Review

Lipid emulsions in parenteral

nutrition: current applications and
future developments
1. Introduction
Tianyang Ren, Lin Cong, Yueqi Wang, Yilin Tang, Bin Tian, Xia Lin,
2. Biological properties of various
Yu Zhang & Xing Tang†
fatty acids (FAs) in parenteral †
Shenyang Pharmaceutical University, Department of Pharmaceutics Science, Shenyang, China
LEs
3. Developments of lipids used in Introduction: A parenteral lipid emulsion (LE), used as a key source of energy,
parenteral LEs essential fatty acids (FAs), and fat-soluble vitamins, is an integral part of a
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4. Applications of alternative parenteral nutrition (PN) regimen. The conventional LEs, such as soybean
parenteral LEs in different oil (SO)-based emulsions, have caused concerns about the potential adverse
patients effects involving oxidative stress, inflammation, and immune response
5. Conclusions probably because of undesirable FA composition.
6. Expert opinion
Areas covered: Recently, alternative LEs, optimizing the FA composition with
partial substitution of SO with medium-chain triglyceride (MCT), olive oil
(OO), and fish oil (FO), have been developed and applied in clinical practice.
This review summarizes the characteristics and beneficial clinical effects of
alternative parenteral LEs in critically ill, pediatric, and long-term PN patients.
Expert opinion: More clinical data from sufficiently high-powered studies are
required to characterize the integral biological properties of alternative LEs
For personal use only.

for further selection to fit individual needs and disease characteristics. Simul-
taneously, potential lipid sources with desirable FA compositions and biolo-
gical properties should be selected to develop new therapeutic LEs. As
supplements to current parenteral lipids, the new LEs with different thera-
peutic effects are expected to fit specified subpopulations of patients with
different diseases. Great efforts should be devoted to the development of
parenteral LEs.

Keywords: fatty acids, lipid emulsions, lipid sources, parenteral nutrition

Expert Opin. Drug Deliv. [Early Online]

1. Introduction

Parenteral nutrition (PN) is an efficient and often life-saving therapy when oral or
enteral nutrition is impossible, insufficient, or contraindicated. Initially, PN solu-
tions were primarily composed of amino acids and glucose to meet the demand
for energy [1]. However, intravenous administration of these solutions led to a series
of complications, including hyperglycemia and essential fatty acid (EFA) defi-
ciency [1,2]. Then, in 1961, the first well-tolerated parenteral lipid emulsion (LE),
a soybean oil (SO)-based LE (Intralipid), was introduced for PN [2]. It not only pro-
vided sufficient energy, EFAs, and fat-soluble vitamins, but also reduced the side
effects of a high glucose intake [3]. Since then, parenteral LEs have been widely
used and have become an important part of PN regimens. However, studies during
the 1970s and 1980s found that conventional SO-based emulsions were associated
with potential adverse effects involving oxidative stress, inflammation, and immune
response [4-8]. In order to address these concerns, over the past several decades, great
efforts have been devoted to the development of new parenteral LEs and now alter-
native LEs with altered FA composition have been developed and applied in
clinical practice.

10.1517/17425247.2013.824874 © 2013 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 1

All rights reserved: reproduction in whole or in part not permitted
 T. Ren et al.
Article highlights.
. A parenteral LE is an integral part of a PN regimen, but
the conventional LEs, such as SO-based emulsions, have
caused concerns about their potential harmful effects.
. The biological properties of FAs in different classes have
great effects on the applications and developments of
parenteral LEs.
. The evolution of current LEs can be considered as a
process of optimization of the FA composition of the
lipids used in parenteral LEs by partial substitution of SO
with MCT, OO, and FO.
. On the basis of current clinical data, the alternative LEs
have demonstrated their safety and efficacy, and even
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their superiority to the conventional LEs in critically ill,
pediatric, and long-term PN patients.
. The options for parenteral therapy should consider the
integral properties of LEs to meet individual patient
needs and disease characteristics.
. Potential lipid sources with desirable FA compositions
should select and develop new therapeutic LEs to fit
specified subpopulations of patients with
different diseases.
This box summarizes the key points contained in this article.
This article aims to review the characteristics and clinical
For personal use only.
applications of alternative parenteral LEs and provide insights
into the development of parenteral lipids.
2. Biological properties of various fatty acids
(FAs) in parenteral LEs
Parenteral LEs contain numerous biologically active compo-
nents, but the most important ones remain a variety of FAs
from different lipid sources. Exogenous FAs are commonly
used by cells as an energy source, cell membrane components
and, more importantly, biologically active substrates. FAs can
be classified according to three structural characteristics affect-
ing their physical and physiological properties: i) chain length:
medium-chain FAs (MCFAs, C8--C12) and long-chain fatty
acids (LCFAs, ‡ C14); ii) degree of saturation: saturated fatty
acids (SFAs), monounsaturated fatty acids (MUFAs), and
polyunsaturated fatty acids (PUFAs); iii) position (w) of the
first double bond relative to the noncarboxylic end of the
carbon chain: w-3 FAs, w-6 FAs, and w-9 FAs. The active
FAs used in PN commonly contain MCFAs, w-9MUFAs,
w-6PUFAs, and w-3PUFAs, and their typical lipid sources
are summarized in Table 1. These FAs are metabolized by
different pathways (Figure 1) to exert unique biological
properties, which have marked effects on the applications
and developments of parenteral LEs.
2.1 MCFAs
MCFAs are not EFAs, but they possess unique chemical and
structural characteristics as desirable substrates for energy.
When introduced into the blood, medium-chain triglycerides
2 Expert Opin. Drug Deliv. (2013) 10(11)
(MCTs) are more quickly hydrolyzed and cleared from the
circulation than long-chain triglycerides (LCTs) [9,10]. In tis-
sues, they enter the mitochondria rapidly to be oxidized with-
out the carnitine transport, which is required for LCFAs [11].
The oxidation of MCFAs eventually leads to an increase in
ketone bodies (acetoacetate and b-hydroxybutyrate), which
are efficient sources for energy [11]. Moreover, MCFAs are
preferentially and completely metabolized with no accumula-
tion in the liver and no storage in adipose tissues [12]. It has
been reported that MCFAs exhibit a positive effect on
improving nitrogen balance, probably because of a protein-
sparing effect caused by their rapid and complete oxidation
to produce energy [13,14]. Other studies have also described
the protein-sparing effect on the elevated levels of insulin
caused by the MCFAs [15,16] because insulin can reduce nitro-
gen loss in injured patients [17]. More importantly, MCFAs
neither promote the synthesis of active eicosanoids nor serve
as precursors of oxygen free-radical production, which are
harmful to human body and even provide a positive effect
on the reticuloendothelial system (RES) [13].
2.2 v-9MUFAs----oleic acid (OA)
OA is also not an EFA, but it has metabolic advantages
regarding lipid peroxidation and the immune response. Lipid
peroxidation is thought to be one important mechanism
involved in the pathogenesis of inflammation, cancer, and
atherosclerosis [18-20]. PUFAs are preferentially attacked by
free radicals and oxidized to lipid peroxides because of
their multiple double bonds [21]. In contrast, MUFAs are
less prone to peroxidation because they contain only one dou-
ble bond [22]. Thus, OA acts in a safe manner in oxidative
stress and even helps to reduce the harm caused by peroxides
and free radicals. Moreover, OA has a more neutral effect on
immune and inflammatory responses. On one hand, OA does
not produce active eicosanoids and its derivatives do not pro-
mote inflammation [2] while, on the other hand, it might
actually offset the proinflammatory effects [23,24] and induce
few or no immunomodulatory effects [22]. Some studies
in vitro have shown that it has no impact on lymphocyte pro-
liferation or NK cell activity [25,26] and a limited toxic effect
on human lymphocytes [27]. The ‘immuno-neutrality’ of OA
is preferred in parenteral LEs.
2.3 v-6PUFAs/v-3PUFAs
It is well known that both w-6PUFAs and w-3PUFAs are very
important FA families for ensuring good health as not only
are they the basis of cell membrane structure and function
but they are also the precursors of a series of important biolog-
ically active substrates. The w-6 and w-3 FAs are metabolized
by two independent pathways, although these share the same
series of enzymes [28]. This leads to a competition between the
two families for metabolism with an excess of one causing a
significant decrease in the conversion of the other [28]. LA
and ALA, both essential FAs are, respectively, the origin of
the two metabolism pathways (Figure 1). AA and EPA, the
 Lipid emulsions in parenteral nutrition: current applications and future developments
Table 1. Typical lipid sources of fatty acids in
parenteral lipid emulsions.
Fatty acids Lipid sources
MCFAs Coconut oil; palm kernel oils
v-9MUFAs
OA Olive oil
v-6PUFAs
LA Soybean oil, safflower oil, sea buckthorn
seed oil, corn oil, sunflower oil
GLA Borage oil, evening primrose oil, black
currant seed oil
v-3PUFAs
ALA Flaxseed oil, perilla seed oil, chia oil, camelina oil
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EPA, DHA Fish oil
DPA Seal oil
ALA: a-linolenic acid; DHA: Docosahexaenoic acid; DPA: Docosapentaenoic
acid; EPA: Eicosapentaenoic acid; GLA: g-Linolenic acid; LA: Linoleic acid;
MCFA: Medium-chain fatty acid; MUFA: Monounsaturated fatty acid;
OA: Oleic acid; PUFA: Polyunsaturated fatty acid.
key intermediates, are the precursors of eicosanoids. AA-
derived eicosanoids, such as the prostaglandin-2-, thrombox-
ane-2-, and leukotriene-4-series, have pro-inflammatory,
atherogenic, and prothrombotic effects, while EPA-derived
For personal use only.
eicosanoids, such as the prostaglandin-3-, leukotriene-5-,
and thromboxane-3-series, antagonize the pro-inflammatory
effects [29]. In addition, the EPA-derived E-series of resolvins
and DHA-derived D-series of resolvins, protectins, and mare-
sins exhibit anti-inflammatory- and inflammatory-resolving
activities [29,30]. The opposing metabolic effects of w-6PUFAs
and w-3PUFAs demonstrate the significance of the balance
between w-6 and w-3 in the human body. It has been shown
that the w-6/w-3 ratio is positively correlated with inflamma-
tion and coagulation [23], cardiovascular diseases [31], and can-
cer [32]. A very high w-6/w-3 ratio is considered detrimental to
human health, while a value as close to 1 as possible is consid-
ered protective against degenerative pathologies [31]. The opti-
mal ratio varies from 1/1 to 4/1 depending on the prevalent
chronic disease under consideration [32]. It is also recom-
mended that the optimal range for anti-inflammatory effects
is 1:1 -- 2:1 [33-36], the optimal range for immunomodulation
is 1:1 -- 4:1 [37,38], and the ratio of 2:1 is proposed to be
immunologically neutral [39,40]. The recommended ratio
changes in different countries [41], and further studies are
required.
2.4 v-6PUFAs----linoleic acid (LA)
LA is a predominant extracorporeal source of w-6PUFAs
in the human body. An alteration in the supply of LA
will lead to corresponding changes in the in vivo quantity of
w-6PUFAs and w-3PUFAs and their bioactive derivatives,
and a further derangement in physiologic function. It has
been reported that an excessive intake of LA can lead to alter-
ation of membrane compositions and structures, increase in
Expert Opin. Drug Deliv. (2013) 10(11)
the lipid peroxidation and reduction in the synthesis of pro-
tective EFA derivatives, especially w-3PUFAs derivatives,
because of their competitive metabolisms [42,43]. LA is always
associated with a pro-inflammatory state, as proved by an
increased production of inflammatory mediators, such as
IL-1, TNF-a, and IL-6 [44]. Furthermore, LA also has a
dose-dependent immunosuppressive effect [45]. In vitro and
in vivo evidence indicates that LA leads to impairment of neu-
trophil chemotaxis and phagocytosis, lymphocyte prolifera-
tion and reactivity, natural killer and lymphokine-activated
killer cell activities as well as monocyte chemotaxis and prolif-
eration [7,8,27,46]. Moreover, a prolonged graft survival has
been found in animal transplant models when LA is given
in excess [47]. In addition, hepatobiliary dysfunction is
associated with LA supply [21,48,49].
2.5 v-6PUFAs----g-linolenic acid (GLA)
GLA does not widely exist, but is a significant w-6PUFA in
the human body. The w-6PUFAs and their derivatives are
always considered pro-inflammatory, but GLA has been
shown to have a potential anti-inflammatory effect [50]. Fol-
lowing GLA uptake, it is first rapidly converted to dihomo-
g-linolenic acid (DGLA), and then partly metabolized to the
prostaglandin-1 series which are anti-inflammatory [51]. On
the other hand, because of the limited activity of desaturase,
only a small fraction of DGLA is converted to AA, and the
accumulation of DGLA relative to AA is capable of attenuat-
ing the biosynthesis of AA metabolites, and producing an
anti-inflammatory effect [51]. Moreover, it has been reported
that different biological effects of prostaglandin-1- series
are ~ 20 times stronger than prostaglandin-2-series [51].
Regarding their benefits, dietary GLA has been demonstrated
to be an effective treatment of certain chronic diseases, for
example, rheumatoid arthritis [52] and atherosclerosis (in
mice) [53]. More recently, an enteral diet of GLA, combined
with EPA and antioxidants, has shown significant beneficial
effects on pulmonary inflammation in patients with acute
lung injury and severe sepsis [54-56].
2.6 v-3PUFAs----a-linolenic acid (ALA)
ALA is an important plant source of w-3PUFAs in the human
body. Its important role may primarily lie in it being a sub-
strate for the synthesis of longer chain, more unsaturated
w-3PUFAs, especially EPA and DHA, which have positive
roles in maintaining optimal health [57]. Increased attention
has been paid to the conversion of ALA into longer chain
w-3PUFAs, but many studies have shown that the conversion
of ALA to its derivatives, especially DHA, is very limited in
humans, although the conversion is greater in women than
men and in infants than in adults [58-60]. The capacity of
ALA conversion remains controversial, and some evidence
indicates that it is based on a tissue-selective need for longer
w-3PUFAs [59,61]. A series of studies of ALA conversion in
cell cultures, animals, and humans has been reviewed by
Barceló-Coblijn and Murphy [62], who suggested that a
3
 T. Ren et al.

ω-6 pathway ω-3 pathway ω-9 pathway

Linoleic acid (LA) α-Linoleic acid (ALA) Oleic acid (OA)

18:2 (ω-6) 18:3 (ω-3) 18:1 (ω-9)
Elongase Elongase
Δ6 desaturase Δ6 desaturase

Eicosadienoic acid γ-Linoleic acid (GLA) Stearidonic acid Eicosatrienoic acid Octadecadienoic acid
20:2 (ω-6) 18:3 (ω-6) 18:4 (ω-3) 20:3 (ω-3) 18:2 (ω-9)

Δ6 desaturase Elongase Δ6 desaturase Elongase

Prostaglandin-1-series COX Dihomo-γ-Linolenic acid Eicosatetraenoic acid Eicosadienoic acid

(anti inflammatory) 20:3 (ω-6) 20:4 (ω-3) 20:2 (ω-9)
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Δ5 desaturase Thromboxane-3-series Δ5 desaturase

COX
Thromboxane-2-series COX COX Prostaglandin-3-series
Prostaglandin-2-series COX Arachidonic acid (AA) Eicosapentaenoic acid (EPA) LOX Leukotriene-5-series Eicosatrienoic acid
LOX 20:4 (ω-6) 20:5 (ω-3) (anti inflammatory) 20:3 (ω-9)
Leukotriene-4-series
(pro inflammatory)
Elongase E-series resolvins
(anti inflammatory)
Adrenic acid Docosapentaenoic acid
22:4 (ω-6) 22:5 (ω-3)

Elongase

Peroxisomal retroconversion
Tetracosatetraenoic acid Tetracosapentaenoic acid
24:4 (ω-6)
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24:5 (ω-3)

Δ4 desaturase Δ6 desaturase Δ4 desaturase

Tetracosapentaenoic acid Tetracosahexaenoic acid

24:5 (ω-6) 24:6 (ω-3)

β-Oxidation

Docosapentaenoic acid Docosahexaenoic acid (DHA)

22:5 (ω-6) 22:6 (ω-3)
D-series resolvins,
protectins and maresins
(anti inflammatory)

Figure 1. The metabolic pathways of v-9MUFA, v-6PUFA, and v-3PUFA.

Modified from [29] with permission from Elsevier.
COX: Cyclooxygenase; LOX: Lipoxygenase; MUFA: Monounsaturated fatty acid; PUFA: Polyunsaturated fatty acid.

sufficient ALA supply can provide the human body with
ample w-3PUFAs, such as DHA. In addition to the ALA
conversion, ALA is also used in b-oxidation and extensive car-
bon recycling, which account for a high percent in ALA con-
sumption [58,62]. Following b-oxidation, some ALA is used
by tissues for energy, and the rest is recycled by tissues to be
used as a carbon source for the production of SFAs and
MUFAs [63].
ALA may have numerous beneficial effects in promoting
human health and, although the mechanisms are still not
clear, they may involve conversion to its bioactive derivatives,
or action on its own. Principally, ALA has a positive effect on
lipid metabolism and, in animal studies, the hepatic and
plasma lipid levels were significantly reduced in rats fed with
a high-fat diet when it was administered with flaxseed oil
(rich in ALA) for 60 days [64]. Likewise, in rats fed with perilla
oil (rich in ALA) for 4 weeks, hepatic triglyceride (TG) and
total cholesterol levels were reduced to the levels observed in
the group fed fish oil (FO) [62]. A lipid-lowering effect was
also found in hamster experiments [65,66]. In human studies,
a high-ALA diet reduced the total cholesterol and LDL--cho-
lesterol concentrations in normolipidemic [67] as well as
hypercholesterolemic [68] patients. Secondly, ALA also has
anti-inflammatory properties, which can be achieved by effec-
tively inhibiting the expression of inflammatory markers. Two
studies in healthy subjects have shown that inflammatory

4 Expert Opin. Drug Deliv. (2013) 10(11)

 Lipid emulsions in parenteral nutrition: current applications and future developments
mediators were significantly reduced after administration of
an ALA-rich diet [69,70]. Another study in hypercholesterol-
emic men and women also reported that the intake of an
ALA-rich diet has been associated with a large 75% reduction
in plasma C-reactive protein levels, markers of vascular
inflammation [71]. Both the anti-inflammatory properties
and hypolipidemic activity of ALA play important roles in
reducing the risk factors of cardiovascular diseases. Moreover,
ALA also has antiarrhythmic properties, neuroprotective
properties, and has a positive effect on preterm and neonatal
development, although further evidence to support this is
needed [62].
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2.7v-3PUFAs----eicosaopentaenoic acid (EPA) and
docosahexaenoic acid (DHA)
EPA and DHA are animal sources of w-3PUFAs in the
human body. In the last few decades, detailed studies of
EPA and DHA have been conducted in both human beings
and animals, and evidence has been collected to prove their
significance in human health and disease. Their beneficial
effects have been shown in many conditions including meta-
bolic disorders, cardiovascular disease, inflammation and
immunomodulation, and infant development [72]. Several dis-
For personal use only.
tinct mechanisms, including alterations in cell membrane
composition and function, gene expression, or eicosanoid
production are related to their pleiotropic effects [72].
Metabolic disorders, including hyperglycemia, insulin
resistance, hypertension, hypertriglyceridemia, and reduced
HDL--cholesterol concentration, are usually defined as a clus-
tering of interrelated risk factors for cardiovascular diseases
and diabetes. EPA and DHA can improve dyslipidemia by
regulating lipolysis and lipogenesis through several inflamma-
tion mediators and reduce the lipid deposition in the liver and
other tissues [73]. Simultaneously, glucose homeostasis can be
maintained by altering glycolysis and gluconeogenesis [74].
Studies in animal models and humans, reviewed by Lom-
bardo and Chicco [75], have demonstrated that dietary FO
(rich in EPA and DHA) efficiently improves or reverses dysli-
pidemia, impaired glucose tolerance, and insulin resistance. In
addition, biological effects of EPA and DHA in preventing
arrhythmias, reducing platelet aggregation, lowering plasma
TG and blood pressure, and reducing inflammation, have
been found to be closely correlated to the prevention of
CVDs [76,77].
DHA and EPA have long been recognized as having
anti-inflammatory activity [78]. Treatment with EPA and
DHA significantly reduces the plasma levels of inflammatory
biomarkers, such as tumor necrosis factor-a, C-reactive
protein, and interleukin-6 and interleukin-1-b [72]. EPA
and DHA and their derivatives, especially eicosanoids and
resolvins, all exert important effects in the suppression and
resolution of inflammation [77,79]. Their anti-inflammatory
activity plays a key role in reducing the risk of CVDs, because
CVDs are always associated with vascular inflammation [80].
Expert Opin. Drug Deliv. (2013) 10(11)
Moreover, FO is a proposed adjunctive therapy for inflam-
matory diseases, such as rheumatoid arthritis [81]. The
immuno-modulatory effects of EPA and DHA are achieved
by improving the inflammatory state and regulating immune
cell functions through modulating the synthesis of eicosanoids
and resolvins and modifying the FA composition of immune
cells [82].
3.Developments of lipids used in parenteral
LEs
Lipids suitable in PN should fulfill two requirements: (1)
They should provide sufficient energy and material (EFAs
and vitamins) to meet essential needs for the human body;
(2) They should possess a suitable FA composition with
desirable biological properties to suit the needs of different
patients. Nutritional support is the basic function of paren-
teral LEs. With the development of parenteral LEs, more
attention is being paid to the FA composition and biological
properties of parenteral lipids, although the most desirable
composition is still not well understood. First of all, it
should not be potentially harmful to the human body.
Moreover, it is expected to have beneficial effects, either a
so-called well balanced pattern or a simple composition,
to fit certain patients. The metabolic properties of FAs in
different classes could guide us to select the ‘good’ lipid
sources.
3.1 Evolution of current available lipids for PN
3.1.1 The first-generation parenteral LEs
The first successful intravenous LE was introduced for PN in
1961 [2]. The primary lipid sources were pure soybean or saf-
flower oils or a mixture of both, which are able to provide suf-
ficient energy and EFAs. They not only offered an alternative
energy source to glucose, but also efficiently avoided EFAs
deficiency, and were rapidly and widely applied in patients
requiring PN. So far, these conventional LEs have been used
in clinical practice for > 50 years. Among them, SO-based
emulsion is the most widely used parenteral LE. Despite their
key role in PN regimens, concerns have been raised because
of their less than ideal FA composition. The high content of
LA and only moderate amounts of ALA in SO lead to a
high w-6/w-3 ratio (7:1), which is considered pro-inflam-
matory, immunosuppressive, and susceptible to lipid per-
oxidation [2,5,6]. The provision of excess LA in SO-based
emulsions is thought to be the cause of a series of new compli-
cations (i.e., RES dysfunction, exaggerated systemic inflam-
matory response in the critically ill, and liver dysfunction in
acutely ill infants and in patients of any age requiring long-
term PN) associated with PN [3,33,83,84]. Although there is a
lack of detailed evidence regarding clinical outcomes, one
view is that SO may not be the optimal lipid source for use
as parenteral LE.
5
 T. Ren et al.
3.1.2 The second-generation parenteral LEs
The concerns about the potential harm of excess LA have led
to the development of alternative LEs for PN. One approach
is to replace part of the SO with another neutral oil that has
no or only a mild effect on the immune and inflammatory
response to reduce the side effects. This strategy has led to
the introduction of a second generation of parenteral LEs,
including MCT/LCT LE, structured LE, and olive oil
(OO)-based LE. MCT, the predominant component of coco-
nut and palm kernel oils, has traditionally been regarded as a
good energy source with few other physiologic functions [2].
However, compared with LCT (SO), MCT has both benefits
and risks as far as metabolism is concerned. On one hand, it
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provides rapidly available energy, avoids lipid peroxidation,
and has no effect on immune and inflammatory response;
on the other hand, it leads to major acidosis or ketosis when
administrated with a large quantity [13]. In order to balance
the benefits and risks both of MCT and LCT, an MCT/
LCT emulsion, based on a mixed lipid of SO (50%) and
MCTs (50%), was developed. These emulsions became
available for PN in the mid-1980s [2]. On the basis of the
same considerations, structured MCT/LCT lipids, synthe-
sized using SO and MCTs, have also been used in intravenous
LE. Compared with the SO-based emulsions, both MCT/
For personal use only.
LCT and structured emulsions have a lower content of
w-6 PUFAs and are cleared more rapidly from the plasma
after infusion [85,86]. OO-based emulsion, derived from a
physical mixture of SO (20%) and OO (80%), became avail-
able for use in PN in the late 1990s [2]. These contain a
reduced content of n-6 PUFAs, approximately 20% which is
enough to meet the requirement for EFAs and more impor-
tantly, they have a high content of long-chain w-9MUFA
OA (65%) from the OO. Regarding the benefits from OAs,
it has been suggested that the OO-based emulsions offer an
immunologically neutral alternative to SO-based LE for use
in PN, with the potential benefit of some mild anti-inflamma-
tory effects [22]. Moreover, OO is naturally rich in the antiox-
idant a-tocopherol, which has an important role in the
clearance of free radicals [87]. Together with the fact that
OA, an MUFA, is less prone to lipid peroxidation, it has
also been suggested that OO-based emulsions will produce
less oxidative stress compared with PUFA-rich emulsions [22].
3.1.3The third-generation parenteral LEs
An alternative approach has been to use another oil, which
has potential benefits to the immune and inflammatory
response to prevent side effects. This strategy led to the intro-
duction of the third-generation parenteral LEs, FO-contain-
ing LEs. Pure FO-based emulsion came into use for PN in
the late 1990s. It contains FO as the single lipid source,
which has a high content of w-3PUFAs EPA (13--28%) and
DHA (14--31%), leading to a very low w-6/w-3 PUFA ratio
(1:8) [2]. In clinical application, it is recommended to com-
bine the FO-based emulsion with other emulsions (SO-based
or MCT/LCT emulsion), so that FO contributes 10--20% of
6 Expert Opin. Drug Deliv. (2013) 10(11)
total infused lipid [2]. There is another commercially available
FO-containing emulsion, SMF, which contains a mixture of
50% MCT, 40% SO, and 10% FO. SMOF is a novel LE
with a complex mixed lipid formulation of 30% SO, 30%
MCT, 25% OO, and 15% FO, reflecting the wish to opti-
mize the FA profile and provide the benefits offered by vari-
ous types of FAs. The different oils are chosen for different
goals: SO provides sufficient amounts of essential FAs;
MCT offers rapidly available energy with no storage in the tis-
sues; OO has an immunologically neutral effect by supplying
large amounts of MUFA--oleic acid and is less prone to
lipid peroxidation; FO exerts immunomodulatory and
anti-inflammatory effects by adjusting the ratio of w-6/w-
3 PUFAs with EPA and DHA. The proportion of the four
oils (30/30/25/15) in SMOF leads to a well-balanced FA pat-
tern and an optimal w-6/w-3 PUFAs ratio of 2.5:1 [37]. In
addition, SMOF is additionally supplemented with sufficient
amounts of a-tocopherol to maintain an adequate antioxidant
status and avoid lipid peroxidation [37].
3.2 Potential lipid sources for PN
The evolution of current LEs can be considered as a process
that selects new lipid sources and optimizes the FA composi-
tion of the lipids used in parenteral LEs (Table 2). However,
until now, there are still very limited amounts of lipids avail-
able in PN, including SO, MCT, OO, FO, and mixtures of
two or more of these, although their compositions are much
better than before. FO is the first lipid with potential thera-
peutic effects that has been successfully used in PN. More
potential lipid sources with advantages in their FA composi-
tion and biological properties should be developed to increase
the choice of lipids used in parenteral LEs.
Sea buckthorn (SBT) seed oil is extracted from the ripe
seeds of Hippophae rhamnoides L., which has been used exten-
sively in oriental traditional medicine for the treatment of dif-
ferent diseases for > 1000 years [88]. It is one of the most
versatile natural oils rich in two EFAs, LA, and ALA, account-
ing for 30--40% and 20--35% of their composition, respec-
tively [89]. The proportion of the two FAs leads to a superior
w-6/w-3PUFAs ratio, approximately 1.5--2.0, which is within
the recommended range. The oil also has a high content of
MUFA, OA (13 -- 30%) [89]. In addition, other bioactive sub-
stances, such as carotenoids and tocopherols, contained in the
SBT seed oil produce a better anti-oxidative effect compared
with other PUFA-rich lipids. Because of these constituents,
SBT seed oil has produced a significant improvement on tis-
sue rebuilding and immune functions [89]. Studies have been
designed to evaluate the potential benefits in burn wounds
and gastric ulcers in rats and, as a result, SBT oils have been
proposed for the healing of wounds and burns in the skin or
mucosa [89,90]. Some investigators have been engaged in the
development of SBT seed oil for further use in PN.
Perilla seed oil is extracted from the seeds of Perilla frutes-
cens. Compared with other plant oils, it consistently contains
the highest proportion of w-3PUFAs, ALA with a content of
 Lipid emulsions in parenteral nutrition: current applications and future developments

good anti-oxidant status

54 -- 64% [91,92]. In addition, the LA and OA components

lipid peroxidation and

immuno-modulatory;
account for 14 -- 20% and 13 -- 21% of the total content,

Soybean oil/coconut

Anti-inflammatory;

less susceptible to
oil/olive oil/fish oil

ALA: a-linolenic acid; DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acid; FA: Fatty acid; FO: Fish oil; LA: Linoleic acid; MCT: Medium-chain triacylglyceride; NA: Not available; OA: Oleic acid; OO: Olive oil;
SMOF respectively [92]. It has been widely used in Asian countries,
Fresenius Kabi

(30:30:25:15)
such as China, India, Japan, and Thailand, for cooking and

150 -- 296
as a traditional medicine for centuries, but still not well
known in western countries. The traditional use of perilla

2.5:1
37.2

55.3

47.6
seed oil in the diet and as a medicine has demonstrated that
4.7
9.1
it is beneficial to human health and in the prevention of sev-
oil/fish oil (40:50:10)

immuno-modulatory
eral diseases such as cardiovascular conditions. Moreover, it
Soybean oil/coconut

Anti-inflammatory;
provides an alternative w-3PUFAs source to FO for nutrition
and, similar to FO, it also exerts an anti-inflammatory
SMF

190 ± 30 effect [91] and also reduces the levels of serum lipids [93,94].
B. Braun

Perilla seed oil-based LE is being developed in China and

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Alberta on 09/12/13

2.7:1
25.7

Japan, and its successful introduction will also be a break-

3.4
6.2

NA
--

through in parenteral LEs. Other primary sources of plant

w-3PUFAs include flaxseed (Linum usitatissimum) oil which
good anti-oxidant status has a 51 -- 55% ALA content [64,95] and chia (Salvia hispanica)
immuno-modulatory;
Anti-inflammatory;

susceptible to lipid

oil which has an ~ 63% ALA content [96].

peroxidation but

Borage oil (BO) and evening primrose oil are the main
Fresenius Kabi
FO

Pure fish oil

sources of GLA, which have potential anti-inflammatory

effects. BO is extracted from the seeds of Borago officinalis
and contains 18 -- 26% GLA [53]. Evening primrose oil is
18.7

62.3

200
2.3

1:8

extracted from the seeds of Oenothera biennis L. and contains

0
--

7 -- 10% GLA [53]. Both of them have shown benefits in the

and good anti-oxidant
For personal use only.

to lipid peroxidation

treatment of rheumatoid arthritis and atherosclerosis as

effect; insusceptible
Olive oil/soybean

dietary supplements. Furthermore, their enteral use with FO

Immuno-neutral

has shown beneficial effects on pulmonary inflammation in

OO

oil (80:20)

patients with acute lung injury and severe sepsis [54-56].

327 ± 8

Similar to FO, all these natural lipid sources have potential

Baxter

status
31.3
15.1

therapeutic effects depending upon the specific FA content

4.4
1.8

9:1
32

SMF: Soybean, coconut and fish oils; SMOF: Soybean, coconut, olive, and fish oils; SO: Soybean oil.

and can be regarded as ‘functional lipids’ (Figure 2). Their

Table 2. Characteristics of current commercial lipid emulsions [2,155].

Less immunosuppressive;

incorporation into PN not only serves as an alternative source

Soybean oil/coconut oil

less pro-inflammatory;

of nutrients and energy but also provides adjuvant therapeutic

Less susceptible to

effects for specified patients with appropriate indications.

LCT/MCT

lipid peroxidation

They can be used alone or combined with other oils already

available to obtain the optimal FA composition to meet indi-
B. Braun

vidual patient needs. As a supplement to the third generation

85 ± 20
(50:50)

of LE, they provide a range of interesting perspectives for

29.1
4.5

7:1

NA
11

future development.
--
Fresenius Kabi/Baxter

Immunosuppressive;

4. Applications of alternative parenteral LEs

susceptible to lipid
pro-inflammatory;
Pure soybean oil

in different patients
peroxidation
SO

348 ± 33

4.1 Critically ill patients

Energy deficit is a major problem in critically ill patients and a
7:1
53

24

38

progressive negative energy balance is always correlated with

8
--

an increased incidence of infectious complications, prolonged

EPA,DHA

length of hospital stay, and mortality [3]. PN is a key method

Ratio of w-6/w-3PUFAs

for the treatment of intensive care patients to correct an

ALA

a-Tocopherol (mg/L)
OA
Lipid source (by wt)

LA

Phytosterols (mg/L)

energy deficit and improve clinical outcomes when enteral

Biological effects
Lipid emulsion

nutrition is not feasible or inadequate. As an integral part of

FA (%, by wt)
Manufacturer

a PN regimen, parenteral LEs have been widely used in this

patient population. Patients with severe illness, such as
trauma, surgery, sepsis, and shock, commonly exhibit meta-
bolic stress and potential systemic inflammatory responses [3].

Expert Opin. Drug Deliv. (2013) 10(11) 7

 T. Ren et al.
MCT Fish oil
Soybean oil
safflower oil
SBT seed oil,
Olive oil
perilla seed oil,
borage oil, etc.,
Conventional lipids Neutral lipids Functional lipids
1st generation 2nd generation 3rd generation
Figure 2. The development of parenteral lipids used in lipid
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Alberta on 09/12/13
emulsions. The first generation of parenteral lipids is
represented by conventional lipids (soybean oil and saf-
flower oil) with high contents of w-6PUFAs. The second
generation of parenteral lipids is preferred with improved
fatty acid compositions by incorporation of neutral lipids
(MCT and olive oil). The third generation of parenteral lipids
is marked by the introduction of functional lipids, which
have potential therapeutic effects based on specific fatty
acid compositions. In addition to fish oil available for
parenteral use, more potential lipid sources (SBT seed oil,
perilla seed oil, and borage oil) with beneficial biological
properties are proposed for development as parenteral
For personal use only.
nutrition.
MCT: Medium-chain triglyceride; PUFA: Polyunsaturated fatty acid; SBT:
Sea buckthorn.
The use of the conventional LEs has caused concerns about
aggravating complications because of exacerbated oxidative
stress and inflammatory response, and impaired immune
function. Many researchers have focused on the potential
benefits on clinical outcomes of using alternative LEs as a
treatment for critically ill patients.
4.1.1 The MCT/LCT LE in critically ill patients
The MCT/LCT emulsion was initially used as a substitute for
the SO-based emulsion in intensive care patients and it pro-
duced mild benefits on some clinical endpoints. In a study
of 72 septic patients who received PN with MCT/LCT or
LCT for 10 days, a greater recovery of nutrition status and
nitrogen balance was found in the MCT/LCT group com-
pared with the LCT group [97]. The outcomes were in line
with the findings in another study of 30 gastrointestinal tract
cancer patients following surgery requiring PN for 7 days [98].
In that study, the MCT/LCT significantly improved nutri-
tional status with an increased serum pre-albumin level in
patients receiving treatment [98]. Both of the trials demon-
strated an elevated plasma insulin level, which was considered
as a factor explaining the MCT promotion of nitrogen reten-
tion in the patients [97,98]. Another randomized study also
reported a reduction in postoperative complications in surgi-
cal patients treated with MCT/LCT with LCT [99]. However,
there was no marked difference in the length of hospital stay
and mortality between the two LEs when they were used in
8 Expert Opin. Drug Deliv. (2013) 10(11)
critically ill patients [97-99]. Furthermore, the MCT/LCT
emulsion may be helpful in minimizing the adverse effects
associated with SO-based emulsions on respiratory function.
In a study of nine mechanically ventilated septic patients,
there were no significant alterations in systemic or pulmonary
hemodynamics and ventilation/perfusion ratios following
treatment with an MCT/LCT emulsion, although it is not a
randomized, controlled study [100]. Similarly, other studies
also reported that the infusion of an MCT/LCT emulsion
produced no adverse respiratory effects in patients with acute
respiratory distress syndrome (ARDS) [101,102]. This has been
attributed to the rapid oxidation of MCT and limited synthe-
sis of eicosanoids from w-6 PUFAs [100]. As for structured
LEs, similar to MCT/LCT, these are well tolerated in surgical
patients with positive effects regarding an improvement in
nitrogen balance and RES function [85,103,104].
4.1.2 The OO-based LE in critically ill patients
As already known, severely ill patients under stress are sus-
ceptible to oxidative stress and immuno-suppression. The
OO-based emulsion has demonstrated immuno-neutral
effects and benefits on lipid peroxidation compared with
SO-based emulsion. In clinical studies, thiobarbituric acid-
reactive substances (TBARS), formed during the decomposi-
tion of lipid peroxidation products, are commonly used to
assess the oxidative stress. In a study of patients following
major abdominal surgery randomized to receive OO-based
emulsion, MCT/LCT, or a FO-containing emulsion, the
OO-based emulsion group had significantly lower levels of
TBARS and a higher antioxidant status compared with the
other groups [22]. Similar results were obtained in studies
involving children, which demonstrated a lower TBARS level
and significantly higher plasma a-tocopherol concentration
following treatment with OO-based LE versus SO-based
LE [87,105,106]. These outcomes suggested that the OO-based
LE may reduce the risk of oxidative stress, but more evidence
are needed because many studies have failed to show statisti-
cally significant effects on vitamin E concentration or lipid
peroxidation [106,107]. The immuno-neutral function of OO-
based emulsions is primarily supported by evidence obtained
in vitro. The effects of OO-based emulsion on human periph-
eral blood mononuclear cells have been compared with those
of two SO-based emulsions [25]. Both the SO-based emulsions
suppressed lymphocyte proliferation and IL-2 production,
whereas the OO-based emulsion had no effect on these pro-
cesses [25]. In another in vivo study, rats were given intrave-
nous saline (controls), an SO-based emulsion, an MCT/
LCT emulsion, or OO-based emulsion before the intravenous
administration of Escherichia coli. Both the SO and MCT/
LCT emulsions significantly reduced the bacterial clearance
in blood, whereas the OO-based emulsion did not [108]. Clin-
ical trails of OO-based emulsion have shown that it is well
tolerated in critically ill patients with no adverse effect on
inflammatory and oxidative stress makers, infection rate, and
immune function [109-111].
 Lipid emulsions in parenteral nutrition: current applications and future developments
4.1.3 The FO-containing LEs in critically ill patients
Compared with MCT and OO-based LEs, FO-containing
emulsions are preferable in intensive care patients. FO-supple-
mented PN has led to significant improvements in clinical
outcomes, such as the rate of infection and lengths of stay in
intensive care units or hospital. In a study of 24 severely ill
patients under intensive care, who were randomized to receive
PN short-term with FO-based emulsion or an SO-based
emulsion, both of these were well tolerated without any
adverse metabolic effects [112]. In another randomized, dou-
ble-blind, placebo-controlled clinical trial, 28 patients with
severe sepsis in an intensive care unit were randomly given
either FO-based emulsion or saline (as control) at a dosage
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Alberta on 09/12/13
of 100 ml/day for 5 days. FO-based emulsion was found to
be safe and helpful in terms of rapidly improving the clinical
severity, although there was no change in the length of ICU
and hospital stay [113]. Moreover, in two randomized clinical
trials, fish plus SO emulsion (an SO-based emulsion as
control) was used in the treatment of gastrointestinal cancer
surgical patients [114,115]. One study found that FO supple-
mentation had a favorable effect on the outcomes of postoper-
ative patients by lowering the inflammatory responses and
modulating the immune response [114]. The other study also
demonstrated that FO-supplemented PN significantly reduced
For personal use only.
the systemic inflammatory response syndrome (SIRS) and
length of hospital stay [115]. A large open-label multicenter
study, in which 276 patients suffering from abdominal sepsis
received FO-based emulsion as regular PN, showed a dose-
dependent effect of supplemental FO [116]. A significantly lower
rate of infection and shorter lengths of intensive care unit and
hospital stay were found in those patients receiving > 0.05 g
FO/kg per day compared with those receiving less than this.
Mortality was significantly reduced in those patients who
received > 1 g FO/kg per day [116]. A meta-analysis of random-
ized controlled trials was conducted to assess the safety and
efficacy of FO-based emulsions on postoperative patients
undergoing major abdominal surgery [117]. It showed that an
FO-enriched PN regimen had a positive effect on the length
of hospital stay, length of intensive care unit stay, and postop-
erative infection rate [117]. These clinical beneficial outcomes
were supported by a systematic review of clinical trials in
surgical patients by Wei et al. [118]. In this review, patients
undergoing elective major operations treated with FO-enriched
LEs had significantly fewer infectious complications and a
shortened length of hospital stay [118]. Recently, there have
been clinical trials exploring pre-operative parenteral infusion
of isolated FO-based LE as an adjuvant pharmacological agent
for the treatment of surgical patients. In a randomized, double-
blind, and controlled clinical trial, 63 patients with gastrointes-
tinal cancer received pre-operative infusion of FO-based LE or
MCT/LCT LE for 3 days, and it was found that FO-based LE
favorably modulated post-operative immune mediators with
the preservation or improvement in leukocyte phenotype [119].
Furthermore, parenteral supplementation with omega-3 FO
emulsion efficiently reduced the hyperinflammatory response
Expert Opin. Drug Deliv. (2013) 10(11)
and attenuated systemic disease sequelae, and also improved
the condition of patients with acute pancreatitis [120,121].
Similar effects on clinical endpoints were obtained when
SMF and SMOF were administered. A prospective, random-
ized, double-blind, multicenter trial indicated that the admin-
istration of SMF in the postoperative period after major
abdominal surgery is safe and results in a significantly shorter
length of hospital stay [122]. Similarly, in a randomized, con-
trolled trial, 25 septic patients were randomized to receive
MCT/LCT or SMF for 5 days, and an increased plasma
EPA status was found in SMF group, associated with modi-
fied plasma cytokines concentrations, improved the gas
exchange, and decreased the length of hospital stay [123]. In a
double-blind, randomized study, the effects of SMOF was
assessed in 33 surgical patients who needed PN over 5 days,
with MCT/LCT as the control. As a result, the treatment
with SMOF was well tolerated and improved the FA and leu-
kotriene profiles in plasma with an elevated LTB5/LTB4 ratio
and a low w-6/w-3 ratio. Furthermore, the length of hospital
stay was significantly reduced following SMOF treatment
compared with the control [124].
Many studies have suggested that the beneficial outcomes
in critically ill patients are related to the immunomodula-
tion, inflammatory regulation, and metabolism regulation
of w-3PUFAs (EPA and DHA) obtained using FO-contain-
ing emulsions [1,125]. Intravenous administration of emul-
sions containing FO will lead to a fast incorporation of the
w-3PUFAs into the plasma phospholipid pool [117,126] and
further downregulate the w-6/w-3 ratio in the monocyte
and leukocyte membrane in a relative short time (days)
[127-129]. Moreover, FO-containing emulsions lead to an
increase in the ratio of LTB5:LTB4, a decrease in serum pro-
inflammatory cytokines, such as IL-6, tumor necrosis factor-
a, and a positive effect on lymphocytes compared with other
Les (SO or MCT/LCT) [114,130,131]. More studies are required
to explain how FO efficiently modulates the excessive inflam-
matory response and abnormal immune response in severely
ill patients. In addition, in most of the clinical trials, the com-
parisons of FO-containing emulsions were done against SO-
based emulsions. Attentions should be paid to this because
probably SO-based emulsion is not the best control LE to
FO-containing emulsions, although it is the most widely
used LE.
Critically ill patients are the most important group receiv-
ing parenteral LEs as PN. FO-containing emulsions have
demonstrated beneficial effects on clinical outcomes in these
populations. The rationale is still not clear, but FO with a
high content of w-3PUFAs regulates the w-6/w-3 ratio in
the human body. Furthermore, patients under metabolic
stress react to different FA compositions. It has been suggested
that the biological effects of FA vary according to the level of
stress in severely ill patients [3]. The potential lipid sources
with an appropriate FA composition can be selected to be
developed to new LEs for subpopulations with critically
illness.
9
 T. Ren et al.
4.2 Pediatric patients
PN is essential to provide sufficient nutrients to sustain
growth in infants and children suffering from intestinal failure
or severe functional intestinal immaturity. Parenteral lipids
are important sources of nutrients such as EFAs and fat-
soluble vitamins. However, compared with adults, infants
and children have a lower tolerance to Les [132]. The adminis-
tration of conventional LEs has been linked to more serious
complications with increased pulmonary vascular resistance,
impaired pulmonary gas exchange, hyperbilirubinemia, chole-
static liver disease, enhanced oxidative stress, and adverse
immunologic effects [133]. It is expected that alternative LEs
will be selected and will be useful for the treatment of
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Alberta on 09/12/13
pediatric patients.
Clinical data about MCT/LCT emulsions used in infants
are limited, although one study has reported their use in pre-
term infants for 8 days but no better outcomes were obtained
compared with LCT emulsions [86]. The OO-based emulsions
are well tolerated and support EFA and provide an improved
antioxidant status when used in preterm infants, and are rec-
ommended as a valuable alternative for the parenteral feeding
of preterm infants who are often exposed to oxidative stress,
while their antioxidative defense is weak [105]. Moreover, clin-
ical trials have also demonstrated beneficial effects on the
For personal use only.
immune response and the prevention of immunosuppression
in these patients compared with SO-based emulsions [134,135].
It is definite that DHA supplements have favorable effects
on both visual and cognitive development in infants and
contribute to ongoing cognitive development and metabolic
programming of bone turnover and adipogenesis in chil-
dren [136]. FO-containing emulsions enriched in DHA have
potential benefits on the growth of preterm infants [137].
One study has reported that preterm infants receiving a LE
containing 10% FO had lower plasma lipids and improved
FA status [137]. A randomized, double-blind clinical trial, in
which 60 premature neonates received PN with either
SMOF 20% (study group) or a conventional LE (control
group) for a minimum of 7 up to 14 days, also demonstrated
the good safety and efficacy of SMOF in premature infants.
Moreover, the study group showed increased a-tocopherol
and low g-glutamyl transferase levels in plasma, suggesting a
potential beneficial effect on plasma anti-oxidant status and
liver function [138]. These results are in line with another
study, in which a reduced plasma bilirubin and increased
a-tocopherol status without changing lipid peroxidation
were found in children treated with SMOF 20% compared
with SO-based emulsion 20% for 29 days [139].
In the case of pediatric populations with intestinal failure,
parenteral nutrition-associated liver disease (PNALD) is the
most prevalent complication. It is involved in a series of severe
hepatic abnormalities, including biochemical (i.e., elevated
bilirubin and transaminases) and histologic alterations (i.e.,
steatosis, steatohepatitis, cholestasis, fibrosis, and cirrho-
sis) [84]. Approximately 30--60% of children develop hepatic
dysfunction while receiving a prolonged PN [84]. In the case
10 Expert Opin. Drug Deliv. (2013) 10(11)
of infants, it is a significant life-threatening complication.
The etiology of PNALD is considered to be multifactorial,
and contributing factors of parenteral LEs mainly include
the high w-6/w-3 FA ratio and high content of phytosterols
in SO, and lipid metabolites accumulating in hepatic
sinusoidal macrophages [35].
FO plays an important role in the prevention and reversal
of PNALD. The reversal of cholestasis was first reported in
two infants with short bowel syndrome (SBS) treated with
FO-based emulsion instead of an SO-based emulsion as PN.
One child was removed from the liver transplantation list
because of improved hepatic function, and the other child
had complete resolution of cholestasis [140]. Also, there have
been two open-labeled studies, in which the safety and effi-
cacy outcomes of an FO-based emulsion in 18 or 42 infants
with SBS who developed cholestasis (serum direct bilirubin
level > 2 mg/dL) while receiving SO-based emulsions, involv-
ing a comparison with other cohorts of 21 or 49 infants with
SBS and cholestasis only receiving SO-based emulsions. As a
result, the FO-based LE groups experienced reversal of chole-
stasis (direct bilirubin £ 2 mg/dL) 4.8 and 6 times faster than
the control groups, respectively, and these groups also had a
lower mortality and transplantation rate [84,141]. Same results
were also reported in some other studies [36,142,143]. These ben-
eficial outcomes of FO-based emulsions are considered
very meaningful for clinical applications because PNALD is
a major cause of morbidity and mortality in children with
SBS [35]. Recently, five premature infants with SBS were
treated with a combination of FO-based and OO-based
emulsions (1:1, w/w) replacing initial SO-based emulsion
for periods ranging from 7 to 17 months, and they avoided
developing PNALD, with normalized direct bilirubin lev-
els [34]. The efficacy of an FO-based emulsion on PNALD
in patients with SBS has been demonstrated not only in chil-
dren, but also in adults [33,144]. Another report also describes
FO-based LE in the treatment of three patients with microvil-
lous inclusion disease (MVID) who developed PNALD. Con-
sistently with previous results, all three patients responded
rapidly with improvement in liver function tests within weeks
and normalization of total and direct bilirubin in addition to
g-glutamyl transpeptidase levels [145]. The mechanism has
been investigated by Diamond et al. [35], and the evidence sug-
gests that w-3 PUFAs in FO-based LE may influence PNALD
by improving bile flow, inhibiting steatosis, and modulating
the immune response. Moreover, FO-based LE has shown
positive effects in protecting liver function [131,146].
In addition to the compositions of parenteral LEs, the
administration dose of parenteral LEs is also considered to
be an important contributing factor to their potential harmful
effects. Especially in pediatric patients who have a low toler-
ance to parenteral lipid, the risk of hepatic abnormalities is
correlated to the load of lipid [147] and duration of administra-
tion [148]. A clinical study also reported that decreasing the
lipid load or temporarily stopping the lipid administration
led to the resolutions of PN-associated cholestasis in children
 Lipid emulsions in parenteral nutrition: current applications and future developments
Stress state (hyper inflammation)
• SARS FO-containing LEs
• Severe sepsis
• Shock
• Major surgery
PO-containing LEs
• Severe burn
• Severe trauma SBT LE
• ARDS
• Severe acute pancreatitis BO-based LE
SO-based LE
FO-containing LEs
• Premature infants
• IFALD/PNALD OO-based LE
• HPN
MCT/LCT LE
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Alberta on 09/12/13
Common state (moderate inflammation)
Figure 3. Selection of alternative parenteral lipid emulsions
for patient populations suffering from various degrees of
inflammation. Patients requiring parenteral nutrition can be
classified into groups according to the severity of their
inflammatory state. The conventional lipid emulsions are
unselectively applied in all these patients, but sometimes
they are unsuitable for certain populations. Alternative
parenteral lipid emulsions (including potential parenteral
lipids) provide more choice to fit individual patient needs
For personal use only.
and disease characteristics.
ARDS: Acute respiratory distress syndrome; HPN: Home parenteral nutrition;
IFALD: Intestinal failure--associated liver disease; PNALD: Parenteral nutrition--
associated liver disease; SIRS: Systemic inflammatory response syndrome.
who depended on long-term PN [149]. More studies are
required to explore the correlation of adverse effects to the
administration dose of parenteral LEs.
4.3 Long-term PN and home PN patients
Long-term PN is indicated for patients with prolonged gastro-
intestinal tract failure that prevents the absorption of adequate
nutrients to sustain life. Long-term HPN has been introduced
as a treatment primarily for chronic intestinal failure in
patients who are able to receive therapy outside an acute
care setting. Until now, the lipid most commonly used for
long-term PN remains SO. However, due to the potentially
side effects involving inflammation, immune and lipid perox-
idation, long-term administration of SO-based emulsions has
been proposed as one factor for several metabolic complica-
tions, among which hepatic disorders have long been the
most relevant in view of patients’ prognosis [150].
The OO-based emulsion was first introduced for used in
long-term PN. An early study in 18 children showed that pro-
longed (60d) administration of OO-based emulsion was well
tolerated and maintained a normal EFA status [87]. Two other
studies [107,151] also evaluated the efficacy and safety of
OO-based emulsion in adults receiving home PN for 3 and
6 months, respectively. The results are consistent with
previous studies, showing that the OO-based emulsion is
safe and effective in adults with no EFA deficiency and
Expert Opin. Drug Deliv. (2013) 10(11)
the inflammatory response was unaffected. Furthermore,
OO-based emulsion is potentially useful for the preservation
of liver function. In a comparison of the effects of SO- and
OO-based LEs on hepatobiliary function, the OO-based
emulsion was more effective in preserving the integrity of cho-
lestatic markers [152]. In another study of patients with HPN-
associated liver disease, liver parameters were significantly
improved after treatment with OO-based emulsion [150].
OO-based emulsion has been recommended as an alternative
to SO-based emulsions used in long-term HPN [153].
FO-containing emulsions have also been proven to be
safe in long-term HPN. Recently, a randomized, double-
blind, multi-centre study was conducted to evaluate the
safety and tolerability of SMOF in adults with intestinal fail-
ure on long-term PN [154]. In this study, 73 patients were
given either SMOF or SO-based emulsion for 4 weeks. Con-
sistent with previous studies, SMOF was well tolerated and
led to a series of positive changes in plasma alanine transam-
inase, aspartate transaminase, total bilirubin, anti-oxidant
status (a-tocopherol concentrations), and w-6/w-3 ratio [154].
5. Conclusions
The conventional LEs, used as standard PN, remain the most
widely used formulations, although many concerns have been
expressed about their potential harmful effects. Alternative
LEs, which are optimized in terms of lipid compositions
and sources employing partial substitution of SO with
MCT, OO, and FO, have demonstrated their safety and effi-
cacy, and even their superiority to the conventional LEs in
current clinical trails. They all exerted their unique benefits
on clinical outcomes in critically ill, pediatric, and long-
term PN patients. Furthermore, potential lipid sources with
desirable FA compositions have caused more attentions and
will play important roles in future developments of parenteral
LEs.
6. Expert opinion
A parenteral LE is a conventional and efficient therapy when
PN support is needed. The conventional LEs are unselectively
applied in all these patients, but sometimes they are unsuit-
able for certain populations. Alternative parenteral LEs with
improved biological effects provide more choice for clinical
use in different patients (Figure 3). On the basis of current
clinical data, FO-containing LEs, including pure FO-based
emulsion, SMF and SMOF, are preferable to be used in
patients with hyper-inflammation, especially critically ill
patients. That probably dues to the immunomodulation,
inflammatory regulation, and metabolism regulation of
w-3PUFAs (EPA and DHA) obtained from FO-containing
LEs. As for patients with moderate inflammation, all alterna-
tive LEs have shown their superiority to SO-based emulsions
in clinical studies. Especially, FO-based LE is proposed to
be used in the prevention and reversal of PNALD or IFALD
11
 T. Ren et al.

associated with both pediatric and adult patients. Also,
OO-based LE with an immunologically neutral effect has
been recommended as an alternative to the SO-based emul-
sion used in long-term PN and HPN. Moreover, benefits
from the well-balanced FA pattern, SMOF also has the poten-
tial to be used in premature infants and long-term HPN
patients. However, it will be a long time before these alterna-
tive LEs are widely used clinically. Ongoing clinical data from
well-designed, controlled, and sufficiently highly powered
studies are required to characterize the integral biologic
properties of newer LEs to ensure their safe and appropriate
applications. Furthermore, the options for parenteral therapy
should consider the properties of LEs to meet individual
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Alberta on 09/12/13
regulation by downregulating the w-6/w-3 ratio in patients.
It provides an alternative to FO in PN when FO is not suit-
able in certain circumstances, such as patients likely to have
a hemorrhagic condition or an allergy. Compared with FO,
perilla seed oil is less likely to cause EFA deficiency when
used as monotherapy or long-term support for critically ill
patients. Furthermore, perilla seed oil can be used in combi-
nation with SO, OO, and FO to obtain a well-balanced FA
composition. BO or evening primrose oil combined with
FO can be developed as an efficient treatment of ARDS and
septic patients. As a supplement to FO-containing emulsions,
these new LEs not only serve as an alternative source of
nutrients and energy, but also provide an adjuvant therapeutic

patient needs and disease characteristics. effect. By using them alone or mixed with other available
The clinical uses of commercially available LEs have shown lipids, they will have an FA pattern to fit specified subpopula-
us the importance of the FA pattern in the lipids used in PN. tions of patients with different diseases. Great efforts should
The evolution of current LEs provides information to select be devoted to the development of suitable parenteral LEs.
potential lipid sources with desirable FA compositions to be
developed new therapeutic LEs (Figure 3). SBT seed oil, sim-
ilar to SMOF, has an optimal w-6/w-3 ratio within 1:1--4:1 Acknowledgement
which is considered immunomodulatory and anti-inflamma-
DB Jack is gratefully thanked for correcting English of the
tory. It can be used in patients in a highly proinflammatory
manuscript.
state, induced by surgery, trauma, sepsis, and shock. Accord-
ing to the potential therapeutic effects on wounds and burns
For personal use only.

in skin or mucosa, SBT LE has been suggested for develop- Declaration of interest
ment for the treatment of burn patients requiring PN. Perilla
seed oil, rich in w-3PUFA, has potential benefits on immu- The authors state no conflict of interest and have received no
nomodulation, inflammatory regulation, and metabolism payment in preparation of this manuscript.

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Affiliation
Tianyang Ren1, Lin Cong2, Yueqi Wang1,
Yilin Tang3, Bin Tian1, Xia Lin1, Yu Zhang1 &
Xing Tang†4
†
Author for correspondence
1
Shenyang Pharmaceutical University,
Department of Pharmaceutics Science,
Shenyang, China

Potential usefulness of olive oil-based 2

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prevention of liver disease. Eur J
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of parenteral nutrition associated liver
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disease in an adult patient. E Spen Eur E
J Clin Nutr Metab 2010;5(5):e243-e46
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Puder M. Use of an omega-3 fatty
acid--based emulsion in the treatment of
parenteral nutrition--induced cholestasis
lipid emulsions in selected situations of
home parenteral nutrition-associated liver
disease. Clin Nutr 2004;23(6):1418-25
Thomas-Gibson S, Jawhari A, Atlan P,
et al. Safe and efficacious prolonged use
of an olive oil-based lipid emulsion
(ClinOleic ) in chronic intestinal
failure. Clin Nutr 2004;23(4):697-703
Pálová S, Charvat J, Kvapil M.
Comparison of soybean oil-and olive
oil-based lipid emulsions on hepatobiliary
function and serum triacylglycerols level
during realimentation. J Int Med Res
2008;36(3):587-93
Shenyang Pharmaceutical University,
Department of Pharmacology Science,
Shenyang, China
3
Xi’an Jiaotong University,
School of Materials Science and Engineering,
Xi’an, China
4
Professor,
Shenyang Pharmaceutical University,
Department of Pharmaceutics Science,
Wenhua Road 103 Shenyang,
110016 Liaoning Province, China
Tel: +8602423986343;
Fax: +8602423911736;
E-mail: tangpharma@gmail.com

Expert Opin. Drug Deliv. (2013) 10(11) 17