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3-in-1 vs 2-in-1 Parenteral Nutrition in Adults: A Review

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research-article2014
NCPXXX10.1177/0884533614533611Nutrition in Clinical PracticeSlattery et al

Review
Nutrition in Clinical Practice
Volume 29 Number 5
3-in-1 vs 2-in-1 Parenteral Nutrition in Adults: A Review October 2014 631­–635
© 2014 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0884533614533611
ncp.sagepub.com
hosted at
Eoin Slattery, MD, MRCPI1; Martha M. Rumore, PharmD, JD, LLM, FAPhA2; online.sagepub.com
Janine S. Douglas, RPh, MS3; and David S. Seres, MD, ScM, PNS1

Abstract
Parenteral nutrition (PN) provides a means of nourishment for patients in whom oral or enteral nutrition is not possible or practical. Initial
formulations consisted of carbohydrates (dextrose), amino acids, vitamins, trace minerals, electrolytes, and water. A stable intravenous
fat emulsion (IVFE) permitted the combination of all 3 macronutrients in the same admixture (3-in-1 or total nutrient admixture [TNA]).
Many institutions have adopted these TNAs as the standard formulation. Others, due to a variety of concerns (including historical concerns
regarding stability), continue to administer PN as a formulation of dextrose and amino acids (2-in-1) with separate IVFE infusions. The
aim of this article is to review the literature regarding the use of TNA vs 2-in-1 formulations. The published data were critically analyzed,
and a preferred strategy was suggested based on an interpretation of the data. Concerns surrounding the safety of 2-in-1 vs 3-in-1 PN
formulations can be grouped with respect to those regarding infections, emulsion instability (“cracking”), and precipitant formation. These
concerns are largely historical and would seem to be no longer relevant to adult PN formulations. We believe that the available (limited)
data support the safe transition to the 3-in-1 formulation as the standard of care in adult PN. (Nutr Clin Pract. 2014;29:631-635)

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

Parenteral nutrition (PN) provides a means of nourishment for
patients in whom oral or enteral nutrition is not possible or
practical. It was first described at the turn of the 20th century
by Vassilyadi et al1 but, for a multitude of reasons, was aban-
doned due to the belief that PN was not feasible. Other investi-
gators later attempted (without much success) to nourish
patients with intravenous (IV) formulations. Dudrick et al2
described the successful administration of PN in 6 beagle pup-
pies. In the 1960s, they reported on an infant with biliary atre-
sia whose only source of nutrition was PN, who flourished
over the course of 2 years.3 Further human trials followed
shortly thereafter, and with them, the acceptance and science of
PN became mainstream and evolved at pace.4
Initial formulations consisted of carbohydrates (dextrose),
amino acids, vitamins, trace minerals, electrolytes, and water.
PN is by nature hypertonic. These early PN admixtures were
infused via a peripheral vein, and thus, issues with phlebitis
were commonplace. Administering PN in large volumes, and
later via central great veins, helped to address but not over-
come some of these issues. This led to an interest in the infu-
sion of intravenous fat emulsions (IVFEs) as a source of
concentrated energy.5
The development of a safe and viable emulsifying agent
had been the major obstacle to releasing a commercially avail-
able IVFE up to that point. The first commercially available
IVFE product (Lipomul IV, Upjohn, Kalamazoo, MI) was
approved by the Food and Drug Administration (FDA) and
then hastily withdrawn in 1960 because of the occurrence of a
constellation of life-threatening symptoms known as “fat
overload syndrome” (characterized by an immune-mediated
anaphylaxis reaction associated with anemia, thrombocytope-
nia, hemoptysis, fever, and abdominal pain).6 The toxicity of
Lipomul IV (made from cottonseed oil) appeared to relate to
an unsafe emulsifying agent. As a consequence of these
adverse events, the FDA banned the use of all IVFEs.6
The subsequent absence of IVFEs in PN led to a slew of
reports in the United States on the occurrence of essential fatty
acid deficiency (EFAD).7 EFAD was heretofore a rare entity
only seen in experimental animal models and in unusual cir-
cumstances in infancy. EFAD may manifest itself clinically as
depression, dermatitis, hair loss, abnormal serum lipid profiles,
and potentially, hypertension and coronary artery disease. The
absence of linoleic acid from PN led to a reliance on endoge-
nous production from the patient’s own adipose tissue, and
From 1Department of Medicine, Division of Preventive Medicine and
Nutrition, Columbia University Medical Center–New York Presbyterian
Hospital, New York, New York; 2Department of Pharmacy, Cohen
Children’s Medical Center, New Hyde Park, New York; and 3Department
of Pharmacy, Practice and Administration, University of St. Joseph,
Hartford, Connecticut.
Financial disclosure: None declared.
This article originally appeared online on May 28, 2014.
Corresponding Author:
Eoin Slattery, MD, MRCPI, Columbia University Medical Center,
630 West 168th Street, New York, NY 10032, USA.
Email: slattery.eoin@gmail.com.

Downloaded from ncp.sagepub.com at American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) on March 16, 2015
632 Nutrition in Clinical Practice 29(5)
EFAD was near universal in all patients without an exogenous
source of linoleic acid. It became particularly evident in starved
patients with minimal adipose tissue in whom the clinical man-
ifestations of EFAD presented earlier (even within a few days).
It was not until 1972 that the FDA approved the use of
Intralipid (an emulsion of soybean oil, egg phospholipids, and
glycerin, which had been approved for use in Europe 10 years
prior; Intralipid 20, Baxter Healthcare, Deerfield, IL).6 It
remains one of the mainstays of an IVFE to this day.
A stable IVFE permitted the combination of all 3 macronu-
trients in the same admixture (3-in-1 or total nutrient admix-
ture [TNA]). Many institutions have adopted these TNAs as a
standard formulation. Others, due to a variety of concerns
(including historical concerns regarding stability), continue to
administer PN as a formulation of dextrose and amino acids
(2-in-1) with separate IVFE infusions.
The aim of this article is to perform a descriptive review of
the current (limited) literature regarding the use of TNA vs
2-in-1 formulations. The published data will be critically ana-
lyzed, and a preferred strategy will be suggested based on an
interpretation of the data.
Methods
A literature search was performed using the keywords “paren-
teral nutrition,” “total nutrient admixture,” “three-in-one par-
enteral nutrition,” and “intravenous fat emulsion” in Medline
(1970 to November 2013), PubMed, and Google Scholar. The
search included English language articles, reviews, original
research, and case reports in the adult and pediatric literature.
The bibliographies of references retrieved were reviewed for
additional sources of data.
Results
The distinctions between the 2 different formulations of PN
can be grouped with respect to the potential for microbial con-
tamination, the stability of PN (both with and without IVFEs),
mechanical complications, and costs related to the administra-
tion and compounding of the 2 formulations.
Microbial Contamination
It has been suggested that PN formulations are potentially
good growth media for micro-organisms. This is thought to
relate to the relative abundance of nutrients in these formula-
tions. IVFEs, in particular, have been implicated in this regard.
Early in vitro scientific studies demonstrated the ability
of an IVFE to be used as a growth medium (including
Staphylococcus aureus and Candida albicans).8 A subsequent
in vitro study confirmed previous findings that an IVFE was
a good potential growth medium for micro-organisms. In
contrast, PN formulations without IVFEs do not allow the
growth of microbial colonies (Staphylococcus, Pseudomonas,
Escherichia coli, and Candida).9 When the same organisms
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were added to 3-in-1 PN, the bacteria grew minimally or
died. Interestingly, Candida grew in all 3 solutions but at a
faster rate in the IVFE. The authors concluded on the basis of
these findings that 3-in-1 PN was safe.
Because of persisting concerns that the addition of an IVFE
to PN could make the formulation more hypotonic and less
acidic, and thus more hospitable to micro-organisms, 2 quasi–
in vivo studies were performed.10,11 Both studies concluded
that while an IVFE alone represents a potentially hospitable
breeding environment for micro-organisms, the combination
of amino acids and dextrose with IVFEs does not.
Several clinical studies have confirmed the association of
IVFE infusions (in addition to PN of dextrose/amino acids)
with the occurrence of staphylococcal bloodstream infections
in pediatric cohorts. In the larger of the 2 studies, a case-con-
trol study demonstrated a 5.8-fold increase in staphylococcal
bacteremia in pediatric neonatal intensive care units (NICUs)
associated with IVFE infusions.12 This association was con-
firmed in a similar NICU-based study of very low birth weight
infants.13 In this case-control study, the authors documented a
>9-fold increase in staphylococcal bloodstream infections in
their cohort associated with the use of IVFE infusions.
Only 1 clinical trial to date has attempted to address the
issue of dextrose/amino acids vs TNAs with respect to the
occurrence of clinical infections as a primary endpoint.14
D’Angio et al14 randomized 98 patients to receive either a TNA
or an IVFE piggybacked with the 2-in-1 infusion. They found
no statistically significant difference in the occurrence of infec-
tions between either of the groups.
Stability
Emulsion.  Emulsions are the result of one immiscible liquid
immersed in the form of small droplets in another immiscible
liquid. An IVFE is an example of an oil-in-water type of emul-
sion. The natural inclination of these solutions is to coalesce
into 2 separate liquids. To prevent coalescence, an emulsifying
(ie, stabilizing) agent is required to act as a barrier. IVFEs con-
tain ionic phospholipids (ie, lecithin) as emulsifiers to maintain
stability. These become stabilized emulsions by creating an
electrostatic barrier between the 2 incompatible liquids. The
ionization of the hydrophilic portion of the emulsifier creates
electrostatic repulsive forces, which then maintains lipid drop-
let separation and so prevents globule coalescence.15 The higher
the electrostatic surface potential of the droplet, the more stable
the emulsion. Typically, IVFEs are at their most stable when
manufactured (ie, at a pH of 8 and surface potential of –35 mV).
The addition of electrolytes or altering the pH can potentially
change the surface potential of an emulsion droplet. This can
result in breakdown of the emulsion. Typically, repulsive forces
of the lipid emulsion are lost when the solution becomes electri-
cally neutral, which occurs at a pH of 2.5.
Dextrose/amino acid formulations are acidic and so can
potentially decrease the pH of an IVFE, thus putting any
admixture at risk for lipid globule coalescence (ie, “cracking”).
Slattery et al 633
Cracking is the term given to emulsions when fat droplets
coalesce and separate from the emulsion with water. This can
occur in stages: from creaming to oiling and eventually crack-
ing. Creaming of IVFEs is potentially reversible. A whitish
layer is observed at the top of the emulsion and can be dis-
persed by gentle agitation. It does not result in an alteration of
the particle size. However, if this progresses (ie, the lipid glob-
ules enlarge), it may result in the release of free oil or cracking.
This stage is irreversible. At this point, an off-color layer is
observed at the top of the PN formulation. If infused into the
patient at this stage, potentially life-threatening complications
may ensue.
IVFE stability is also dependent on additives to the PN for-
mulation. Brown et al15 described the potential for destabiliza-
tion of IVFEs by adding monovalent and divalent cations. The
higher the cation valence, the greater the destabilizing power.
Thus, trivalent cations such as Fe3+ (from iron dextran) are
more disruptive than divalent cations such as calcium (Ca2+)
and magnesium (Mg2+). Monovalent cations such as sodium
(Na+) and potassium (K+) are least disruptive to the emulsifier.
Yet, when given in sufficiently high concentrations, even mon-
ovalent cations may produce IVFE instability. There is no safe
concentration of iron dextran demonstrated in any TNA. In
general, for the monovalent and divalent cations, most adult
patients’ clinical needs are met without significant concern for
producing an unstable and potentially dangerous formula-
tion.16 The same is not necessarily true for pediatric PN and
will be discussed below.
It has been suggested that the administration of an IVFE as
part of a PN admixture fosters a safe administration route (with
respect to immune dysfunction and pulmonary gas diffusion
abnormalities) but may induce emulsion instability and thus
“cracking.”17 This is of particular concern for PN administered
to the very young. Neonatal PN is typically more acidic (pH
4.8–5.4) than that of adults and older children (pH 5.8–6.4).
This is because neonatal PN typically has a higher concentra-
tion of branched chain amino acids.18
Similarly, macronutrient profiles vary between adults and
neonates. The energy requirement for neonatal and pediatric
patients is typically 4–6 times higher than that of adult patients.
The higher doses required further lend themselves to instability
of the emulsion.18
Electrolyte contents will also vary significantly between
adults and neonates. In neonates, this can become problematic
because of the higher requirements for calcium and phosphate
required for bone mineralization (ie, in neonates, the calcium
requirement is 3.5–4.5 mEq/kg/d and phosphate [PO4] is 1.5
mmol/kg/d vs 0.5–3.0 mEq/kg/d calcium and PO4 of 0.5–2.0
mmol/kg/d in adults).
Calcium phosphate precipitation.  Calcium phosphate precipi-
tation (ie, formation of CaPO4, a white crystalline particle) in
PN formulations is a potential source of concern, especially
with 3-in-1 formulations. These concerns stem from 2 reported
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fatalities associated with the use of a 3-in-1 formulation.19 In
this report, 2 young females receiving PN died from fatal
microvascular emboli. Their autopsies revealed amorphous
material in their pulmonary arterioles, consistent with calcium
phosphate precipitates. To further investigate, the authors
infused the same PN into pigs and found that the pigs died
within 4 hours of starting the infusion. The authors concluded
that the amino acid product used was one of a number of poten-
tial problems because of its pH and phosphate content. Hill
et al19 demonstrated that (in the implicated PN formulation)
precipitation occurred when the pH was raised to 6.68. Solu-
tions of dextrose and amino acids are acidic, and as discussed
earlier, the addition of IVFEs to dextrose/amino acids does
raise the pH of the formulation and thus places it at risk of
precipitating.
The ratio of calcium to phosphate in PN is an important
consideration; that is, the higher the ratio, the more likely it is
to precipitate. The authors further postulated that the sequence
of calcium addition (ie, in the middle vs at the end), coupled
with the lack of agitation while compounding the admixture,
were also contributory factors in precipitate formation. A TNA
does not allow for accurate visualization of precipitates because
of the opaque nature of the admixture.
The authors concluded that careful attention to the com-
pounding process, monitoring of pH, and importantly, the use
of a 1.2-µm filter may help decrease the chance of fatal pre-
cipitants developing. Following these events, the FDA issued
a recommendation advising caution in the calculation of cal-
cium and phosphate requirements.20 It also advised on the rou-
tine use of filters in PN. For 3-in-1 PN, it recommended a
1.2-µm filter, and for 2-in-1 formulations, it suggested a 0.22-
µm filter. A TNA contains lipid globules, and thus, a larger
filter size is required to allow these globules to be infused into
the patient.
Cost and Simplicity of Infusions
Administering 1 TNA solution over 2 separate (dextrose/
amino acids plus an IVFE) infusions has some potential
advantages. In theory, TNAs will reduce the potential for
touch contamination (ie, by minimizing line manipulation).
Secondly, removing the need for 2 separate infusions is also a
way of streamlining the process. Streamlining practices (by
removing unnecessary steps) is an effective way of decreasing
errors, particularly with respect to medication errors in critical
care areas.21
In a study, nurses who administer PN were queried about
their preference for TNA vs 2-in-1 formulations.22 In this sim-
ple survey, 100% of nurses preferred to use TNA vs 2-in-1 for-
mulations. While not particularly robust evidence, the opinion
of the person infusing PN is an important one.
The administration of 1 solution over 2 solutions also has
the potential to be cost-effective. In the same study of nurses,
the authors reported that administering TNA formulations led
634 Nutrition in Clinical Practice 29(5)
to a saving of US$50,000 over the course of a year (1985) as
compared to 2-in-1 formulations at their institution.22 Recent
comparative data are lacking.
Discussion
The purported benefits of TNAs over dextrose/amino acids
(and vice versa) would appear to be largely academic and theo-
retical in the adult population. It is our belief that the argument
in favor of 2-in-1 PN as less microbially friendly is flawed. This
is because it neglects the fact that a separate infusion of an
IVFE is required. Proponents of 2-in-1 formulations point to
studies described above that show 2-in-1 PN to be a poor growth
medium for microbes. The addition of an IVFE to a 2-in-1 solu-
tion does appear to make the PN formulation less noxious to
bacteria; however, it would seem not to any great extent. Most
importantly, administering 2-in-1 PN requires the separate
administration of IVFEs, which has been shown in a number of
studies to be independently associated with bacterial infections.
It would seem that the cumulative risk (with respect to infec-
tions) of infusing 2 solutions could easily be more than with a
single TNA. It should be noted, however, that the only random-
ized trial to address the differences between the 2 formulations
found no differences between the 2 groups. It seems likely
though that the study was not sufficiently powered to detect the
small magnitude of difference between the 2 formulations.
Indeed, a simple post hoc power analysis of this study would
suggest that to detect a 20% difference in infectious complica-
tions, a study cohort of 140,000 would have been required.
Notwithstanding the importance of the constituents of PN
as a source of infections, the vast majority of infections
observed are in fact central line–associated bloodstream infec-
tions (CLABSI). The introduction of care bundles and overall
good hygiene has proven to be the most effective method of
reducing catheter-associated infections in patients receiving
PN.23 Excessive manipulation of central lines has been shown
to be a risk factor for the development of CLABSI, and thus,
minimizing this may help reduce infections. Infusing 1 formu-
lation instead of 2 formulations would seem a reasonable way
to achieve this. Data to support this opinion are not available.
Lowering the pH of the IVFE is a potential risk factor for
IVFE coalescence, and cracking is therefore perceived to be a
problem with TNAs. Specifically, combining an IVFE with the
acidic environment of a 2-in-1 PN mixture may itself lead to
cracking. However, fastidious attention to safe practices and
proper compounding procedures (as should now be common-
place) and maintaining the pH of TNAs should help prevent
this problem. In the modern world of adult PN, this should no
longer be a realistic concern.
Another perceived benefit of using 2-in-1 PN relates to a
lesser chance of calcium phosphate precipitation. This is
thought to be related to 2 factors: first, the pH of 2-in-1 PN, and
second, the allowance of using a smaller filter pore size (ie,
0.22-µm filter compared to 1.2-µm filter). As discussed above,
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maintaining an appropriate pH of TNAs is now commonplace.
Modern technologies and automated processes are such that
this should no longer be a realistic concern.
The theoretical benefit of using a smaller filter pore size is
that less precipitates will be infused directly into the patient.
Every parenteral injection used has the potential for precipi-
tants.24 Indeed, a body of literature exists around the dangers of
using glass vials for IV injections, with some authors suggest-
ing that glass particles may be responsible for granulomatous
diseases.25 It is assumed that the smaller filter pore size used in
2-in-1 PN will thus make it less likely that the precipitate will
be infused. However, the size of a pulmonary capillary is less
than that of a red cell (ie, 7 µm). It therefore seems unlikely
that a particle <1.2 µm will cause a pulmonary embolism, even
in the unlikely event of a precipitate forming.26,27 The routine
use of a filter with PN would appear to negate this issue and so
should no longer be a realistic concern.
Similarly, in the unlikely event of a 3-in-1 admixture
coalescing (or “cracking”), the administration of lipid globules
≥5 µm in size is the chief concern (ie, a fat embolus). As with
calcium phosphate precipitants, a 1.2-µm filter should also pre-
vent this from happening.
In fact, it would appear that the only theoretical benefit of
0.22-µm filters over 1.2-µm filters is the prevention of the pas-
sage of endotoxins from the biofilm of retained bacteria if the
filter is not changed every 24 hours. The use of filters for >24
hours, however, is contrary to current practice.
The ongoing debate regarding the mode of administration of
PN as a source of concern with respect to infections has led to the
development of multichamber bags (MCBs), which potentially
represent a compromise between dextrose/amino acids with sep-
arate IVFEs and TNAs.28 Turpin et al28 have previously pub-
lished on the rates of infection between these 2 modalities and
found decreased infections with potential cost savings in the
MCB group. Pontes-Arruda et al29 recently published their find-
ings in the first prospective trial of MCBs vs TNAs. They
observed a statistically significantly increased rate of blood-
stream infections in TNAs when compared to MCBs. While
encouraging, it should be noted that patients receiving TNA
obtained lipids in the form of medium-chain triglycerides/long-
chain triglycerides (MCT/LCT) and olive oil derivatives, which
are different to those used in routine clinical practice in the United
States. Thus, some care should be taken in interpreting these data.
Nevertheless, initial results are encouraging and warrant further
investigation. Ultimately, cost (apparently less with MCBs) may
become a major driver in the adoption (or not) of MCBs.
Conclusion
Concerns surrounding the safety of 2-in-1 vs 3-in-1 PN formu-
lations can be grouped with respect to concerns regarding
infections, phase separation (“cracking”), and precipitant for-
mation. These concerns are largely historical and would seem
to be no longer relevant to adult PN formulations. It should be
 Slattery et al 635
noted, however, that no prospective randomized clinical data
exist on the superiority (or indeed inferiority) of either formu-
lation over the other.
We would suggest that 3-in-1 PN with the use of a 1.2-µm
filter, as is already standard practice, is more convenient and
may in turn have some potential (theoretical) clinical benefits.
We believe that the available (limited) data would support the
safe use of TNA formulations as the standard of care in adult
PN as opposed to PN of dextrose/amino acids. PN of MCBs
may represent a future compromise between those on either
side of the debate; however, further work is required before PN
of MCBs can become part of standard clinical practice.
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