
Water for injection, USP qs qs qs qs qs qs qs qs qs qs
Preservative None None None None None None None None None None
pH 2.3–2.7 1.5–3.5 1.5–3.5 1.5–3.5 1.5–2.5 2.0–3.5 2.0–3.5 1.8–2.4 2.0–4.0 2.0–4.0
Osmolarity, mOsm/L 50 NR 34.7 114 308 327 3.64 16 96.5 157.2

Abbreviations: NR, not reported; USP, United States Pharmacopeia.

a
Manufacturer has voluntarily ceased production to develop US Food and Drug Administration (FDA)–approved products that align with American Society for Parenteral and Enteral Nutrition (ASPEN) recom-
mendations.
b
Tralement is indicated for pediatric patients ≥10 kg as well as adults.
qs: the amount that is enough or sufficient to result in an accurate final volume of the product.
BOULLATA ET AL .
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION 283
11

can be measured using neutron activation analysis, atomic absorption TA B L E 5 Pediatric parenteral multivitamin ingredients
spectrophotometry, or ICP-MS, these reflect total manganese and can-
Vitamin Source Amount84,86
not distinguish between the free and the complexed mineral.
A Retinol palmitate 2300 IU (0.7 mg)
B1 Thiamin hydrochloride 1.2 mg
Selenium
B2 Riboflavin 5-phosphate sodium 1.4 mg
Selenium can exist in a number of oxidation states. Selenious acid
(H2 SeO3 ) incorporating the selenite ion (SeO3 2– ) and containing B3 Niacinamide 17 mg

61% selenium has been more commonly used than sodium selenate B5 Dexpanthenol 5 mg
(SeO4 2– ) for parenteral preparations. Nitric acid may be used to adjust B6 Pyridoxine 1 mg
product pH to 1.8–2.4. Although selenium concentrations can be mea- C Ascorbic acid 80 mg
sured using atomic absorption spectrophotometry or ICP-MS, these D3 Cholecalciferola 400 IU (10 mcg)
reflect total selenium and cannot distinguish oxidation state, includ-
D2 Ergocalciferola 400 IU (10 mcg)
ing the poorly soluble elemental (Se0 ) form, or distinguish between the
E DL -α-Tocopheryl acetate 7 IU (7 mg)
free and complexed mineral.
K1 Phytonadione 200 mcg

Zinc B9 Folic acid 140 mcg

Fortunately, zinc is very soluble across a wide range of pH in its ionic Biotin Biotin 20 mcg

and stable divalent (Zn2+ ) form. So there has been no concern about
reduction to the less soluble elemental form. Zinc sulfate is a hydrated
salt (MW = 287.56 Da) containing 22.7% zinc. Sulfuric acid may be used
to adjust product pH to 2.0–4.0. Zinc can form complexes with organic
anions, including some amino acids with multifaceted coordination
structure. Zinc chloride may form a flocculent precipitate in aqueous
solution, owing to cationic hydrolysis to the oxychloride, which is less
evident when adjusted to low pH with hydrochloric acid.68 Although
zinc concentrations can be measured using atomic absorption spec-
trophotometry or ICP-MS, these reflect total zinc and cannot distin-
guish the free from the complexed mineral.
Iron
For several reasons, iron salts are not typically added to PN admix-
tures, nor are they a component of currently available multi–trace ele-
ment products in the United States. However, iron salt is present as
ferric chloride in one product, Addamel N (Fresenius Kabi), that has
been imported in times of shortage.78 Iron dextran injection, USP is
a dark brown, slightly viscous sterile liquid complex of ferric hydrox-
ide and dextran containing 50 mg/ml iron. In its undiluted state, the
pH of the solution is between 5.2 and 6.5 with added sodium hydrox-
ide and hydrochloric acid for pH adjustment.79 Although iron dex-
tran has been the traditional iron product used in PN, iron sucrose
is being used more frequently in clinical practice for iron replace-
ment therapy because of its lower incidence of adverse effects. Iron
sucrose injection is a brown, sterile, aqueous complex of polynuclear
iron (III)–hydroxide in sucrose (MW = 34,000–60,000 Da). Iron sucrose
injection (20 mg/ml) contains ∼30% sucrose wt/vol (300 mg/ml) and
has a pH of 10.5–11.1. Undiluted, the injection has an osmolarity of
1250 mOsm/L.80
Iron is rarely indicated for inclusion in PN admixtures for short-
term use. Typically, patients receiving long-term PN (ie, >3 weeks) will
require some form of iron supplementation to meet ongoing needs.
Microcytic, hypochromic anemia resulting from iron deficiency can
occur in patients receiving iron-free PN in as little as 2 months.81 When
administered parenterally, concern for iron overload limits its use-
B12 Cyanocobalamin 1 mcg
a 86
Pediatric Infuvite Multiple Vitamins contains cholecalciferol, whereas
M.V.I. Pediatric84 lyophilized powder contains ergocalciferol.
fulness. Unlike enterally administered iron, parenteral iron bypasses
the complex homeostatic control of iron bioavailability at the gas-
trointestinal tract. Routine monitoring of iron status should be con-
sidered, as iron overload can increase oxidative stress and the risk of
infection.82 In addition to the clinical issues associated with parenteral
iron (eg, impaired immune function, anaphylaxis risk, support bacte-
rial growth during acute infection), there are significant compatibility
concerns.81,83
Vitamins
Multivitamins
Commercially available adult and pediatric IV multivitamin formu-
lations comprise water-soluble and lipid-soluble vitamins (Tables 5
and 6).84–87 The M.V.I.-12 formulation for adults, which did not con-
tain vitamin K, is no longer available. Various excipients are added to
the multivitamin products to maintain the integrity of the product. To
maintain stability, the adult and selected pediatric IV multivitamin for-
mulations are separated into two vials.85–87 Vial 1 of the Infuvite Adult
and Pediatric formulations has a pH of 5.0–6.0, whereas the pH of
vial 2 is 5.0–7.0 (Sandrine Banzundama Bazuta Feza, Medical Infor-
mation Coordinator, Sandoz Canada Inc, written communication, May
20, 2020). After the contents of vials are combined, the mixture is
only stable for 4 h under refrigeration.85–87 Furthermore, once con-
tents of both vials are introduced into a PN admixture, the infusion
should be completed within 24 h. A pediatric multivitamin formulation
is also available as a lyophilized powder for reconstitution.84 The adult
multivitamin products should be further diluted in compatible solu-
tions of volumes ≥500 ml,85–87 whereas pediatric multivitamin prod-
ucts require diluent volumes ≥100 ml.84,86
284
12 BOULLATA ET AL .

TA B L E 6 Adult parenteral multivitamin ingredients given to the patient to determine the allergenicity.93 If identified, the
allergenic component should be avoided. The patient should be closely
Vitamin Source Amount85,87
monitored in an inpatient setting when the test dose or modified PN
Vial 1 (5 ml) ingredients
formulation is initiated.93
A Retinol palmitate 3300 IU (1 mg)
B1 Thiamin hydrochloride 6 mg
Ascorbic acid
B2 Riboflavin 5-phosphate sodium 3.6 mg Besides being a component of IV multivitamin formulations, ascorbic
B3 Niacinamide 40 mg acid is available as a single-entity product with a concentration of 500
B5 Dexpanthenol 15 mg mg/ml.94,95 Excipients include disodium edetate, a chelating agent to
B6 Pyridoxine 6 mg protect against oxidation,89 and sodium hydroxide and sodium bicar-

C Ascorbic acid 200 mg bonate to buffer the solution to a pH range between 5.5 and 7.0.94,95
The solution should be stored under refrigeration and protected from
D3 Cholecalciferola 200 IU (5 mcg)
light.94,95 A hypertonic product (5900 mOsm/L), the ascorbic acid solu-
D2 Ergocalciferola 200 IU (5 mcg)
tion must be further diluted with a compatible diluent (eg, dextrose 5%
E DL -α-Tocopheryl acetate 10 IU (10 mg)
in water) to a final concentration of 1–25 mg/ml.95 Ascorbic acid is used
K1 Phytonadione 150 mcg at lower concentrations when included as an additive to PN admixtures
Vial 2 (5 ml) ingredients to avoid compatibility and stability concerns.
B9 Folic acid 600 mcg
Biotin Biotin 60 mcg Thiamin
B12 Cyanocobalamin 5 mcg Thiamin hydrochloride is available as a 100-mg/ml solution as well
as an ingredient in IV multivitamin products. The single-entity vial
a
Adult Infuvite Multiple Vitamins87 contains cholecalciferol, whereas M.V.I.
may contain chlorobutanol anhydrous and/or monothioglycerol as
Adult85 contains ergocalciferol.
preservatives.89,96,97 Sodium hydroxide is added to maintain a pH
range of 2.5–4.5.96,97 The thiamin solution should be stored at room
For both adult and pediatric multivitamin products, the lipid-soluble temperature and protected from light.96,97
vitamins are solubilized with the aqueous vitamins through the addi-
tion of the surfactant polysorbate 80.84–87 Both M.V.I. Adult and Pedi- Pyridoxine
atric products contain an additional surfactant, polysorbate 20.84,85 Pyridoxine is available as a 100-mg/ml solution in addition to being
Infusion of large amounts of polysorbate 80 has been associated with included in IV multivitamin products. The excipients of the single-
serious adverse events, including fatality in low-birth-weight infants.88 entity product include chlorobutanol anhydrous, a preservative,89
In the 1980s, an injectable vitamin E formulation (E-Ferol), contain- and sodium hydroxide to maintain the pH between 2.0 and 3.8.98
ing polysorbate 80 (9%) and polysorbate 20 (1%), administered intra- The solution should be protected from light and stored at room
venously led to the development of a multiorgan toxicity referred to temperature.98
as E-Ferol syndrome.88 E-Ferol syndrome is a life-threatening con-
dition characterized by vasculopathic hepatotoxicity, ascites, throm- Folic acid
bocytopenia, and renal failure in low-birth-weight infants.88 Follow- Folic acid is available as a sodium folate 5-mg/ml multiple-dose solu-
ing reports of this lethal reaction, E-Ferol was withdrawn from the tion as well as being a component of IV multivitamin solutions. The
market.88 Commercially available pediatric multivitamin products con- single-entity folic acid solution is yellow and contains edetate disodium
tain a small quantity (50 mg) of polysorbate 80 in 5 ml of solution or 1% and benzyl alcohol 15 mg as a preservative.89,99 Benzyl alcohol has
(wt/vol).84,86 been associated with hypersensitivity reactions and gasping syndrome
Propylene glycol facilitates the dissolution of vitamins in the adult in neonates, characterized by respiratory depression, metabolic acido-
multivitamin products.89 Because of the risk of hyperosmolality in low- sis, encephalopathy, and intracranial hemorrhage.89 The pH of the folic
birth-weight infants, propylene glycol is not included in pediatric mul- acid solution is maintained between 8.0 and 11.0 with hydrochloric acid
tivitamin products.90 Antioxidants such as gentisic acid ethanolamide, and sodium hydroxide, because of the risk for precipitation out of solu-
butylated hydroxytoluene, and butylated hydroxyanisole are added tion at lower pH.99 The folic acid vial should be protected from light and
to selected adult multivitamin products.89,91 In addition to butylated stored at room temperature.99
hydroxytoluene and butylated hydroxyanisole, mannitol serves as an Vitamins can be highly reactive molecules, setting up potential com-
antioxidant in pediatric multivitamin products.92 Buffer agents such patibility issues with each other or with other components of a PN
as sodium hydroxide/hydrochloric acid or citric acid/sodium citrate admixture as well as stability issues on their own or for other com-
optimize the pH of the multivitamin products.84–87 Multivitamin vials ponents of a PN admixture. Incompatibilities depend on the rela-
of current US products should be refrigerated and protected from tive concentrations of ingredients; pH; exposure to temperature, oxy-
light.84–87 Hypersensitivity reactions to multivitamin products (active gen (air), and light; and the duration of time in reaction. As a result
ingredients and excipients) have been reported.93 A test dose can be of compatibility and stability concerns, the vitamins are added as
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION
the last component and as close to the time of administration as
practical.
COMPATIBILITY
Admixture compatibility—Focus on macronutrients
Preparing a PN admixture will influence the properties and safety of
the individual macronutrient components. The acidic pH of IV dextrose
is well buffered when combined with an amino acid solution. The vis-
cosity of the concentrated dextrose (eg, 70% product) is also tempered
in an admixture. One of the first compatibility studies evaluated the
combination of amino acids at a final concentration of 4.25% (ie, 4.25 g
of amino acids per 100 ml of PN admixture) and dextrose at a final con-
centration of 25% (AA4.25%-D25%), stored at 4◦ C, 25◦ C, or 37◦ C.100
The mixture showed a slight decrease in pH over time as well as color
formation, especially at higher temperature. Some amino acid degrada-
tion occurred (see Stability section). In another study with an AA4.25%-
D25% solution without any additives, the pH only changed from 6.5 to
6.4 initially but then remained constant for up to 2 weeks.101 In these
glass containers, the average counts of particulate matter in the PN
preparation over time were reported, using the microscopic method, as
2.7 per milliliter (particle size 10–25 μm) and 0.13 per milliliter (particle
size 25–50 μm), which is well below the USP threshold.101 That thresh-
old criteria (USP method 2) for IV admixtures with a volume >100 ml
state there should be ≤12 particles/ml of size ≥10 μm and ≤2 parti-
cles/ml of size ≥25 μm.102
Owing to the reducing properties of dextrose, a chemical inter-
action referred to as the Maillard reaction may occur between glu-
cose and free (nonionized) amino acids. As a result, no commercial
products with amino acids and dextrose premixed can be manufac-
tured because this glycation reaction would occur during the prod-
uct’s heat sterilization. The Maillard reaction is the same nonenzy-
matic series of reactions that causes browning in food and that also
accounts for HbA1c formation. Glucosylamines form between glucose
carbonyl groups and amino groups of the amino acids, creating unsta-
ble Schiff bases that rearrange chemically to form Amadori compounds.
The initial steps can be reversible, but subsequent reaction steps are
not and lead to loss of amino acid bioavailability. A solution color
change may be noted from yellow to a darker amber and brown in
the presence of the pigmented compounds.103 Unrecovered urinary
losses of Maillard products may be accompanied by increased loss
of trace elements (eg, zinc).104 The reaction is more likely to occur
with time and at 25–30◦ C compared with 4◦ C but is minimized at
pH 3.5–4.0.103,105 For example, at AA4.25%-D25%, the average loss
of amino acids to the Maillard products was ≤2% between 1 and 30
days when stored at 4◦ C.106 This increased to a ∼6% loss at room
temperature and will be even greater in the presence of electrolytes
and increasing pH values.106 Amino acid losses may be significant over
time, depending on storage conditions.105 The rates of reaction will
vary with the amino acid involved, and lysine may be the most reac-
tive in the Maillard reaction. A nearly 20% loss of lysine may occur by
1 month at 30◦ C, which tends to be more reactive, especially at higher
285
13
pH (∼7.5).107 At lower molar ratios of glucose to amines, the activation
energy for the reaction may increase compared with those at higher
ratios.105
The addition of ILE to the admixture of amino acids-dextrose not
only will increase the complexity by combining active ingredients and
excipients and by shifting pH character but will alter the physical
system as the entire PN admixture becomes an oil-in-water emul-
sion. An early study of a PN admixture (Veinamine AA3.2%-D20%-
L4% Intralipid) noted no visually apparent incompatibility, and fatty
acid analysis revealed no significant changes in composition at 24
or 48 h at 4◦ C.20 An evaluation of several adult amino acid prod-
ucts (Travasol, Aminosyn, FreAmine III, FreAmine HBC, HepatAmine,
and NephrAmine) in TNAs using a 100% soybean-oil ILE (Soyacal
20%) and dextrose 70% in a 1:1:1 volume ratio plus micronutri-
ents was conducted over 14 days at 4◦ C.49 Although the PN admix-
ture pH and osmolality differed between preparations, they did not
change significantly over the study period. An evaluation was per-
formed of a pediatric amino acid product (TrophAmine 10%) in a
PN admixture using ILE 20% (Intralipid, Liposyn II, or Nutrilipid)
and dextrose 70% with micronutrients at several final macronutri-
ent concentrations for 24 h at 4◦ C and an additional 24 h at room
temperature.108 No visible precipitates or color changes were noted,
and pH remained 5.5–6.6, with the lowest value associated with the
highest dextrose concentrations.108 In addition to the buffering capac-
ity provided by higher amino acid concentration, the higher final dex-
trose concentration may provide some emulsion protection based on
its viscosity.109,110 Stability of the final admixture emulsions will be
described later (see Stability section). This section on admixture com-
patibility reinforces that PN admixtures should be stored at 4◦ C for
reasons above and beyond sterility concerns (ie, the focus of USP Chap-
ter <797>). A broader point is that setting a beyond-use date for
PN admixtures will depend on sterility as well as compatibility and
stability.
Admixture compatibility—Focus on electrolytes
Adding electrolytes directly to an amino acids solution resulted in visi-
ble precipitates in a large proportion of over 80 combinations that dif-
fered in proportional ratios of the minerals and in mixing sequences.111
The majority of the precipitates evaluated were revealed to contain
calcium and phosphate. Monovalent ions can associate with the zwit-
terionic form of amino acids but are not expected to form precipitate.
When varying the concentration of calcium and magnesium with
high phosphorus content (65 mmol/L), higher levels of magnesium
protected against precipitation of calcium phosphate.112 This is likely
because magnesium forms a more stable and soluble salt with
phosphate.112 Methods for predicting calcium phosphate precipitation
must be validated by experimentation and consider the entire formula-
tion, preparation technique, and chemical kinetics.
In the United States, we still use inorganic phosphate salts (Na or
K), which pose the risk for insoluble complexes with cations—especially
calcium. It is important to note that precipitates can occur in PN but are
not always visible, will not appear immediately after compounding, and
286
14
can occur later in the administration set/catheter. These precipitates
develop because the three ionic phosphate species exist in an equilib-
rium in aqueous solution—monobasic (H2 PO4 – ), dibasic (HPO4 2– ), and
trivalent (PO4 3– ). Based on the pKa values for each equilibrium, the pH
of solution will determine which phosphate species predominates. The
risk of insolubility depends on much more than just the combination
of calcium and phosphate salt forms and concentrations. This includes
final pH, amino acid product, amino acid final concentration, dextrose
final concentration, the calcium salt, the phosphate salt, temperature,
sequence of calcium and phosphate addition, time that the PN is stored
prior to administration, and other factors.112–114
pH
The final pH of the PN admixture is the most important factor in
determining calcium and phosphate compatibility. Inorganic salts (such
as calcium chloride, monobasic/dibasic phosphates) are more likely
to dissociate into free ions compared with organic salts (eg, cal-
cium gluconate, sodium glycerophosphate). The extent of this dis-
sociation is largely governed by the pH of the final formulation.112
In aqueous solutions, phosphate may exist in three anionic forms—
monobasic (H2 PO4 – ), dibasic (HPO4 2– ), and trivalent (PO4 3– )—and all
three forms can produce insoluble calcium phosphate complexes.115
Because extreme alkalinity is generally required to ionize the tribasic
phosphate species, it is not normally found in PN admixtures. Although
the trivalent phosphate is not expected in PN, the dibasic species read-
ily forms an insoluble complex with calcium that crystallizes and precip-
itates out of solution. The concentrations of the monobasic and dibasic
are pH dependent, and a small change of 0.05 in pH can increase the
dibasic phosphate salt concentration by >10% and contribute to the
precipitation of dibasic calcium phosphate (CaHPO4 ).115 Essentially,
as the pH of the final admixture increases, there is more dibasic phos-
phate present to bind with free calcium. Conversely, the lower the final
admixture pH, the greater the percentage of the monobasic (H2 PO4 – )
salt at which it can form more soluble calcium dihydrogen phosphate
salt (Ca[H2 PO4 ]2 ).
Amino acids
Amino acid products from different manufacturers can vary in pH,
ranging from 5 to 7. Amino acid products also have an intrinsic buffer-
ing system, largely determined by the concentrations of arginine, his-
tidine, and lysine. Higher final concentrations of amino acids have a
greater buffering capacity, and therefore, there is less of an increase in
pH when phosphate is added to the final formulation. The more moder-
ate pH will support calcium and phosphate solubility. High concentra-
tions of amino acids have also been reported to sequester calcium and
decrease its reaction with phosphates. Lysine has been identified as the
amino acid most likely to complex with calcium, and the degree of that
complexation is also pH dependent. Better determination of safe PN
BOULLATA ET AL .
admixtures, especially for neonates, will require additional study using
different amino acids products, as well as varying the salt form and con-
centrations of calcium and phosphate.116
Phosphate salts
Inorganic phosphates injections available in the US market contain a
mixture of monobasic and dibasic salts of either sodium or potassium.
The sodium phosphates injection contains monobasic sodium phos-
phate and monohydrate and dibasic sodium phosphate, anhydrous.
Similarly, the potassium phosphates injection contains a mixture of
monobasic and dibasic potassium phosphate, anhydrous. All sources of
potassium or sodium phosphate (ie, amino acids) must be taken into
consideration, as high concentrations of phosphate increase the risk of
precipitate formation with calcium. Although the use of a single calcium
phosphate product has been advocated for use in predicting compati-
bility, this approach is fraught with error as the results from multiply-
ing the PN calcium concentration (in mEq/L) with PN phosphorus con-
centration (in mmol/L) vary inconsistently as the calcium concentration
decreases and phosphorus concentration increases.117
Sodium glycerophosphate is an organic form of phosphorus avail-
able in Europe and has been temporarily available for use in the
United States during phosphorus drug shortages. In contrast to inor-
ganic phosphate injections, the phosphate component of sodium glyc-
erophosphate is covalently bound to a glycerol backbone, which hin-
ders the formation of a precipitate with divalent calcium ions. The
availability of a monobasic potassium phosphate product in Canada
enhanced calcium and phosphate solubility to allow for a greater con-
centration in a PN admixture, although the aluminum content was not
described.118
Calcium salts
Calcium gluconate salts are recommended over calcium chloride salts
when compounding PN because of superior compatibility with inor-
ganic phosphates. Because the gluconate salt of calcium dissociates
much less extensively in water compared with calcium chloride, it is the
preferred salt for use in PN admixtures. Calcium chloride almost com-
pletely dissociates in aqueous solutions, so precipitation with phos-
phate occurs at much lower chloride salt concentrations vs gluconate
salt concentrations. One drawback associated with calcium gluconate
injections in glass vials is that it is heavily contaminated with alu-
minum, so the higher aluminum load must be considered, especially
when used in neonatal PN admixtures.112 Of note, calcium chloride is
the salt included in commercial, standardized, multichamber PN prod-
ucts with electrolytes. Compatibility testing has demonstrated that cal-
cium chloride is physically compatible with sodium glycerophosphate
in pediatric PN formulations.119 Thus, compounding with sodium glyc-
erophosphate and calcium chloride provides a mechanism for reducing
the aluminum load in PN.
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION
Dextrose concentration
The USP monograph for dextrose injections indicates that these prod-
ucts are generally acidic, with a pH range between 3.2 and 6.5. Thus,
higher concentrations of dextrose will lower the final admixture pH,
providing a greater percentage of monobasic phosphate (H2 PO4 – ),
which can form more soluble calcium dihydrogen phosphate salt
(Ca[H2 PO4 ]2 ).117
Temperature
Temperature may influence the dissociation of organic calcium salts,
such as calcium gluconate. As the temperature rises, there is a greater
dissociation, rendering more free calcium ions available to complex
with phosphate salts. This phenomenon is not associated with inor-
ganic calcium chloride salts, as they are almost fully ionized in aqueous
solution. A temperature change from 5◦ C (41◦ F) to body temperature
at 37◦ C (98.6◦ F) has been shown to promote formation of calcium
phosphate crystals.120 Precipitation from temperature increases
may also be related to the shift in the phosphate equilibrium from
monobasic to dibasic salts.112
Sequence of calcium and phosphate additions
The order of mixing calcium and phosphate into PN admixtures
can affect the final solubility profile. Inorganic phosphate injections
should be added early in the mixing sequence, and calcium glu-
conate injections should be added nearly last to what should be
the most dilute phosphate concentration possible. The official pH
range of calcium gluconate injection is 6.0–8.2, and the formulation
is more likely to be mildly alkaline than acidic. Thus, it is reason-
able to add calcium gluconate at the end of the sequence, so it is
most dilute and least likely to influence the overall pH of the for-
mulation. Increasing hypertonicity or osmolarity of the PN formula-
tions, such as those infused into central veins, may also improve cal-
cium and phosphate solubility. High concentrations of amino acids
may sequester calcium and decrease its complexation with phosphate
salts, whereas higher concentrations of dextrose can reduce the final
admixture pH.115
Duration of storage
The duration of time lapsed after compounding has been shown to
impact the process of precipitation. Although precipitates may form
during the compounding process because of poor mixing procedures, it
is more typical for dibasic calcium phosphate crystallization to progress
through a time-related induction period. Precipitation of calcium phos-
phate during PN infusion may not be observed until 12 or more hours
after preparation, and a delayed onset of precipitate formation may
287
15
take up to 24–48 h.112,113 The variable rates in precipitate forma-
tion have been attributed to slow crystallization from supersaturated
mixtures.117
Admixture compatibility—Focus on trace elements
and vitamins
Shortly after the initial American Medical Association (AMA) published
recommendations on parenteral trace elements, a study evaluated the
compatibility of individual trace elements (chromium chloride, cop-
per sulfate, manganese sulfate, zinc sulfate), as well as the combina-
tion of the four trace elements, while accounting for metal contami-
nants in all components used.121 The solutions tested included amino
acids alone (Travasol 8.5% [pH 5.7]) and a PN formulation (Travasol
AA4.25%-D25% [pH 5.75]) in glass with electrolytes and multivitamins.
Over the 48-h study period, the initial concentration of each trace ele-
ment was unchanged, based on atomic absorption spectrophotometry,
and infusion through a 0.22-μm filter did not reveal any visible precip-
itate. Of note, each individual trace element led to some slight color
change when admixed with amino acids alone. The incompatibility of
copper with some amino acids, resulting in precipitates, was described
in an earlier section.112
In a study of pediatric PN (Vaminolac AA2.75%-D5.64%) that
included calcium chloride and glycerophosphate, the addition of multi–
trace elements (Pediatrace) led to an unexpected ongoing precipitate
within 4 h of admixture, which amounted to ∼14,000 particles/ml,
mostly smaller than 1 micron.122 The fine subvisual particles were
noted using Tyndall light, light obscuration, and turbidimetry and pro-
posed to be the result of incompatibility between copper and cysteine.
This was not analyzed further, and additional factors such as pH, con-
taminant minerals, redox conditions, mixing sequence, temperature,
and container type would need to have been taken into account.
Another study evaluated the compatibility of copper in two
cysteine-containing pediatric PN admixtures (TrophAmine AA2.4%-
D25% plus cysteine 960 mg/L and copper 0.3 mg/L, and AA3.7%-D16%
plus cysteine 1480 mg/L and copper 0.45 mg/L) over a 24-h simulated
infusion through infusion sets with 0.22-μm inline filters.123 Aside from
visual signs of incompatibility, including precipitation, samples were
obtained at several time points throughout the infusion and assayed
for both cysteine and copper. The first solution exhibited >10% reduc-
tion in cysteine and in copper, whereas the second solution had an
8% reduction in cysteine concentration and 11% reduction in cop-
per concentration over the study period. However, no visible partic-
ulate matter or discoloration was observed on the filters. Previous
work had noted cupric sulfide precipitates that discolored inline fil-
ters when using an adult bisulfite-free amino acid product (Novamine
AA4.25%) plus cysteine (200 mg/L) and copper (0.88 mg/L).124 Switch-
ing to a bisulfite-containing amino acid product resulted in no pre-
cipitate formation.124 A study to examine mechanisms compared a
bisulfite-containing but cysteine-free amino acid product (Travasol)
with a cysteine solution (400 mg/L), following the addition of copper
288
16
(1.2 mg/L), and noted significant (98%) reduction of copper concentra-
tion only in the cysteine solution.125
Early studies suggested that insoluble iron phosphate precipitation
can occur in stored PN solutions devoid of multivitamins.42 The mech-
anism is unclear but appears to be inversely related to the amino acid
concentration and the duration of storage prior to the addition of the
multivitamins. Amino acid brand may also play a role with precipitates
seen more with Synthamin (identical to Travasol at the time).42 No sim-
ilar reports have been noted using other amino acid products available
in the United States.
Others have reported incompatibility of iron dextran with lower-
volume neonatal PN solutions. Incompatibility may be related to the
final amino acid concentration, although it is uncertain whether the
incompatibility is due to the pH or related to the nature of the amino
acid solution used in the PN. In their investigation, Mayhew et al evalu-
ated 20 neonatal PN admixtures that varied in their amino acid concen-
trations (TrophAmine 0.5%–2.5%) and otherwise contained dextrose
10% as well as micronutrients, heparin and cysteine.126 Iron dextran
was included at 10 mg/L and control solutions omitted either the iron,
trace elements, or multivitamin component and all were stored at 19◦ C
for up to 48 h and observed for precipitate, color change, turbidity, and
phase separation. Iron precipitate (rust colored) formed within 12–24
h in those PN admixtures with ≤1.5% amino acids. The authors con-
cluded that lipid-free neonatal PN solutions with a final amino acid con-
centration of 2% or greater were visually compatible with iron dextran
10 mg/L for 48 h. These findings suggest that adding iron dextran to a
peripheral PN solution, which typically has a lower final concentration
of amino acids, would be less stable and not recommended.126
In a more recent retrospective study, Lee et al evaluated the safety
of mixing low-MW (LMW) iron dextran in a cohort of 89 pediatric
patients (0–21 years of age) who received PN containing a mainte-
nance dose of LMW iron dextran with a total of 2774 days of exposure
(1–196 days per patient).127 The mean dose of iron dextran in children
decreased with increased weight from <5 kg (0.21 ± 0.05 mg/kg/day)
to ≥40 kg (1.9 ± 0.5 mg/day). The authors concluded that PN contain-
ing a maintenance dose of LMW iron dextran could be safely admin-
istered to hospitalized children with respect to anaphylaxis risk, and
further studies would be needed to evaluate the potential to prevent
iron deficiency anemia and the need for additional IV iron infusions.127
Unfortunately, an evaluation of risks due to potential physicochemical
interactions was not performed.
The multivitamin products are compatible in dextrose 5% in
water, 0.9% sodium chloride, and PN admixtures according to the
manufacturers.84–87 The compatibility is contingent on the individ-
ual vitamins. The vitamins may react with each other, macronutrients,
excipients, or the PN bag material.112 For example, vitamin A has long
been known to adsorb to plastic materials, making it less available for
the patient.112 Sorption to the bag (ie, adsorption) is more likely to
occur with retinol acetate than with retinol palmitate because of its
greater affinity to plastics.128 This has become less of a concern with
the use of PVC-free bags and administration sets and the switch from
the acetate ester to the less reactive palmitate ester.129,130 As a dif-
ficult vitamin to incorporate into parenteral products, vitamin D may
BOULLATA ET AL .
bind to plastic containers and infusion sets, but over 65% of the content
is expected to remain available.131 It remains unclear whether there is
a significant difference between ergocalciferol and cholecalciferol.
STABILITY
Focus on macronutrients (alone or combined)
Amino acids
Amino acid degradation may be general or specific to an amino acid side
chain. General degradation can generate ammonia and carbon dioxide
through deamidation/deamination in the presence of elevated temper-
ature. The amino acid L-glutamine is excluded from products because
of rapid degradation to toxic by-products upon heat sterilization. The
presence of oxygen and/or light will also influence amino acid stabil-
ity. Higher degradation occurs in plastic than in glass containers, likely
associated with greater oxygen permeability.
Nonionizing radiation (eg, ultraviolet or visible light) may cause
some minimal decomposition but, in the presence of a chromophore
(functional group or substance), may generate oxidizing species (eg,
hydrogen peroxide), which can further degrade amino acids. Most sus-
ceptible to photo-oxidation are cysteine, histidine, methionine, pheny-
lalanine, tryptophan, and tyrosine. Reactive side chains of cysteine,
tryptophan, and tyrosine make them the most susceptible to oxidation.
Photo-oxidation of amino acids (eg, tryptophan, tyrosine) is enhanced
in the presence of riboflavin (a chromophore). A study of a 1% concen-
tration of pediatric amino acids product in the presence or absence
of riboflavin and metabisulfite (an antioxidant preservative) exposed
to phototherapy light (425–475 nm wavelength) generated hydrogen
peroxide.132 Histidine, methionine, and tryptophan undergo photo-
oxidation in ambient light in the presence of riboflavin with some
protective effect in the presence of adequate ascorbic acid.133,134
Tryptophan is an interesting case because multiple oxidation reac-
tions influence this amino acid with several different degradation
products. The indole moiety of tryptophan is prone to ring opening
from oxidation with electrophilic substitution. The degradation of
tryptophan over time may be associated with yellowing of the amino
acid solution.135 An AA4.25%-D25% solution stored for 2–4 weeks
did not experience significant (>10%) degradation of amino acids,
including tryptophan, the most labile component, especially under
refrigeration (4◦ C).100,101
Lipid emulsions
When the ILE is incorporated into the PN admixture, the entire prepa-
ration becomes an oil-in-water emulsion in character. As a result, any
evaluation of PN admixture stability needs to consider the physical
integrity of the emulsion. In general terms, the final macronutrient con-
centrations that are expected to provide the best likelihood of a sta-
ble emulsion in the PN admixture, for up to 30 h (at 25◦ C) or 9 days
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION
(at 5◦ C), are amino acids ≥4%, dextrose ≥10%, and ILE ≥2%.4 This
recommendation was based on data using 100% soybean-oil ILE prod-
ucts and varies with ILE products containing other source oils.
Extemporaneously prepared TNAs (ie, 3-in-1 PN admixture) are
expected to be less stable than the ILE product. The compendia PFAT5
limit of 0.05% might be too strict; hence, the use of PFAT5 <0.4%
(one log higher) has been proposed as the acceptance criterion, even
though studies do indicate that it is possible to compound a PN formu-
lation that fulfills the PFAT5 limit of USP. Driscoll et al demonstrated
that when the PFAT5 level exceeded 0.4%, obvious phase separation or
“cracking” occurred, reflecting the irreversible terminal stage of emul-
sion instability.114
An evaluation was performed of a pediatric amino acid product
(TrophAmine 10%) in a TNA using ILE 20% (Intralipid, Liposyn II,
or Nutrilipid) and dextrose 70% with micronutrients at several final
macronutrient concentrations for 24 h at 4◦ C and an additional 24 h
at room temperature.108 Although evidence of creaming was observed
in all sample PN admixtures over time, no coalescence or phase sepa-
ration was visible. Particle size analysis revealed that mean diameters
remained <0.4 μm; however, greater numbers of large lipid particles
(>5 μm) were present with higher concentrations of electrolytes, rep-
resenting as much as 0.6% of oil droplets.108 This value is well above
the current compendia PFAT5 limit of 0.05% or the proposed limit of
0.4%, indicating an unstable emulsion.
PN admixture stability is determined by how well lipid droplets
remain dispersed in the external (aqueous) phase, as cations and lower
pH values decrease the electric charge of the emulsifier tasked with
preventing aggregation. With the advent of TNAs, studies emerged
that described the influence of trace elements on emulsion stabil-
ity. One study compared organic (gluconate) with inorganic (chlo-
ride) salt forms of trace elements (copper 240 mcg/L, iron 0.5 mg/L,
zinc 2 mg/L) with a PN admixture (Azonutril-25 AA2%-D17.5%-L5%
Intralipid) stored at 4◦ C or 25◦ C for up to 1 week.136 Lipid particle mea-
sures relied on Coulter counter analysis capable of including diameters
from 1 to 25 μm. The gluconate salts did not significantly alter admix-
ture pH, whereas chloride salts decreased pH slightly over the course
of the study. Although the numbers and sizes of lipid droplets were not
significantly different between them, those in the PN admixture with
the chloride salts had more broadly dispersed values over time risking
tendency towards emulsion destabilization.
In an early study of emulsion stability of a PN admixture, the influ-
ence of two different multimineral solution additives was evaluated.137
The PN admixture (Travasol AA3.34%-D12.5%-L3.34% Intralipid) in
large ethylene–vinyl acetate (EVA) bags included either a commercial
additive (Addamel) or a compounded eight-component additive, but
no vitamins, stored for up to 2 weeks at 4◦ C. Of note, Addamel is not
currently approved for use in the United States and is only marketed
elsewhere. The lipid droplet size, determined by Coulter counter (able
to assess particle diameters between 0.6 and 20.2 μm), did not vary
significantly in distribution during storage, nor did the proportion of
large (>5 μm) to small (<2 μm), with mean droplet size of ∼0.674–
0.684 μm, all of which was no different than the control of the ILE
alone.137 A study of a 3.1-L PN admixture (Vamin-N AA3.4%-D16%-
289
17
L1.6% Intralipid), which included electrolytes, multi–trace elements,
and multivitamins, was performed (pH of 5.5 with osmolality ∼1472
mOsm/kg) over 14 days at 4◦ C plus 2 days at 22◦ C using visual obser-
vation, light microscopy, electron microscopy, and Coulter counter
techniques.138 These revealed an increase in particle size over time,
including some exceeding 2 and 5 μm in diameter. The amino acid and
dextrose content of a TNA alone is unlikely to be adequate to overcome
the influence of high divalent ion concentrations in a PN admixture.139
The multivalent cations such as calcium and magnesium, as well as
high concentrations of the multivalent copper, iron, and zinc, have the
potential to alter the stability of ILE by reducing the negatively charged
repulsive forces that keep lipid droplets separated. A recent study eval-
uated the influence of trace elements (copper 200 mcg, fluorine 570
mcg, iodine 10 mcg, manganese 10 mcg, selenium 60–90 mcg, zinc 3.4–
3.5 mg) as well as carnitine (100 mg) on the stability of six different 1-L
PN admixtures (TrophAmine AA2.3-3%–D10-14%–L1.9-2.3%; various
ILE products used) for pediatric patients that included electrolytes and
multivitamins in EVA bags.140 These admixtures were stored at 4◦ C
or room temperature for up to 96 h with 450 samples analyzed. Lipid
droplet diameters were evaluated by laser diffraction. The diameter
of droplets did not change significantly throughout the duration of the
study and remained between 0.4 and 1 μm in most of the tested admix-
tures. An interesting exception occurred in those admixtures using a
fish-oil component with calcium concentration of 4.5 mmol/L (9 mEq/L)
or higher in which 2% of droplets exceeded 5 μm and 12% exceeded
1 micron immediately after compounding.140 Whether the inclusion of
the trace elements increased this risk is not known because no controls
without trace elements (or carnitine) were studied.
Compounded PN admixtures for home infusion may rely on a dual-
chamber EVA bag in which the ILE portion is stored in one chamber
while the remainder of the PN ingredients are in the other for a 7-
day period. In this way, any concern for the final emulsion’s stability
over time is deferred. Just prior to administration, the contents of both
chambers are combined with the addition of multivitamins at that time.
However, the emulsion stability of the final PN admixture must still be
ensured. Varying contents and component concentrations will deter-
mine which PN admixtures for use at home remain stable and safe for
administration and which do not.141,142
In the smaller volumes of neonatal PN admixtures, the influence
of trace elements and vitamins were evaluated on formulation sta-
bility in a practice setting where trace elements and vitamins were
routinely not combined in the same bag.143,144 Three PN admixtures
were evaluated—one with multivitamins but without multi–trace ele-
ments, another with the trace elements but not multivitamins, and the
third containing all components.143 The formulations were otherwise
identical (Primene AA3%-D8%-L3% Lipofundin) in EVA bags with elec-
trolytes that included organic phosphate. Samples were taken at pre-
determined points for up to 7 days, with storage conditions at 5◦ C,
25◦ C, and 40◦ C, for evaluation of emulsion stability using zeta poten-
tial, optical microscopy, dynamic light scattering, and PFAT5 . The osmo-
lality of the PN admixtures was slightly higher than 1000 mOsm/kg.
Slight creaming and a darkening color on visual inspection were appar-
ent after 48 h in admixtures stored at 25◦ C and 40◦ C.143 Zeta potential
290
18
values and pH did not change significantly throughout the study period
for any formulation, nor did lipid droplet diameter.143 Most impor-
tantly, none of the formulations exceeded a PFAT5 of 0.05%.143
Iron, in either the bound ferric (Fe3+ ) or free ferrous form (Fe2+ ), can
generate free oxygen radicals, which has raised concerns regarding its
safety with IV administration. This is especially true in the presence of
ILE, which serves as an excellent substrate for iron-induced peroxida-
tion because of the large number of double bonds present in the unsat-
urated fatty acids.145 Despite its potential benefits, iron, especially the
dextran form, should not be added to ILE or TNAs, as it can result in a
destabilization of the emulsion.146 Similar to divalent cations (ie, cal-
cium, magnesium), trivalent cations such as iron may cause a decrease
in the surface potential of the lipid droplets, destabilizing the nega-
tive surface charge between lipid particles, resulting in aggregation and
coalescence of the smaller lipid particles to form larger ones.114,147
These larger lipid globules can be potentially dangerous if infused, as
they can result in fat emboli, especially in neonates requiring the iron. In
a study involving the necropsy findings of nearly 500 live-born infants
(including 30 of 41 PN patients who had received ILE), Puntis and Rush-
ton found intravascular lipids in the small pulmonary capillaries of 15
infants receiving ILE that were not found in the necropsy of enterally
fed infants.148 This group had received significantly more ILE during
their PN course (in total amount [grams per kilogram] and duration
[number of days]) compared with another group of 15 infants receiv-
ing ILE who did not have lipid staining.148
Focus on micronutrients (alone or combined)
Trace elements
Trace elements may interact with other micronutrients. For example,
copper and ascorbic acid interact with each other. Copper can accel-
erate the degradation of ascorbic acid in solution, especially at pH >4.
Conversely, higher concentrations of ascorbic acid can reduce copper
to the cuprous form, which is why ascorbic acid content of adult multi-
vitamins was reduced to 100–200 mg from 500 mg.
A study evaluated trace element stability in a 1000-ml PN admix-
ture (Travasol AA3%-D18%) in a DEHP-free but nevertheless semiper-
meable bag, using an additive of six multi–trace elements and multi-
vitamin with high ascorbic acid (1000 mg) content.149 Using ICP-MS,
trace element concentrations were reported to decline over time (36 h
or 30 days) with storage (at 4◦ C or 20◦ C protected from light). Of the
trace elements formulated into the PN admixture, three (Cu, Mn, Zn)
decreased significantly in concentration over the storage time, even
when refrigerated.
The influence of copper on ascorbic acid stability was studied in 1-L
adult PN admixtures (AA5%-D25%) containing electrolytes and mul-
tivitamins (100 mg ascorbic acid), with or without trace elements (1.2
mg copper) in PVC bags at room temperature.150 Samples were taken
at time points from baseline up to 36 h to assay ascorbic acid con-
tent (using both spectrophotometry and high-performance liquid chro-
matography [HPLC] with ultraviolet detection). Based on the preferred
BOULLATA ET AL .
HPLC method, ascorbic acid concentrations had diminished to 67% of
baseline when no copper was present but decreased to 33% of baseline
in the presence of copper by 24 h. The generation of the ascorbic acid
degradation product oxalic acid was not quantified in this study.
Both ascorbic acid and copper have the potential ability to reduce
selenite to the poorly soluble elemental selenium.151 This may be more
likely at ascorbic acid concentrations >100 mg/L in PN admixtures with
pH of 5 or lower or at ascorbic acid doses above 500 mg, and it may be
less likely in well-buffered admixtures with pH >5.151–157
After selenium was recognized as a critical trace mineral to include
in PN admixtures, several studies evaluated its stability, in particular
given the potential risk for reduction to insoluble elemental selenium
by ascorbic acid. When only ascorbic acid (100 mg/L) and selenious
acid (100 mcg/L) were combined in solution, a 90% loss of selenium
occurred by 24 h, with higher concentrations (500 mg/L) of ascorbic
acid responsible for near-complete loss of selenium within 1 h using a
thin-layer electrophoresis method.155 The incorporation of selenious
acid into a PN admixture (Travasol AA4.25%-D25%) that included elec-
trolytes, a product with four trace elements, and multivitamins with
100 or 500 mg of ascorbic acid revealed minimal selenium loss at the
lower amount but over 10% loss with ascorbic acid 500 mg at 24 h.
The lower losses in the PN admixture were attributed to the amino acid
content of the admixture and its influence on overall pH. Of note, other
studies either did not determine the chemical form of selenium or did
not evaluate the interaction using a PN admixture.152–154
When added to a 1.85-L PN admixture (Travasol AA5%-D14.3%-
L5.7% Intralipid) with electrolytes, multi–trace elements, and multi-
vitamins in an EVA bag, the inclusion of iron dextran (100 mg) was
associated with repeated filter obstruction during infusion accompa-
nied by a yellow-brown fluid layer floating on top of the mix.146 That
supernatant contained much higher lipid concentrations than expected
from the homogeneous mix. This was not repeated with an identical PN
admixture, which excluded the iron dextran. When much lower concen-
trations of iron dextran (2 mg/L) were incorporated into simulated 0.5-
L PN admixture (Travasol AA0.55-2.2%–D0.4-10%–L2-4% Intralipid or
Liposyn II) in glass bottles without added electrolytes, trace elements,
or vitamins and stored at 4◦ C or 25◦ C protected from light for 48 h,
no visually apparent precipitation or phase separation was noted com-
pared with controls.158 Photon correlation spectroscopy suggested
that 90% of lipid droplets were smaller than 1.3 μm, although PFAT5
was not performed.
In one investigation evaluating the stability of iron sucrose added to
lipid-free PN containing pediatric amino acids (TrophAmine AA2.6%-
D20% [pH 5.7]; TrophAmine AA3.5%-D20% [pH 5.5]) with electrolytes
and trace elements, it was shown that the physical stability of iron
sucrose in PN is time and concentration dependent, based on visual and
microscopic inspection.159 Iron sucrose concentrations up to 2.5 mg/L
in lipid-free PN compounded with neonatal-range amino acid concen-
trations and cysteine were physically stable. Iron sucrose concentra-
tions of ≥10 mg/L were physically unstable, with particulate formation
within 12 h and evidence of gross physical incompatibility within 24
h.159 In the PN admixture containing a lower final amino acid concen-
tration, visible particulates manifest by 8 h at the highest iron concen-
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION
trations and within 24 h for all lower iron concentrations, with crystals
determined to be iron complexes including calcium and phosphate.159
Vitamins
The stability of multivitamin solutions depends on the individual com-
ponents. The instability of vitamins can be due to oxidation, pho-
todegradation, or exposure to container materials.160 The main fac-
tors affecting the stability of the individual vitamins and the excipients
include light exposure, pH, temperature, and PN bag material (eg, plas-
tic or glass).112 Light-induced peroxidation reactions may occur with
polysorbate 80 and 20.92 This reaction is enhanced at higher tempera-
tures and upon exposure to air.161
When exposed to ultraviolet light, riboflavin has been shown to cat-
alyze oxidation reactions.162,163 Riboflavin can act as a photosensitizer
initiating production of reactive oxygen species or directly reacting
with other components (eg, amino acids, fatty acids).164–166 Ultravio-
let light activates riboflavin-catalyzed oxidation reactions with some
amino acids.133 Exposure to 24 h of ultraviolet light was associated
with a statistically significant decrease in the methionine, proline, tryp-
tophan, and tyrosine concentrations in a 2-in-1 PN admixture con-
taining a riboflavin concentration of 1 mg/dl.133 Riboflavin itself can
be degraded to luminoflavin, luminochromo, and other compounds
in the presence of oxygen and light, including sunlight and artificial
light.167–169 The concentration of riboflavin in a 2-in-1 PN admixture
decreased by 47% and 100% upon exposure to 8 h of indirect and direct
sunlight, respectively.170
PN admixtures with pH values above 5.0 reduce the risk for pre-
cipitation of folic acid.171 Results from stability studies are conflict-
ing with regards to the effects of storage container, light exposure,
and temperature.112 In an early study evaluating the safety of vita-
min addition to PN, Chen et al (using a microbiological assay, which
was standard at the time for several B vitamins) found that folic acid
was stable in a 1-L PN admixture (Travasol AA4.25%-D25%) contain-
ing electrolytes, trace elements, and a nine-vitamin formula plus 1 mg
folic acid when exposed to fluorescent light, indirect sunlight, or direct
sunlight at room temperature for 8 h.170 When the PN was stored
frozen (−40◦ C) for 5 weeks and then refrigerated (4◦ C) for another 2
weeks, folic acid maintained stability.170 This study also revealed that
riboflavin, pyridoxine, and thiamin were unstable in sunlight (direct or
indirect) over that 8-h period.170 Precipitation forms at a folic acid con-
centration of 0.2 mg/L in the low pH, at a high concentration of dextrose
40% at room temperature, and under refrigeration.172 Direct sunlight
was found to degrade pyridoxine by 86% in a 2-in-1 PN admixture after
8 h.170
Thiamin degradation is dependent on several factors such as the sul-
fite concentration, pH, temperature, exposure to direct sunlight, and
presence of oxygen.112 The stability of thiamin is less of an issue now
that bisulfites are rarely included as an antioxidant/preservative in
other PN components (eg, amino acid solutions).112 The irreversible
degradation of thiamin in solution into a thiazole and pyrimidine by
sodium metabisulfite proceeds in a concentration- and pH-dependent
291
19
manner.173 It should be noted that combining the amino acid and dex-
trose solutions results in a decreased sulfite concentration, minimizing
the risk of thiamin degradation.174
A study conducted by Scheiner et al found that 93% of the initial thi-
amin amount remained after 24 h in a PVC bag containing a dextrose-
electrolyte solution (Normosol M-D5%) and multivitamins, with a pH of
∼5 (pH range, 4.0–6.5; 363 mOsm/L) and storage temperature of 23◦ C
in the presence of fluorescent light.173 The labeling of the Normosol M-
D5% solution indicated bisulfites as an ingredient, but they were not
detected. The authors concluded that the increased oxygen permeabil-
ity of the PVC bag (as compared with the glass container) accelerated
the loss of sulfites, thereby decreasing the potential for destruction of
thiamin.173 When Normosol M-D5% with multivitamins was stored in
a glass container (under the same room temperature, pH, and light con-
ditions), the amount of thiamin decreased to 51% relative to the origi-
nal amount after 24 h.173 Only 3% of the initial thiamin remained in an
undiluted FreAmine III 8.5% glass-bottle solution consisting of a high
concentration of bisulfites and with a pH of 6.5.173 A later study by
Smith et al revealed that thiamin degradation was the greatest in 2-in-1
and 3-in-1 PN admixtures (containing electrolytes, trace elements, and
multivitamins without vitamin K) with a final bisulfite concentration of
3 mEq/L and pH of 6.4 at a temperature of 25◦ C compared with other
solutions at various pH and bisulfite concentrations.175 Bowman et al
found that no thiamin degradation was detected for 22 h in a 1-L PN
admixture (AA4.25%-D25% with sulfite 0.05%) contained in a plastic
bag.174 The PN bags were stored at a temperature of 30–31◦ C, and the
average pH of the PN solution was 5.8.174
The main determinants of thiamin degradation are the presence of
sulfites and direct sunlight. Refrigeration has been shown to slow thi-
amin loss.173 When exposed to direct sunlight, the thiamin concentra-
tion in a 2-in-1 PN admixture decreased by 26% after 8 h.170 But in
a sulfite-free 2-in-1 PN admixture remaining refrigerated until use, at
least 75% of a large thiamin dose (50 mg) was maintained at 28 days.176
Patients should be monitored for signs and symptoms of thiamin defi-
ciency if there is a concern for thiamin loss from the PN admixture.
Ascorbic acid is the vitamin most susceptible to degradation, under-
going reversible oxidation to dehydroascorbic acid catalyzed in part by
trace elements (ie, copper, manganese, zinc), which can then undergo
hydrolysis to diketogulonic acid.112,177,178 The latter undergoes irre-
versible oxidation to several metabolites, including oxalic acid.112 Of
note, oxalic acid can interact with calcium, forming a poorly solu-
ble complex with risk for precipitation. This decomposition of ascor-
bic acid is dependent on the content of oxygen available in the PN
admixture from bag permeability, dissolved air in solution, and other
additives.177 The degradation is more likely at pH >4 and at higher
temperatures (22–35◦ C).179,180 The oxidation reactions are primarily
due to the introduction of oxygen into the PN admixture during the
compounding process, through permeation of the PN container, or dur-
ing infusion.112,162,181 Smith et al found that ascorbic acid degrada-
tion was more pronounced in plastic containers compared with glass
containers.175 The use of multilayered bags to reduce oxygen perme-
ability has been recommended to reduce ascorbic acid degradation,
with the caveat that they may trap oxygen transferred into the bag
292
20
during filling. The monolayered EVA bag is more permeable to oxy-
gen than a multilayered bag, which allows for a greater potential for
reactivity with ascorbic acid.181 Inclusion of cysteine, by complexing
with copper, may reduce the degradation of ascorbic acid.182 However,
cysteine has a reducing capacity able to irreversibly degrade ascorbic
acid/dehydroascorbic acid.183
Vitamins may also interact with other micronutrients. A specific
evaluation of several B vitamins using nuclear magnetic resonance
spectroscopy evaluated the interaction within this group and with
other micronutrients.144 Interactions between the vitamins, especially
pyridoxine, reflect proton exchange phenomena as opposed to inter-
molecular reactions. Pyridoxine and riboflavin are sensitive to the pres-
ence of electrolytes—especially pyridoxine in the presence of calcium
gluconate and phosphate—and, together with magnesium sulfate, may
suggest some self-aggregation of pyridoxine. Divalent cations (calcium,
magnesium, and copper and zinc as chloride salts) may also lead to
some self-aggregating precipitate of riboflavin, although the presence
of nicotinamide seems to inhibit riboflavin aggregation. Notwithstand-
ing these observations, hydrophilic vitamins and minerals in the same
PN admixture could be stable for up to 48 h.144
Studies investigating the effect of riboflavin on ascorbic acid oxi-
dation and in combination with ILE are conflicting. The manufacturers
recommend against the direct injection of multivitamins into ILE.84–87
In the presence of ultraviolet light, riboflavin catalysis of ascorbate
to dehydroascorbate, generating hydrogen peroxide and free radicals,
has been described in the literature.162,163 The hydrogen peroxide may
be the result of lipid and/or ascorbic acid oxidation.163 Laborie et al
found that ILE containing riboflavin (0.11 mmol/L) and ascorbic acid
(13.6 mmol/L) had higher amounts of peroxide production compared
with ILE alone or with riboflavin only.163 Contrary to the Laborie et al
results, Silvers et al found that the hydrogen peroxide concentration
decreased by 40% in ILE with multivitamins compared with dextrose
5% in water–0.45% sodium chloride with multivitamins in an ambient
light environment.162 The authors noted that oxidation of ascorbic acid
still occurred but that ascorbic acid protected against lipid peroxida-
tion. The major source of light and oxygen exposure occurred during
the infusion of the admixture through the catheter. Furthermore, the
opaque color of the ILE likely attenuated light-induced oxidation of
ascorbic acid.162 Silvers et al suggested that the findings by Laborie et
al were based on unreliable assay methods. Considering the beneficial
effect of ascorbic acid on ILE, the precaution against direct injection
of multivitamin solutions into ILE may be unnecessary.162 Conflicting
with previous findings, Dupertuis et al found that multivitamins con-
taining riboflavin did not influence the degradation rate of ascorbic acid
in 3-in-1 PN admixtures exposed to daylight.181 To prevent the possi-
bility of ascorbic acid loss induced by riboflavin, PN admixtures should
be protected from light when practical.
Retinol is the most light-sensitive vitamin, with extensive pho-
todegradation depending on the wavelength and intensity of
light.169,184,185 The presence of ILE in the PN admixture is thought
to reduce the degree of vitamin A instability, but this remains
controversial.128,175,185,186 The use of light-protective covers has
been suggested.185,187 Less reactive than retinol, vitamin E undergoes
BOULLATA ET AL .
photo-oxidation that is dependent on wavelength and light intensity
as well as the oxygen content.188 Bags that prevent oxygen perme-
ability or light-protective covers may each improve the stability of
vitamin E.128,187,189 The potential degradation of retinol and vitamin
E during lipid peroxidation in a PN admixture may be less when MCT
oil accompanies soybean oil, compared with ILEs of a soybean-olive oil
combination or soybean-oil ILE alone.190 More has yet to be learned
about the stability of different vitamin E isomers. Vitamin K content
of the PN admixture is susceptible to photodegradation regardless
of the presence of lipids.128,191 Exposure to daylight decreased the
phytonadione concentration in PN admixtures (2-in-1 and 3-in-1) by
50% after 3 h.128
Given the above, multivitamin solutions are the least stable compo-
nent in PN admixtures, especially when exposed to oxygen and light.112
For this reason, dispensing a 7-day supply of PN admixtures at a time
precludes multivitamin content and requires the patient/caregiver to
add the dose each day just prior to administration. Once the multivita-
mins are added to the compatible diluents, the final admixture should
ideally be administered immediately in the absence of photo-oxidative
protection and completed within 24 h.84–87 The vitamin-containing PN
admixture should be refrigerated when administration is delayed.84–87
To prevent degradation due to light exposure during administration, PN
bags should be wrapped with an opaque protective covering.192 Also,
orange or yellow infusion tubing may be used to prevent light pene-
tration through the tubing during administration.192 The practice of
photoprotection in the United States remains dependent on product
availability.193
OTHER
Aside from the common nutrient components of the PN admixture,
additional compatibility and stability issues arise with other com-
ponents. These include medications added to or co-infused with a
PN admixture, as well as the materials found in automated com-
pounding device circuits, the PN bag, administration sets, and inline
filters.
Medication
As is already apparent, PN admixtures are complex from a compat-
ibility and stability perspective when accounting for all the nutrient
components—active ingredients and excipients. The consideration to
include a nonnutrient medication in a PN admixture is to be undertaken
carefully with serious attention to compatibility and stability concerns.
This is true whether preparing a PN completely from individual com-
ponents or starting with a commercial, standardized, multichamber PN
product. Similar attention needs to be given when considering medica-
tion administration by Y-site infusion along with a concurrently infus-
ing PN admixture. An evidence-based guidance document discussed
the safety of using the PN admixture as a vehicle for nonnutrient medi-
cation delivery along with a summary of published data.4 Although that
JOURNAL OF PARENTERAL AND ENTERAL NUTRITION
can be referred to for further detail, the following provides a concise
summary.
Added to the PN admixture
The PN admixture itself will have been determined to be compati-
ble and stable before introducing a medication. There could be an
advantage to including a drug within the PN admixture if it can con-
solidate drug dosing and volume and decrease manipulations of vas-
cular access. In order to be considered, the IV drug required by a
patient should be a stable regimen that requires no dose titration
and is therapeutically effective by continuous or cyclic infusion. How-
ever, this still requires reviewing the available data on compatibil-
ity and stability. Unfortunately, there are a limited number of IV
drugs that have been evaluated so far, and few of them rely on
currently accepted methods of study design and analysis.4 Specific
criteria for evaluating compatibility and stability studies of medica-
tion in PN admixtures should be followed.113,194,195 Unfortunately,
many published studies have relied exclusively on visual compati-
bility, whereas some newer publications have applied some of the
criteria.
Visual physical compatibility of a medication in a PN admixture by
itself is not indicative of chemical compatibility or drug stability. At the
very least, drug pKa and product pH along with the presumed pH of
the PN admixture are important to consider. Once the physical com-
patibility and chemical stability are both demonstrated, verification of
pharmacologic/therapeutic effectiveness in patient care is also neces-
sary. In other words, the drug needs to be soluble, compatible, and sta-
ble in the PN admixture as well as therapeutically effective—without
altering the compatibility or stability of the initial PN admixture. A
close examination of published data is valuable, when available, but
extrapolation beyond study parameters (eg, component products, con-
centrations of each ingredient including the drug) is discouraged. Ide-
ally, a drug would only be considered if supported by pharmaceuti-
cal data describing physicochemical compatibility and stability of the
added drug and of the final PN admixture under conditions of typical
use, plus clinical data confirming expected therapeutic actions of the
drug.3
A recent example is a study that purported to show that 1 g of
ampicillin (an anion) was stable in two TNAs for 7 days under refrig-
eration and then for 24 h at room temperature following addition of
vitamins and trace elements.196 Although methods went well beyond
visual compatibility, there remained some shortcomings. For example,
the drug assay was not shown to indicate stability (but drug concen-
tration was below 90% by 48 h in storage at 4◦ C), there was no PFAT5
reported, and no clinical rationale was provided as to how long the
ampicillin concentration would be expected to remain above the min-
imum inhibitory concentration of a given bacteria during PN infusion.
There was an increase of admixture pH, no zeta potential lower than
−23 mV, for this low ampicillin dose studied in a 250-ml PN, with lim-
ited sampling points.196
293
21
Co-infused with the PN admixture
When a medication needs to co-infuse with a PN admixture via Y-site
owing to limited patient access, clinicians must consider the drug prod-
uct excipients and contents of the carrier fluid as well as the medica-
tion when evaluating compatibility and stability with PN admixtures.
A number of IV drugs have been studied for Y-site compatibility with
compounded PN admixtures as well as with commercial, standardized,
multichamber PN products.22,197–205
Studies are often performed in vitro, with small sample volumes,
using various dilutions of a PN admixture and a drug to simulate the
concentrations combined during an actual Y-site infusion. Given that
the contact time during infusion is often <4 h, drug stability is rarely
evaluated. Drug compatibility via Y-site administration has most fre-
quently been determined by visual inspection. Within these limita-
tions, 80% (82 of 102) of medication tested with four different 2-in-
1 PN admixtures and 78% (83 of 106) of the drugs tested with nine
different TNAs were revealed to be visually compatible.22,197 Others
revealed 80% (20 of 25) of drugs evaluated were compatible in a PN
admixture.198 Further, 7 of 10 medications used in pediatrics were
compatible by Y-site administration with two commercial, standard-
ized, multichamber PN admixtures.200 Also, drug Y-site compatibility
with neonatal PN admixtures was found for 16 of 21 medications.201
When no restrictions for infusion fluid, concentration, or time were
placed, as may occur for neonates in a pragmatic study, only 5 of 131
drugs were considered compatible with two PN admixtures, based on a
wide-ranging literature search.202 Y-site administration of medication
may rarely need to be considered for patients receiving home PN and
should also be evaluated for compatibility under conditions of typical
use.203
The results of compatibility studies with a drug can differ with a
change of a single component of the PN admixture, including ILE or
the oil source of the ILE.204,205 It is important to appreciate the details
(concentrations of each ingredient), assumptions (contact time of all
active ingredients and excipients), and limitations of these studies. In
the infrequent case that ILE is administered through a separate vas-
cular access device from the 2-in-1 PN admixture, data on Y-site drug
compatibility and stability with ILE infusion have been measured.206
As indicated earlier, all details need to be provided, including the pH
of each component, dilutions used, and contact time of exposure with
performance of PFAT5 . The contact time, including across the filter sur-
face area, can be prolonged during low flow rates, as may be seen with
infants.
Other components
Compatibility needs to account for components of the automated com-
pounding device, the PN bag, administration set, and inline filter. Plas-
ticizers incorporated into plastic containers, bags, and infusion sets are
not chemically bonded to the plastic and have the potential to leach
out. DEHP is the predominant phthalate plasticizer found in PVC con-
294
22
tainers, bags, and administration sets and is known to specifically leach
into lipid-containing admixtures.51,207–210 This poses a risk for toxic-
ity, so the use of EVA or multilayer EVA/ethylene–vinyl alcohol bags is
recommended for lipid-containing admixtures to flow through DEHP-
free infusion sets. The EVA bags depend on vinyl acetate content to
make the plastic supple, and polyolefins do not require a plasticizer for
their flexibility. Beyond the direct clinical risks from the toxicant DEHP
leaching into lipid-containing admixtures, this compound may also dis-
rupt emulsion stability, likely through the release of phthalic acid (pKa
= 2.89).114
Plasticizers are not the only component of concern. For example,
flexible plastic containers, bags, and administration sets (PVC, EVA,
polypropylene) contain several metals (eg, Ba, Cd, Pb, Sn, Zn) to sta-
bilize the plastic polymers.211 These metals also have the potential to
leach into the infusate. For example, a study of trace element stabil-
ity in PN noted that cobalt may have leached from the administration
set.149 When tested using a dextrose (10%), sodium chloride (0.9%),
and Tween-80 (5%) solution, in the three bag composition types, the
primary metal appearing in the solution was zinc (at concentrations
in the micrograms per liter range) from both PVC and EVA.211 The
findings were similar when commercial sodium chloride or dextrose
bags were infused through PVC administration sets, with zinc content
increasing significantly (remaining at the micrograms per liter range)
despite brief infusion. Although not evaluated with an amino acid solu-
tion or a complete PN admixture, given the propensity of amino acids
to complex with cadmium and lead, there may be a risk for those met-
als leaching into the PN admixture as well.40
SUMMARY
Maintaining the safety of patients requiring PN therapy requires a
recognition of the available data and the application of pharmaceu-
tical science to ensure the compatibility and stability of the ordered
PN prescription. This pursuit requires continued vigilance by the phar-
macist reviewing PN orders within the use process. The pharmacist
with the requisite knowledge, skills, and experiences ensures the safety
of PN regimens as they fulfill their professional responsibility. The
effort occurs in collaboration with those recommending, prescribing,
and preparing PN admixtures, as well as those involved in procuring all
the relevant components.
CONFLICT OF INTEREST
Joseph I. Boullata is a consultant and speaker for American Regent, a
consultant and speaker for B. Braun, and a speaker for Fresenius Kabi.
Jay M. Mirtallo is a consultant and speaker for Fresenius Kabi. Gordon
S. Sacks is an employee of Fresenius Kabi. Genene Salman has no con-
flict of interest. Kathleen Gura is a consultant for Fresenius Kabi; on
the advisory board for B. Braun, Baxter, Fresenius Kabi, and Pfizer; and
receives royalties from Fresenius Kabi. Genene Salman, Todd Canada,
and Angela Maguire have no conflict of interest.
BOULLATA ET AL .
FINANCIAL DISCLOSURE
None declared.
ORCID
Joseph I. Boullata PharmD, RPh https://orcid.org/0000-0003-4768-
7703
Jay M. Mirtallo MS, RPh https://orcid.org/0000-0003-0736-6171
Kathleen Gura PharmD https://orcid.org/0000-0002-0431-896X
Todd Canada PharmD https://orcid.org/0000-0002-2704-5749
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