661174

research-article2016
NCPXXX10.1177/0884533616661174Nutrition in Clinical PracticeBiesboer and Stoehr

Invited Review
Nutrition in Clinical Practice
Volume 31 Number 5
A Product Review of Alternative Oil-Based Intravenous Fat October 2016 610618
2016 American Society
Emulsions for Parenteral and Enteral Nutrition
DOI: 10.1177/0884533616661174
ncp.sagepub.com
hosted at
online.sagepub.com
Ann N. Biesboer, PharmD, BCPS, BCCCP1; and Nancy A. Stoehr, PharmD, FACA1

Abstract
Soybean oilbased intravenous fat emulsions have long been used as the primary product for delivery of lipid-based calories in parenteral
nutrition formulations in the United States. Proinflammatory properties of these products may be related with poor clinical outcomes
and have led investigators to develop newer generations of intravenous fat emulsions. These alternative formulations are derivatives
of medium-chain triglycerides, olive oil, and fish oil in hopes to reduce the inflammatory response and potentially produce a clinically
beneficial anti-inflammatory response. Although surrogate markers support this reduction in inflammatory response, clinical data and
outcomes are still limited but potentially promising in the literature. This product review provides a general overview of the alternative-
generation intravenous fat emulsion products and the literature supporting the potential transition to such products. (Nutr Clin Pract.
2016;31:610-618)

Keywords
parenteral nutrition; nutritional support; parenteral nutrition solutions; intravenous fat emulsions

Introduction This is demonstrated by an elevation in common serum inflam-

matory markers, such as tumor necrosis factor and interleukin
Intravenous fat emulsions (IVFEs) have long been used for 6, within hours following administration of SO IVFEs. Several
providing complete nutrition support for patients receiving subsequent studies have demonstrated similar findings.6,7
parenteral nutrition (PN).1 IVFEs for PN-dependent patients is This inflammatory process induced by omega-6 FAs is obvi-
an important source of essential fatty acids (EFAs) and are nec- ously not ideal for patients in the clinical setting, leaving investi-
essary to prevent EFA deficiency. Historically, soybean oil gators and clinicians in search for alternative IVFEs products that
(SO)based IVFEs have been the mainstay of IVFEs available do not contain such a high-content of omega-6 FAs as seen with
on the market in the United States. However, in European, SO IVFEs. Further research has shown that the addition of spe-
Canadian, and Asian markets and with popularity gaining in cific omega-3 FAsnamely, DHA and EPAmay be clinically
the United States, there has been growing interest in the use of beneficial for patients as well.5 Studies have shown that greater
alternative oil-based IVFEs formulated with medium-chain tri- ratios of EPA:DHA lead to greater anti-inflammatory effects.8-11
glycerides (MCTs), olive oil (OO), and/or fish oil (FO). Similarly, the type of triglycerides present within the emul-
The search for alternative IVFE products stems from the sion also potentially has clinical relevance. The 3 main types of
various limitations associated with the chemical properties of
SO IVFEs.2-4 These limitations include, but are not limited to,
From the 1School of Pharmacy, Concordia University Wisconsin,
fat source and its related inflammatory effects, the potential for Mequon, Wisconsin, USA.
allergic reactions, and the potential for the development of
PN-associated liver disease (PNALD). Financial disclosure: None declared.

Conflicts of interest: None declared.

Proinflammatory Effects of SO IVFEs This article originally appeared online on August 15, 2016.

SO IVFEs comprise omega-6 fatty acids (FAs) and long-chain

Download a QR code reader on your smartphone, scan
triglycerides (LCTs) and contain no eicosapentaenoic acid this image, and listen to the podcast for this article
(EPA) or docosahexaenoic acid (DHA). Potential proinflam- instantly. Or listen to this and other NCP podcasts at
matory characteristics associated with SO IVFEs have been http://ncp.sagepub.com/site/misc/Index/Podcasts.xhtml.
attributed to the composition of the product. It is theorized that
these proinflammatory effects result in potentially adverse
clinical outcomes. Corresponding Author:
Ann N. Biesboer, PharmD, BCPS, BCCCP, School of Pharmacy,
As early as the 1990s, it has been shown that administration of Concordia University Wisconsin, 12800 N. Lake Shore Drive, Mequon,
IVFEs with high concentrations of omega-6 FAs, as found in SO WI 53097, USA.
IVFES, has proinflammatory effects in rat and human models.5 Email: annie.biesboer@cuw.edu

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Biesboer and Stoehr 611
Figure 1. Generation progression of intravenous fat emulsions per the position paper of the American Society for Parenteral and
Enteral Nutrition. FO, fish oil; MCT, medium-chain triglyceride; OO, olive oil; SO, soybean oil.
triglycerides present in these emulsions include MCTs, LCTs,
and synthetically structured triglycerides. Studies have sug-
gested a link between LCTs and an increase in risk of infec-
tion.1 A recently published meta-analysis revealed improvement
in nitrogen balance and triglycerides in patients receiving
structured triglyceridebased formulas in comparison with
LCT/MCT-based IVFEs.12 These data again support the transi-
tion away from SO IVFEs to newer formulations.
Allergic Reactions
A soy allergy limits the clinical use of a SO IVFE in a PN for-
mula. Soy allergies put patients at risk for the development of
EFA deficiency, given limitations on commercially available
IVFEs that are not SO IVFEs. Other oil-based formulations
would theoretically provide soy-allergic patients with a clinical
alternative to allow for safe IVFE administration and preven-
tion or treatment of EFA deficiency.
Parenteral NutritionAssociated Liver
Disease
PNALD is the development of liver and biliary complications
secondary to PN administration. The development of PNALD
is a challenging complication that stems from numerous com-
ponents of the PN formulation, including but not limited to the
IVFE selected. This adverse effect can become a life-threaten-
ing disorder and can be of particular concern in patients receiv-
ing prolonged PN, potentially leading to the development of
cirrhosis and end-stage liver disease requiring liver transplan-
tation. The phytosterol content, the oil base of the IVFE, and
the dose of IVFE administered all potentially play a role in the
development of PNALD.4
Phytosterols are plant-based compounds found in vegetable
oils and are present in SO IVFEs. The literature has reported that
patients receiving SO IVFEs can have elevated phytosterol serum
levels, which have been implicated in the development of impaired
biliary flow, potentially leading to biliary sludge and stones.4
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As mentioned above, SO IVFEs contain LCTs. LCTs have
been reported to be associated with the development of PNALD.
It has been shown that the replacement of LCTs with MCTs, as
with different non-SO IVFEs, may reduce the risk of PNALD.4
High doses of IVFEs have been documented to lead to liver
complications such as steatosis and cholestasis. These adverse
effects result from the livers inability to metabolize the phos-
pholipids and FAs at the rate of delivery. Appropriate caloric
delivery may be dependent on the ability to provide the neces-
sary dose of IVFEs. Alternative IVFEs may potentially elimi-
nate this concern.4
Development of different oil-based IVFEs with reduced
phytosterols and LCTs could theoretically reduce the likelihood
of PNALD and its associated clinical morbidity and mortality.
Similarly, different oil-based IVFEs may allow for higher doses
of IVFE to be administered and for assurance of the ability to
provide full caloric requirements to PN-dependent patients.4
IVFE Generations
The progression of IVFE formulations have been classified into
varying generations based on an American Society for Parenteral
and Enteral Nutrition position paper published in 2012 (Figure
1).13 The generations are mainly based on the FA derivative of the
IVFE; however, the generations are further differentiated by their
inflammatory response that is produced upon extended infusion of
the products. As a general rule, due to the FA composition of the
products within each generation, the following can be assumed:
the first-generation products are proinflammatory; the second-gen-
eration and third-generation products are inflammatory neutral;
and the fourth-generation products are anti-inflammatory in com-
position.13 Each generation is described in detail below.
Currently, only first-generation products are available as
manufactured products in the United States. However, 2 prod-
uctsthird-generation Clinolipid (Baxter Healthcare
Corporation, Deerfield, IL) and fourth-generation Omegaven
(Fresenius Kabi, Bad Homburg, Germany)show the most
promise of future availability in the United States. Each is
612 Nutrition in Clinical Practice 31(5)

Table 1. Intravenous Fat Emulsion Properties.*

Total FA IVFE Osmolarity or Manufacturer Product

Product Concentration, % Composition, % Generation kcal/L pH Osmolality Containers
IntralipidA 10 100 SO First 1100 68.9 260 mOsm/L Excel infusion bags
IntralipidA 20 100 SO First 2000 68.9 260 mOsm/L Excel infusion bags
NutrilipidB 20 100 SO First 2000 68.9 390 mOsm/kg Infusion bag or bulk
Lipofundin MCT/ 10 50:50, Second 1022 7.4 345 mOsm/L Glass
LCT 10%16 SO(LCT):MCT
Lipofundin MCT/ 20 50:50, Second 1908 7.4 380 mOsm/L Glass
LCT 20%16 SO(LCT):MCT
Lipovenous MCTC 20 50:50, SO:MCT Second 1950 6.58.7 273 mOsm/kg
Structolipid 20%14 20 64:36, SO:MCT Second 1960 8 350 mOsm/kg Excel infusion bags
ClinOleic19 20 80:20, OO:SO Third 2000 68 270 mOsm/L Ethylene vinyl acetate
plastic bag
Clinolipid20 20 80:20, OO:SO Third 2000 69 260 mOsm/L Clarity polyolefin bag
Lipidem or 20 50:40:10, Fourth 1910 6.58.5 410 mOsm/kg Glass and soft plastic
Lipoplus24 MCT:SO:LCT
SMOFlipid15 20 30:30:25:15, Fourth 2000 8 380 mOsm/kg
Glass and Excel
SO:MCT:OO:FO infusion bags
Omegaven21 10 100 FO Fourth 1120 7.58.7 308376 mOsm/kg 100-mL vials

FA, fatty acid; FO, fish oil; IVFE, intravenous fat emulsion; LCT, long-chain triglyceride; MCT, medium-chain triglyceride (coconut or other tropical
nut); OO, olive oil; SO, soybean oil; , indicates information not available.
*Manufacturer information for products notated with capital letters can be found in the reference list.

discussed separately below. Tables 13 provide summaries of
the specifics of each formulation, dosing recommendations,
and specific excipients for some recognized examples within
each generational category of IVFEs.
FAs: Nomenclature
FA nomenclature needs to be first described to clearly under-
stand the differences among the generations of the IVFEs. FAs
are labeled with 3 classifications: X:Y:Z. The X classification is
the number of carbons within the FA chain. Short-chain FAs are
labeled with an X value from 24; medium-chain FAs are
labeled with an X value from 612; and long-chain FAs are
labeled with an X value 14. Y is the amount of double bonds
within the FA chain. Zero double bonds are labeled saturated
FAs (SFAs); 1 double bond is labeled monounsaturated FAs
(MUFAs); and 2 double bonds are labeled polyunsaturated FAs
(PUFAs). Z is the numeric distance that the first double bond
occurs within the FA chain from the first carbon of that chain.
The Z classification is where the families of unsaturated FAs are
originated: omega 3 vs omega 6 vs omega 9.13 See Table 4 for
FAs commonly found in the described IVFE formulations below.
First Generation: 100% SO
Current first-generation US-manufactured products are Intralipid
(Fresenius Kabi/Baxter, Uppsala, Sweden) and Nutrilipid
(B. Braun Medical Inc, Bethlehem, PA), which contain 100%
SO. SO is composed of all LCTs partitioned between saturated
and unsaturated FAs in about 15% and 85% concentrations,
respectively.13 About 60% of the content of SO is EFAs in the
form of linoleic acid and alpha-linolenic acid. Linoleic acid is an
omega-6 FA, and alpha-linolenic acid is an omega-3 FAwith
each taking up about 50% and 10% of the soybean formulation,
respectively. Oleic acid is an omega-9 FA and composes about
15% of the formulation. The remaining 15% of the formulation
is the SFA component in the form of palmitic and stearic
acids.12,13 As discussed briefly above, the large amount of
omega-6 FA, the lack of EPA and DHA, and the fact that all
these FAs are LCTs result in a less-than-ideal product in the
clinical sense based on its proinflammatory effects; thus, alter-
native oilbased products were introduced to the market.
Second Generation: 50:50, SO:MCT
Second-generation IVFE products contain a 50:50 mixture of
SO and MCTs.13 The exception to this rule is Structolipid
(Fresenius Kabi AB, Uppsala, Sweden), which has a 64:36
mixture of SO:MCT as described below.14 The SO in the sec-
ond-generation products is sometimes labeled as LCT, depend-
ing on the product and the country in which it is manufactured.
The MCT component of these products is derived from coco-
nut oil and other tropical nut oils and is composed of SFAs:
caprylic acid 71% and capric acids 22%.13 MCTs provide the
advantage of a more rapid oxidation, which can lead to a more
immediate energy source than SO. MCTs also hydrolyze and
eliminate from the central circulation more quickly than LCTs,
which makes them a preferential calorie source.15 Additionally,
LCTs have a higher affinity for albumin than do MCTs; how-
ever, both are almost 100% protein bound.15

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 Table 2. Manufacturer Dosing Recommendations.*

Neonate Infant and Preschool School-Age Children Adults

Recommended Ideal Infusion

Product Dose, g/kg/d Rate Dose, g/kg/d Rate Dose, g/kg/d Rate Dose, g/kg/d Infusion Rate Time
Intralipid 10% and 20%A Starting 0.5 Max 3 0.1 g/kg/h Max 2.5 Titrate to 1 mL/min
NutrilipidB Starting 12, Max 0.75 mL/ Starting 12, Max 0.75 1, max 2.5 Max 0.5 mL/ 11.5, max 2.5 Max 0.5 mL/kg/h 1224 h
max 3 kg/h max 3 mL/kg/h kg/h
Lipofundin 10% and 20%16 24 0.050.2 g/ 13 0.050.2 g/ 12 0.050.2 g/ 12 0.050.2 g/kg/h 15 h
kg/h kg/h kg/h
Lipovenoes 10% and 20%C,17 12 0.125 g/kg/h
Lipovenous MCT17 2
Structolipid 20%14 NA NA NA NA NA NA 11.5 0.15 g/kg/h max 1024 h
ClinOleic 20%19 0.53|| 0.25 g/kg/h Max 4 0.25 g/kg/h Max 4 0.25 g/kg/h Max 2.5 0.25 g/kg/h 1224 h
Clinolipid20 NA NA NA NA NA NA 12.5 Titrate to required rate 1224 h
Lipidem or Lipoplus24 NA NA NA NA NA NA 12 0.15 g/kg/h max
SMOFlipid15 0.53 Max 0.125 g/ 0.53 Max 0.125 Max 3 Max 0.15 g/ 12 0.1250.15 g/kg/h
kg/h per 24 h g/kg/h kg/h
Omegaven21 0.10.2 0.05 g/kg/h#

MCT, medium-chain triglyceride; NA, product not indicated for pediatric use or safety and efficacy has not been established in pediatric patients; , information not available to author.
*Dosing guidelines are based on the product package insert from the country represented and do not take into account specific clinical indications or guidelines. Practitioners complete assessment and
judgement should be used for individual patient dosing. Manufacturer information for products notated with capital letters can be found in the reference list.

For pediatric patients generically.

In older pediatric patients.

Titration is required.
||

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Small for gestational age or premature infants with impaired capacity to metabolize fat. If no monitoring can occur, max dose is 2 g/kg/d.

Max with titration.
#
The maximum infusion rate should be strictly adhered to avoid a severe increase in the serum triglyceride concentration.

613
614 Nutrition in Clinical Practice 31(5)

Table 3. Product Excipient Formulation Components per Liter.*

Sodium Water Sodium

Egg Glycerol, Oleate, Ascorbyl Sodium Vitamin for Content,
Product Lecithin, g g g Palmitate Hydroxide E, mg Nitrogen Injection mmol/L
Intralipid 10% and 20%A 12 22.5
Nutrilipid 20%B 12 25 0.3
Lipofundin MCT/LCT 10%16 8 25 0.3 85 20
Lipofundin MCT/LCT 20%16 12 25 0.3
Structolipid 20%14
ClinOleic19 12 22.5 0.3
Clinolipid20 12 22.5 0.3
Lipidem or Lipoplus24 2.6
SMOFlipid15 5
Omegaven21 12 25 150296

*Where no measured amount was given, an simply indicates that the component is within the formulation of the product. Manufacturer information for
products notated with capital letters can be found in the reference list.

From the olive oil.

Table 4. Common Fatty Acids Contained Within the Oils Used in Common Intravenous Fat Emulsion Formulations.

Fatty Acid Chain Length Saturation State13 Source2 Omega Designation

Caprylic Medium SFA CO
Capric Medium SFA CO
Palmitic Long SFA FO, OO, SO
Stearic Long SFA SO
Oleic Long MUFA OO, SO Omega-9
Linoleic Long PUFA SO Omega-6
Alpha-linolenic Long PUFA SO Omega-3
Eicosapentaenoic Long PUFA FO Omega-3
Docosahexaenoic Long PUFA FO Omega-3

CO, coconut oil; FO, fish oil; MUFA, monounsaturated fatty acid; OO, olive oil; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid; SO,
soybean oil.

Lipofundin (B. Braun Melsungen AG, Melsungen,
Germany) is a second-generation product composed of 50:50
SO(LCT):MCT in 10% and 20% concentrations. The omega-
6:omega-3 ratio of this product is the same as the first-genera-
tion products at 7:1. The 10% emulsion can be used for
peripheral or central administration. Per the manufacturer, this
product should be administered in conjunction with a carbohy-
drate product that comprises at least 40% of the total caloric
intake.16
There is limited product information available for
Lipovenoes MCTs (Fresenius Kabi Austria GmbH, Graz,
Austria). However, this second-generation product consists of
a 50:50 ratio of the SO:MCT components.17 There are also
SO-only first-generation products manufactured under the
name Lipovenoes: Lipovenoes 20% LCT and Lipovenoes 10%
PLR, which should be noted to avoid potential inadvertent sub-
stitution error. The PLR of the Lipovenoes 10% emulsion
stands for phospholipid reduced, which means that the 10%
emulsion has a similar phospholipid:triglyceride ratio as the
20% emulsions.18
Structolipid 20% is the aforementioned second-generation
product that consists of a 64:36 ratio of SO:MCT. Structolipid
is unique in that the emulsion is composed of structured tri-
glyceridesa mixture of LCTs and MCTs on the same glyc-
erol molecule. The manufacturer, Fresenius Kabi AB, describes
this difference as being beneficial due to faster elimination of
this product as compared with other LCT-only products or
physical mixtures of LCT/MCT products, such as those
described above.14
Third Generation: 80:20, OO:SO
Third-generation alternative oil IVFE products are composed
of an 80:20 split between OO:SO, respectively.13
The only third-generation product that is available currently
in the European and Canadian markets is ClinOleic 20%
(Baxter Healthcare LTD, Norfolk, United Kingdom). The fat
content of ClinOleic according to the product package insert is
SFAs (15%), MUFAs (65%), and Essential PUFA (20%),
which is important, in part, because MUFAs are less prone to

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Biesboer and Stoehr 615
peroxidation than PUFAs.19 What is also interesting about this
product is that this composition actually increases the total
concentration of omega-6 FAs as compared with omega-3 FAs
from 7:19:1 but still maintains its inflammatory neutral stand-
ing. Although ClinOleic does not have vitamin E listed as a
formulation component, the product does contain some vita-
min E through the alpha-tocopherol within the OO itself. When
ClinOleic is infused alone, it can be for either central or periph-
eral administraion.19
Clinolipid is a product that had an initial US approval in
1975.20 It has been manufactured and sold in the European mar-
kets for the past 15 years and in the Canadian markets for the
past 2 years. In 2013 the Food and Drug Administration (FDA)
approved the 1000-mL Clinolipid product for production and
sale in the United States. However, per the manufacturer (Baxter
Healthcare Corporation, Deerfield, IL), there is no set date to
launch product manufacturing or marketing in the United
States. Currently, without Baxter actively manufacturing the
Clinolipid product in the United States, there is no avenue to
obtain any third-generation product for US patients. FA compo-
nents within the Clinolipid formulation are as follows, listed
from highest to lowest concentration: linoleic acid, oleic acid,
palmitic acid, alpha-linolenic acid, and stearic acid.20
Fourth Generation: FO Other Oils
The fourth-generation IVFEs consist of any product that con-
tains any amount of FO.13 FO IVFEs are the only products
available that provide a large content of DHA and EPA. FO
provides the IVFE product with a pure omega-3 FA compo-
nent; therefore, it has the ability to tip the omega-6:omega-3
FA ratio away from omega-6 and give an overall higher omega-
3-rich product. This shift is what is speculated to provide an
anti-inflammatory effect.13 As more FO-based products come
into the pharmaceutical market, this generation may require a
further split to differentiate products that are 100% composed
of FO vs those that contain a smaller percentage of FO
components.
Omegaven is the only available product that exists in the
Canadian, European, and Asian markets as 100% FO.21 The
ratio of omega-6:omega-3 for this product is 1:8, which is a
huge shift from any other IVFE product available.13 This is
one alternative oil product that the FDA currently allows phy-
sicians in the United States to obtain as expanded access
through the manufacturer, Fresenius Kabi, in Germany. Per
the FDA website, physicians must submit an investigational
drug application (IND), FDA form 1571. Once submitted, it
usually takes a week or less for the FDA to review and
respond. Upon FDA acceptance of the IND, the Omegaven
product can then be legally imported, shipped to the facility,
and administered to the patient. There are 2 types of INDs
that could be submitted to receive the product per the web-
site: a single-patient IND or an emergency IND. The single-
patient IND is specific to Omegaven and can be accessed via
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the following link: http://www.fda.gov/drugs/developmen-
tapprovalprocess/howdrugsaredevelopedandapproved/
approvalapplications/investigationalnewdrugindapplication/
ucm368740.htm. The emergency IND can be requested if
treatment is required before a written request can be com-
pleted through a single-patient IND.
The Omegaven product package insert gives requirements
for simultaneous administration of other non-FO IVFE prod-
ucts concurrently and recommends Omegaven to compose
only 10%20% of the total fat needs of the patient.21 However,
studies have shown patient success with single-therapy FO
IVFE.22,23
Another alternative oil IVFE that deviates slightly from the
traditional second-generation products is the European product
Lipidem (B. Braun Melsungen AG). It is also called Lipoplus
(B. Braun Melsungen AG) depending on the country for which
it is manufactured. Lipidem or Lipoplus contains 3 of the 4
lipid options available for IVFE products in a combination of
50:40:10 MCT:SO:FO, respectively.24 The FO addition to the
MCTs and SO shifts the omega-6:omega-3 ratio to the right,
2.7:1.24 The FA composition from highest concentration to
lowest is as follows: linoleic acid, alpha-linolenic acid, EPA,
and DHA.
SMOFlipid (Fresenius Kabi Limited, Cheshire, United
Kingdom) is an FA combination product that contains all the
major FA components discussed thus far: SO:MCT:OO:FO in
concentrations of 30:30:25:15, respectively.15 The SO compo-
nent of the formulation provides the required daily values of
EFAs. The ratio of omega-6:omega-3 for this product is 2.5:1,
which is an improvement from other omega-6-dominant IVFE
products available.15 Per the package insert, SMOFlipid has
the same safety and efficacy profile as the first-generation
comparator Intralipid. Additionally, pharmacokinetic profiles
suggest that SMOFlipid has an increased clearance rate when
compared with first-generation products.15
Multichamber Parenteral Nutrition
Multichamber products are premade products that commonly
contain all macronutrients necessary for PN, including IVFEs,
dextrose, and amino acids, as well as the potential for micronu-
trients as electrolytes. The only commercial products available
in the United States as multichamber bags that contain lipids in
addition to amino acids, dextrose, and electrolytes are Kabiven
and Perikabiven (both from Fresenius Kabi, Uppsala, Sweden).
Kabiven is manufactured for central administration only, and
Perikabiven is manufactured for central or peripheral adminis-
tration. The lipid component within this product is first-gener-
ation Intralipid 20% with a total product SO concentration of
3.9%.25,26 The varying generations of IVFEs have also been
included within multichamber PN formulations; however,
none of these formulations are currently available in the United
States. A brief summary of some of these products can be
found in Table 5.
616 Nutrition in Clinical Practice 31(5)

Table 5. Multichamber Parenteral Nutrition Products That Contain Lipid Emulsions.*

IVFE Amino US
Product Generation Composition, % Glucose Acids Electrolytes Availability
Kabiven25 First 100, SO Yes
Perikabiven26 First 100, SO Yes
Nutriflex Lipid productsD-F, Second 50:50, SO:MCT +/ No
Numeta 3CB productsG-I, Third 80:20, OO:SO No
Oliclinomel productsJ-L, Third 80:20, OO:SO +/ No
Trimomel with nitrogen productsM,N,|| Third 80:20, OO:SO +/ No
Nutriflex Omega PlusO Fourth 50:40:10, MCT:SO:FO No
Nutriflex Omega SpecialP Fourth 50:40:10, MCT:SO:FO No
SMOFKabiven Central productsQ,R Fourth 30:30:25:15, SO:MCT:OO:FO +/ No
SMOFKabiven PeripheralS Fourth 30:30:25:15, SO:MCT:OO:FO No

FO, fish oil; IVFE, intravenous fat emulsion; MCT, medium-chain triglyceride; OO, olive oil; SO, soybean oil-based; +/, indicates that the product may
or may not contain the component depending on specific product; , indicates that the product contains this component.
*Manufacturer information for products notated with capital letters can be found in the reference list.

Nutriflex is manufactured in a wide variety of macronutrient and micronutrient concentrations.

Numeta is manufactured in multiple concentrations (13%E, 16%E, and 19%E) for designated pediatric age ranges. Additionally, concentrations are
manufactured in different container sizes as well as in a 2-chamber bag (does not contain lipids) and a 3-chamber bag (does contain lipids).

Oliclinomel is manufactured in a range of concentrations, with or without electrolytes: N4-550E, N5-800E, N6-900E, N7-1000E, and N8-800.
||
Triomel products are manufactured in a variety of caloric and nitrogen concentrations.

Packaging, Storage, and Stability
Most IVFE products are manufactured in primary packaging of
either glass or plastic containers with an additional oxygen-
barrier outer packaging. See Table 1 for product specifics. The
outer packaging usually contains an oxygen indicator that
reacts with any free oxygen to detect any permeation into the
outer packaging. Some products also contain an oxygen-absor-
bent material between the primary packaging and the outer
packaging to increase product integrity. If the oxygen indicator
has been activated prior to opening the outer packaging, which
is typically indicated by a color change, the product must be
discarded. Once removed from the outer packaging, all IVFE
products are to be used immediately and should have a milky
white homogenous appearance. Products should not be frozen.
Unopened products may be stored, protected from light, at
controlled room temperature per United States Pharmacopeia,
not to exceed 25C. They are all single-use products, and any
unused portion must be discarded. Prior to use, the products
should be warmed, unaided, to room temperature. Any manip-
ulation of the contents within in the primary packaging should
be done aseptically. All IVFE compatibility data are product
and additive specific. Evidence is mounting to show that the
newer IVFE generations have a longer stability time frame
than that of first-generation products.27 Studies suggest that the
shorter the carbon chain of the oil, exampled by MCTs vs SO,
the longer the stability of the product. Therefore, products that
contain MCTs only or a combination of MCTs and SO, rather
than only SO, are stable for longer periods.28 This could be due
to the shorter carbon chain assisting to create a more stable
lipid globule within the emulsion. Another speculation is that
the increased stability could be attributed, in part, to the
addition of another emulsifying agent, sodium oleate, which
most of the newer IVFE products contain.28 See Table 3 for the
sodium oleate component within IVFE products. It is not rec-
ommended to extemporaneously mix different commercially
available products together as a single compound due to
decreased stability of the products.29
Clinical Implications
SO-based IVFEs carry specific complications limiting their
use in clinical practice, as discussed within the introduction.
The clinical implications of the newer-generation IVFEs
regarding these specific issues are discussed in turn.
Inflammatory Effects
Despite the data supporting the anti-inflammatory properties
of the newer-generation IVFEs, there are limited data support-
ing the clinical impact of these products. Similarly, despite
extensive data demonstrating the inflammatory effects of first-
generation IVFEs, to date, there are limited data evaluating the
potential negative clinical impact associated with the SO
IVFEs. However, the current Society of Critical Care Medicine
and ASPEN recommendations suggest holding or limiting SO
IVFE during the first week of PN therapy.30
In 2012, a systemic review and meta-analysis evaluated the
literature regarding the clinical benefit of fourth-generation
IVFEs on clinical outcomes in critically ill patients.31 Five stud-
ies were included within this publication. This analysis was
unable to determine a statistical difference in any of the out-
comes evaluated, including mortality, intensive care unit length
of stay (LOS), and ventilator days. The ultimate conclusion of

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Biesboer and Stoehr 617
this analysis was that there are insufficient data to support FO
IVFE over other IVFEs.
Since this meta-analysis, Edmunds etal have provided the
greatest insight into clinical comparisons in critically ill
patients among the varying generations.32 This prospective
observational study included 451 critically ill patients who
received lipid-free PN or PN based on SO, MCTs, OO, or FO.
Clinical outcomes were evaluated, including duration of
mechanical ventilation, intensive care unit LOS, hospital LOS,
and mortality. In comparison with SO, patients receiving
OO-based and FO-based PN had shorter durations of mechani-
cal ventilation and shorter intensive care unit LOS. However,
data were insufficient to determine a difference in overall hos-
pital LOS or mortality.
Even more recently, Manzanares and colleagues completed
an updated meta-analysis comparing the clinical outcomes
associated with FO IVFE vs alternative agents.33 This analysis
contained a total of 10 randomized controlled trials. Again, no
statistically significant effect on mortality was detectable.
However, when 5 of the 10 trials were specifically evaluated in
a subgroup analysis of the effect of FO IVFE on infection rate,
there was a statistically significant reduction in infections
noted in patients who received FO-based PN in comparison
with other IVFE formulations.
Based on the current literature, there are limited data to
fully support the transition away from early-generation IVFEs
(eg, SO-based IVFEs) to FO-based IVFEs, based on inflamma-
tory concerns. Indeed, the majority of the literature supports a
trend toward clinical benefit with the use of FO-based IVFEs
in theory, but there is limited statistical support. Edmunds and
colleagues32 provided the greatest support in favor of transi-
tioning away from SO-based IVFEs, but additional and larger
studies are necessary to fully support this transition.
Allergic Reactions
The newer generations of IVFEs provide a promise for soy-
allergic patients in need of IVFE therapy. Case reports have
been published regarding the use of FO IVFEs to treat EFA
deficiency in patients receiving PN who have soy allergies,
with promising results.34 It is reasonable to consider alternative
IVFE use in soy-allergic patients requiring PN.
PN-Associated Liver Disease
The majority of the data evaluating the use of new-generation
IVFEs for the prevention and/or treatment of PNALD are in neo-
nates and pediatrics. The data are extremely limited regarding the
clinical implication of new-generation IVFEs in adult patients.
A recent systemic review and meta-analysis evaluated the
data supporting the use of FO IVFE for the prevention and treat-
ment of PN-associated cholestasis, a specific form of PNALD,
in neonates. The review included 7 studies3 evaluating the use
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of FO IVFE for treatment and 4 evaluating the use of FO IVFE
for prevention. The analysis concluded that FO IVFE was useful
in the treatment of PN-associated cholestasis but was not benefi-
cial for preventing PN-associated cholestasis.35
Similarly, 2 studies evaluated the long-term effects of FO
IVFEs.36,37 Both included patients with PNALD prior to initiating
FO IVFE therapy. Although the outcomes slightly differed in the
studies, both showed positive outcomes with the use of FO IVFE
for treatment of PNALD, including improved survival rates and
limited progression of end-stage liver disease symptoms.
The data consistently provide positive outcomes regarding
the use of FO IVFE for the treatment of PNALD in neonatal
and pediatric patients. However, there are limited data evaluat-
ing the other non-SO IVFEs, and further research is necessary
to evaluate the usefulness of these agents in the treatment of
PNALD. Similarly, data are needed evaluating the use of
newer-generation IVFEs for the prevention of PNALD.
Conclusion
The 4 generations of IVFEs provide clinicians with the ability
to select IVFE products based on very specific chemical prop-
erties, although there is limited availability of non-SO IVFEs
in the United States. Data supporting the use of non-SO IVFEs
is growing. However, there are limited data regarding the new
potential adverse effects of these products, and close monitor-
ing and reporting of any complications are necessary.
Statement of Authorship
A. N. Biesboer and N. A. Stoehr contributed to the conception and
design of the review article, drafted the manuscript, critically
revised the manuscript, agree to be fully accountable for ensuring
the integrity and accuracy of the work, and read and approved the
final manuscript.
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