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Chapter 15
Parenteral Solutions Overview
D. Berlana and E. Leiva Badosa
Introduction
Parenteral nutrition (PN) is a complex mixture containing up to 40 different components, which may potentially lead to stability and compatibility issues. Indeed, the
prescription of PN is one of the most intricate practices commonly employed in a
hospital setting. The purpose of this chapter is to offer an overview of PN solutions,
focusing on the composition of PN admixtures, the types of PN systems,
compounding methods, and the various factors that can affect the stability and
compatibility of PN solutions.
Composition of PN Admixtures
Components used in formulating PN typically include protein in the form of amino
acids (AAs), carbohydrates, and fat, serving as the primary sources of energy.
Additionally, vitamins and trace elements should be included. Moreover, electrolytes and sterile water can be added to achieve the required volume. For intravenous
(IV) administration, sterile, low-particulate dosage forms formulated as solutions are
required—usually aqueous, although they may occasionally include some
Supplementary Information The online version contains supplementary material available at
https://doi.org/10.1007/978-3-031-66541-7_15.
D. Berlana (
Pharmacy Department, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
e-mail: david.berlana@vallhebron.cat
E. L. Badosa
Department
e-mail: eleiva@bellvitgehospital.cat
© The
A. Cotoia et al. (eds.), Nutrition, Metabolism and Kidney Support,
https://doi.org/10.1007/978-3-031-66541-7_15
✉)
of Pharmacy, Bellvitge University Hospital, Barcelona, Spain
Author(s), under exclusive license to Springer Nature Switzerland AG 2024
161
162 D. Berlana and E. L. Badosa
nonaqueous solvents. The prescriber of PN should be well-versed in the appropriate
indications for PN, the vascular access devices (both peripheral and central), and
their associated complications. Furthermore, they should have knowledge of the
suitable amounts of each macronutrient and micronutrient required in the PN
solution. The prescriber of PN should be well versed in the appropriate indications
for PN, the vascular access devices (both peripheral and centr
complications, as well as the appropriate amounts of each macronutrient and micronutrient required in the PN solution [
admixture significantly influences the properties, stability, and safety of the individual macronutrient and micronutrient components. Pharmacists play a critical role in
designing and preparing safe formulations , ensuring sterility, compatibility, and
stability. Various procedures and national guidance documents have been developed
by organizations in different countries to assist pharmacists in adhering to guidelines
or compounding sterile PN admixtures. These include organizations in the USA
f
(US Pharmacopeia and the American Society of Health-System Pharmacy), as well
as in European countries like France and Spain [
1]. The compounding process for a PN
1, 2].
al), and their associated
Energetic Substrates
Carbohydrates and lipids both serve as the energetic sources in PN admixtures.
Carbohydrates
The most used carbohydrate substrate is dextrose, which, in its hydrated form,
provides 3.4 kcal/g of carbohydrate (mainly used in the USA and Canada). In
contrast, anhydrous dextrose, primarily utilized in Europe, provides 4 kcal/g of
carbohydrate [3, 4]. Dextrose is marketed as sterile IV solution available in various
concentrations ranging from 5% to 70% and can be combined with other parenteral
solutions. IV dextrose solutions have an acidic pH, ranging from 3.2 to 6.5, as no
buffer is added. Dextrose monohydrate at a concentration of 5% is considered
isotonic (252 mOsm/L), while concentrations higher than 10% are hypertonic and
should be administered through a centr al line to reduce the risk of
thrombophlebitis [5].
Lipid Emulsions
Intravenous
they provide essential fatty acids, serving as the primary source of non-protei n
energy. ILEs are oil-in-water emulsions designed to replicate the properties of
natural chylomicrons. They consist of one or more oils containing triglycerides, a
phospholipid emulsifier, and glycerol [5]. Commercial ILEs for PN are typically
lipid emulsio ns (ILEs) play a crucial role in parenteral nutrition (PN) as
15 Parenteral Solutions Overview 163
Table 15.1 Characteristics of ILEs for PN available in Europe [7, 9, 15, 16]
Lipid source and
content
Soybean oil 100% 7:1 422–439 38
Soybean oil 50%
Coconut oil 50%
Soybean oil 64%
Coconut oil 36%
Soybean oil 20%
Olive oil 80%
Fish oil 100% 1:8 0 150–296
Soybean oil 40%
Coconut oil 50%
Fish oil 10%
Soybean oil 30%
Coconut oil 30%
Olive oil
Fish oil
25%
15%
Omega-6:omega-3
ratio
7:1 187–278 85–20
7:1 346 6,9
9:1 208–274 32
– 140 –
2.5:1 124–207 200
Phytosterol content
(mcg/mL)
α-Tocopherol
(mg/L)
available in a 20% concentration. While each gram of fat provides 9 kcal, the
glycerol in ILE adds calories, making each gram of fat in ILE 20% equivalent to
10 kcal l [
6, 7]. ILEs are predominantly composed of triglycerides, encompassing
medium-chain fatty acids, long-chain fatty acids, and very long-chain fatty acids
such as docosahexaenoic acid and eicosapentaenoic acid. Essential fatty acids like
ω-6 polyunsaturated fatty acid (PUFA) linoleic acid and ω-3 PUFA α-linolenic acid
are necessary for humans, as they cannot be synthesize d de novo. Both fatty acids are
produced in plants [
8]. To prevent essential fatty acids deficiency, it is recommended
that 2–4% of total energy should come from linoleic acid and 0.25–0.5% from
α-linolenic acid. On the other hand, fish oil-based intravenous lipid emulsions
(ILEs) are rich in omega-3 polyunsaturated fatty acids (PUFAs), which demonstrate
anti-inflammatory, immunomodulatory, and antioxidative properties in preclinical
models [9]. While n-6-derived eicosanoids are considered proinflammatory , omega3-derived eicosanoids are considered anti-inflammatory. The use of fish oil or fish
oil-enriched ILEs has been associated with a reduced risk of hepatic dysfunction, as
well as the recovery of liver dysfunction [
10, 11]. The omega-6:omega-3 ratio has,
therefore, been suggested as an important factor when considering an ILE. Phytosterols are plant sterols structurally similar and functionally analogous to cholesterol
in vertebrate animals. Clinical evidence supports phytosterols as one of the risk
factors for developing parenteral nutrition–associated liver disease [12, 13]. ILEs are
also an important source of vitamin E (tocopherols and tocotrienols). Among the
different vitamin E isoforms, α-tocopherol is the biologically active form, and its
content varies significantly between different emulsions [
14]. The characteristics of
ILEs currently available in Europe are shown in Table 15.1.
The first commercial fat emulsion was based on a soybean oil-based lipid mixed
with egg yolk [17]. Currently available ILEs are derived from soybean, safflower,
coconut, olive, or fish
oil. Soybean-based ILEs have a high concentration of
164 D. Berlana and E. L. Badosa
omega-6 PUFA, containing essential fatty acids, but they are rich in phytosterols
[7, 9, 18]. Olive oils have a low essential fatty acid content, whereas fish oil contains
omega-3 fatty acids and high content of alpha-tocopherol.
Proteins
Proteins are administered via intravenous, sterile, free crystalline AAs solutions to
fulfill the requirements for AAs necessary for protein synthesis and replacement of
protein stores [3, 4]. The nitrogen content varies, not only depending on the
concentration of the AAs but also the type of AA. However, AAs solutions are
generally assumed to contain 16% nitrogen (6.25 g of protein = 1 g of nitrogen)
[3, 19]. These solutions also provide energy (4 kal/g).
Commercial AAs mixtures for PN contain essential, non-essential, and occasionally some conditionally essential AAs to achieve the required quantity of nitrogen. In
these solutions, at least 50% of the total AA support should come from essential AAs
[19]. The use of special AA PN formulations in acute kidney injury is not
recommended since there is no evidence supporting their use in acute renal
impairment.
An AA solution containing large amounts of branched-chain AAs (BCAAs) and
lower doses of aromatic AAs (phenylalanine and tyrosine), methionine, and tryptophan is also commercially available. This mixture has been suggested as a liveradapted formulation for grade III to IV hepatic encephalopathy [20]. While several
guidelines do not support its use in critically ill patients with PN and liver disease
[21, 22], current European guidelines recommend BCAA-enriched formulas for
patients with hepatic encephalopathy in need of enteral nutrition [22].
Standard AA solutions for PN do not include glutamine, which should be added
separately into PN as a supplement. In some countries, a commercial solution of
alanyl-glutamine (20 g/100 mL) is available to treat presumed states of glutamine
deficiency. However, it has been used as an extemporaneous preparation of powdered L-glutamine sterilized by filtration when commercial products are not available [
3]. According to national guidelines, glutamine supplementation should be
considered for certain clinical conditions, but is contraindicated in liver and renal
failure [23–25].
Micronutrients: Electrolytes, Vitamins, and Trace Elements
PN practice guidelines state that vitamins must be included in PN daily [1]. Standard
ranges for electrolytes and trace elements are age-specific and established based on
normal organ function and losses. Maintenance or therapeutic amounts of various
electrolytes are added to PN formulations depending on the patient’s requirements,
and underlying disease. However, the amount of electrolyte in PN may be limited
15 Parenteral Solutions Overview 165
due to compatibility issues [5]. In general, commercially available electrolyte products include only individual salts because of incompatibility concerns. Although
multiple electrolyte products are also available, they do not contain phosphate and
have restricted electrolyte concentrations to avoid potential incompatibility.
Commercially available
single vitamin products and multivitamin products that contain both fat-soluble and
water-soluble vitamins. Additionally, common trace elements incorporated into PN
formulations include zinc, copper, chromium, manganese, and selenium. Li ke vitamin products, they are commercially available as individual products, each
containing a single trace element, and in various multiple trace-element combinations, as an age-specific formulation based on general recommendations [26].
vitamin products used for PN supplementation include
Types of Parenteral Nutrition
PN admixtures can be prepared in two formats: the 2-in-1 formulation, consisting of
dextrose plus AA formulation, and the 3-in-1 formulation, also called “all-in-one” or
“Total Nutrient Admixture” (TNA), which includes dextrose, AA solution, and fat
emulsion. In the 2-in-1 formulation, all essential intravenous macronutrients and
micronutrients (electrolytes, vitamins, and trace elements) are combined in a single
container except ILE, which is administered separately. Both formats have their
advantages and disadvantages. TNA is associated with cost savings, efficient
compounding, and a reduced risk of contamination during administration [1, 5,
27]. However, TNA carries a higher risk of emulsion destabilization due to inap-
propriate macronutrient or electrolyte concentrations. Additionally, it requires the
use of a larger pore filter (1.2 μm) to avoid breaking the emulsion. Conversely, the
2-in-1 formulation allows the use of a 0.22 μm filter, which eliminates a greater
].
amount of particulate matter, including some bacteria [1, 5, 6
vascular access is available, solutions for parenteral nutrition (PN) administration
are not limited by pH, osmolarity, or volume. However, in cases where central
vascular access is unavailable, peripheral PN (PPN) is an option, and the osmolarity
of the PN admixture should be limited to <900 mOsm/L. The components of a PN
formulation will determine its osmolarity. PPN has a similar composition to PN
administered through central lines but with lower concentrations of nutrients to
allow peripheral venous administration by reducing the total osmolarity of the
mixture. General PPN macronutrient content recommendations include ami no
acids (AAs) <4% and glucose <10%, as they are the major contributors to the
increase in osmolarity in PN. The estimated contribution to osmolarity is 10 and
5 mOsm per gram of AA and glucose, respectively, whereas for intravenous lipid
emulsion (ILE), it is lower (0.7 mOsm per gram of fat) [
should also be considered to calculate the final osmolarity of the admixture, as
electrolytes provide approximately 1 mOsm/mEq of the individual electrolyte additive. Table 15.2 summarizes the types of PN.
3, 4].
When central
Electrolyte content
166 D. Berlana and E. L. Badosa
Table 15.2 Types of PN depending on osmolarity and venous access, method to compound, and
type of formulation
Factor
Osmolarity and
venous access
type of
Type of
PN Characteristics
TPN Osmolarity >1000 mOsm/L. To be administered
throughout central access
throughout
or method to
System
compound
Formulation 2-in-1 Admixture containing AAs and carbohydrates.
HPCB They could be tailored or standardized
MCB Commercially available PN
3-in-1 Containing lipids,
TNA, or all-in-one
no central access
AAs and carboh
ydrates. Also called
Different options are available for the compounding process, including commercial multichambered bags (MCBs) and hospital pharmacy compounded bags
(HPCBs). Concerning the compounding process for HPCBs, two methods exist:
automated or manual. HPCBs must be prepared nearly daily by the pharmacy,
mainly due to limited mixture stability, but also because of the need for customized
parenteral nutrition (PN) to meet individual patient requirements. MCBs contain a
fixed number of macronutr ients with or without electrolytes in separate compartments within a single bag; nutrients are mixed during preparation by breaking the
plastic seals between compartments. However, current available MCB formulations
do not contain vitamins or trace elements. Therefore, all MCBs require the addition
of vitamins and trace elements. Vitamins, trace elements, and electrolytes (if needed)
should be added to the bag during the compounding process prior to dispensing for
administration.
MCBs have shown advantages over HPCBs, including reduced costs, time, and
labor, and fewer errors during PN preparation [
27]. Furthermore, the stability of
MCBs is guaranteed by the manufacturing company. Besides, electrolytes and other
nutrients such as glutamine or omega-3 fatty acids can be added because these
criteria have been considered in the development of the MCB form ulations. Regardless of the type of PN (2-in-1 or 3-in-1), the system used (MCB or HCPB), or the
method to compound (automated or manual), the pharmacist bears the responsibility
of ensuring the safety of PN [1, 2].
Compatibility and Stability of the Parenteral Nutrition
PN is one of the most complex intravenous admixtures, containing over 40 chemical
components. Inevitably, the combination of different intravenous products leads to a
less stable admixture than its individual component products, with a risk of incompatibilities. Even micronutrients such as electrolytes, vitamins, and trace elements
can affect PN stability, especially in an all-in-one PN. A classic example of nutrient
15 Parenteral Solutions Overview 167
degradation is the Maillard reaction, which occurs between dextrose and amino acids
(AAs) such as lysine, resulting in a brownish discoloration of the final formulation.
Certain AAs, vitamins, and intravenous lipid emulsion (ILE) are particularly susceptible to instability [
Compatibility refers to the
2, 4, 5].
uneventful physical and chemical coexistence of two
or more components over time after being combined. The stability of PN formulations focuses on the degradation of components over time. Instability , in this context,
refers to the irreversible decomposition or degradation of nutrient components.
Different factors are known to affect the compatibility of any given additive.
These factors include temperature, pH, concentration (even trace elements have
been involved in the formation of precipitates), order of mixing, and the duration
of exposure [4, 5].
The specific
dosages
and combinations of nutrients can significantly affect the
stability of a parenteral nutrition (PN) admixture. It has been suggested that final
macronutrient concentrations should be as follows: amino ac ids (AAs) >4%, dextrose >10%, and lipids >2% to maintain the stability of the admixture [4, 5]. The
acidic dextrose solution should not be added directly to intravenous lipid emulsion
(ILE); instead, it is recommended to combine the dextrose solution with the AA
solution during the compounding process. The AA solutions have an intrinsic
buffering system, and higher final concentrations of AAs have a greater buffering
capacity. Therefore, low final concentrations of AAs (< 2%) may not provide
adequate buffer capacity to p revent destabilization of a 3-in-1 formulation. Similarly,
low ILE concentrations, especially below 2%, may also result in an unstable TNA.
Calcium phosphate solubility is a major compatibility concern with PN formulations and depends on several factors, including the final AA concentration, mixing
sequence, pH, temperature, 2-in-1 vs 3-in-1 formulation, and the relative amount of
calcium and phosphate ions. Lowering the pH of the PN admixture reduces the
likelihood that calcium and phosphate will precipitate. Solubility curves have been
developed and validated, providing guidance on determining the maximum amount
of calcium and phosphate that can be added to the PN admixture. Inorganic salts
(like calcium chloride, monobasic/dibasic phosphates) are more likely to dissociate
into free ions compared to organic salts (such as calcium gluconate, sodium
glycerophosphate). Therefore, organic salts, such as calcium gluconate a nd sodium
glycerophosphate, are the preferred forms of these electrolytes for use in PN
formulations since they are less likely to cause physicochemical incompatibilities
[4, 5, 2
8].
The IL
E consists of an interior oil phase dispersed in an external water phase, and
its physical instability is characterized by an increase in lipid droplet size. Instability
may occur when there are ion interactions, variations in ionic strength, and pH
changes in the aqueous phase of the emulsion. These factors may alter the electrical
charge on the lipid droplet surface. A pH in the range of 6 to 9 is most favorable for
ILE stability. Multivalent cations, such as calcium and magnesium, as well as trace
elements such as copp er, iron, and zinc, may alter the stability of ILE by reducing the
negative forces that keep lipid droplets separated. The higher content of divalent
cations in pediatric formulations (e.g., calcium and magnesium) may reduce the
168 D. Berlana and E. L. Badosa
negative surface charge, resulting in coalescence. In addition, the higher content of
calcium and phosphate in these PN formulations increases the risk of precipitation.
Consequently, some authors discourage the use of TNA for pediatric form ulations,
especially in neonatal/infant PN formulations. However, 3-in-1 formulations are
commonly used in pediatric admixtures, as the stability of the formulations has
been previously established. The “percentage of fat
residing in globules larger than
5 μm” (PFAT5) criteria from USP, limiting the lipid globul e size distribution to
0.05% for large diameters (>500 nm), may reflect the onset of or continuing lipid
destabilization [
5, 6, 29]. Individual vitamins may react with each other, macronu-
trients, excipients, or the parenteral nutrition (PN) bag material. Other factors that
may affect the stability of vitamins include pH, light exposure, and temperature. Like
amino acids (AAs), light and oxygen exposure enhance the degradation of some
vitamins. Consequently, during storage and administration, PN admixtures should
be protected from light to limit photodegradation of some nutrients, such as
vitamins. Moreover, the use of a multilayered bag is also recommended to prevent
oxidation [
2, 5, 6, 30].
Despite data on the compatibility of several drugs with PN, using PN as a drug
delivery
vehicle is not recommended. Compatibility with a drug can differ with a
change in a single component of the PN. Therefore, the addition of a medication to a
PN admixture, or the co-administration of medication by Y-site infusion, should be
undertaken carefully with serious attention to compatibility and stability concerns
3, 5].
[
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