Original Communication
Influence of Vitamins, Trace Elements,
and Iron on Lipid Peroxidation
Reactions in All-in-One Admixtures for
Neonatal Parenteral Nutrition
Journal of Parenteral and
Enteral Nutrition
Volume 35 Number 4
July 2011 505-510
© 2011 American Society for
Parenteral and Enteral Nutrition
10.1177/0148607110381768
http://jpen.sagepub.com
hosted at
http://online.sagepub.com
Anaïs Grand, MD1; Anne Jalabert, MD1; Grégoire Mercier, MD2;
Maurice Florent, MD3; Sylvie Hansel-Esteller, MD1; Gilles Cambonie, MD, PhD5;
Jean-Paul Steghens, MD4; and Jean-Charles Picaud, MD, PhD6
Financial disclosure: none declared.
Background: The purpose of this study was to evaluate the
effect of vitamins, trace elements, or iron on lipid peroxidation in all-in-one parenteral nutrition (PN) admixtures for
preterm neonates. Methods: Malondialdehyde (MDA) concentrations were analyzed over a 24-hour period (H1-H24) in
lipid-containing PN solutions that have a composition identical to that used in the routine clinical care of preterm infants.
Six different solutions were prepared and evaluated when
exposed to ambient light and light-protected conditions as follows: control (without vitamins [Vit], trace elements [TE], or
iron [Fe] [Vit–TE–Fe–]), solution 1 (Vit+TE+Fe–), solution 2
(Vit+TE–Fe–), solution 3 (Vit–TE+Fe–), solution 4 (Vit–TE–
Fe+), and solution 5 (Vit+TE+Fe+). Results: MDA concentrations in PN solutions were significantly higher at H24 than at
H0 when they contained multivitamins (P < .001), trace elements (P = .002), or iron saccharate (P = .018). MDA concen-
tration was particularly high when all 3 micronutrients were
present (P < .001) or when the solutions were exposed to
ambient light. In solutions containing iron, MDA concentrations were elevated at H0, and levels did not change whether
protected from (P < .001) or exposed to (P < .001) from light.
Conclusions: The addition of vitamins and trace elements to
PN solutions induces a significant increase in peroxidation
products, which are lowered when admixtures are protected
from light. Iron should not be included in these solutions,
even if solutions are light-protected. By following these conditions it is possible to use all-in-one admixtures in the nutrition
management of preterm infants. (JPEN J Parenter Enteral
Nutr. 2011;35:505-510)
Clinical Relevancy Statement
all-in-one (AIO) admixtures containing amino acids, glucose, electrolytes, lipids, vitamins, and trace elements,
significant amounts of cytotoxic lipid peroxidation (LPO)
products may be delivered to these patients. A relationship between elevated LPO and poor neonatal outcome
has been reported in preterm infants. Protection of
parenteral solutions from light is an efficient method to
reduce LPO induced by the addition of vitamins, trace
elements, or iron, but not LPO related to the addition of
iron saccharate, which should be administered separately.
Keywords: prematurity; nutrition; neonates; lipid peroxidation;
parenteral nutrition
Parenteral nutrition is essential for the management of
very preterm infants. Depending on the composition of
From 1CHU Montpellier, Pharmacie, Hopital Lapeyronie,
Montpellier, France; 2CHU Montpellier, Departement
d’information médicale, Hopital Arnaud de Villeneuve,
Montpellier, France; 3Laboratoire Fasonut, Montpellier, France;
4
CHU Lyon, Biochimie, Hopital Edouard Herriot, Lyon, France;
5
CHU Montpellier, Neonatologie (Pédiatrie 2), Hopital Arnaud
de Villeneuve, Montpellier, France; and 6CHU de Lyon,
Neonatologie, Hopital de la Croix-Rousse, Universite Claude
Bernard Lyon 1, Centre de Recherche en Nutrition Humaine
Rhone-Alpes, Lyon, France.
Introduction
During the first weeks of life, parenteral nutrition (PN) is
essential for the management of very preterm infants. It can
be provided as an AIO admixture containing amino acids,
glucose, electrolytes, lipids, vitamins, and trace elements.
AIO ad mixtures limit the need to manipulate drip lines and
therefore could reduce the risk of catheter-related sepsis.
Received for publication May 30, 2009; accepted for publication November 20, 2009.
Address correspondence to: Jean-Charles Picaud, Neonatologie,
Hopital de la Croix Rousse, 103 Grande rue de la Croix Rousse,
69004 Lyon, France; e-mail: [email protected].
505
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506 Journal of Parenteral and Enteral Nutrition / Vol. 35, No. 4, July 2011
Table 1. Composition of a Typical Parenteral Solution for a Preterm Infant Weighing 1,500 g
Nutrient
Carbohydrates
Lipids
Nitrogen
Sodium
Potassium
Phosphorus
Calcium
Magnesium
Carnitine
Vitamins
Trace elements
Iron
Brand Name
Dextrose 50%a
Intralipid 20%b
Primene 10%c
NaCl 20%a
KCl 10%a
Phocytanb
Calcium gluconate 10%a
Magnesium sulfate 15%a
Levocarnild
Cernevitc,e
Oligo-éléments pédiatriquesa,f
Venoferg
Total Amount
21 g (14 g/kg)
3 g (2 g/kg)
540 mg (360 mg/kg)
3 mEq (2 mEq/kg)
1.5 mEq (1 mEq/kg)
45 mg (30 mg/kg)
60 mg (40 mg/kg)
9 mg (6 mg/kg)
12 mg (8 mg/kg)
1.25 mL
1.5 mL (1 mL/kg)
1.5 mg (1 mg/kg)
a
Aguettant, Lyon, France.
Fresenius Kabi, Sèvres, France.
c
Baxter, Maurepas, France.
d
Sigma Tau, Ivry-sur-Seine, France.
e
Cernevit (per 1.25 mL): vitamin A (875 IU), vitamin D (55 IU), vitamin E (2.8 IU), ascorbic acid (vitamin C, 31.3 mg), thiamine
(875 mcg), riboflavin (1,035 mcg), pantothenic acid (4,312 mcg), pyridoxine (vitamin B6, 1125 mcg), cobalamin (vitamin B12) (1.5
mcg), niacin (11.5 mg), folate (103 mcg).
f
Oligo-éléments pédiatriques (per mL): iron (0.05 mcg), copper (30 mcg), manganese (10 mcg), zinc (100 mcg), cobalt (15 mcg),
fluoride (0.11 mg), iodine (0.02 mcg), chromium (2 mcg), selenium (5 mcg), molybdenum (5 mcg).
g
Therabel Lucien Pharma, Levallois-Perret, France.
b
The lipid- emulsions, amino acids, vitamins, and trace elements used in AIO admixtures are sources of oxidants.1-3
Furthermore, some authors have suggested the need to add
iron, which is both a pro-oxidant and an antioxidant,4 to
these mixtures when treating preterm infants receiving
erythropoietin.5 The occurrence of peroxidation reactions in
these solutions is influenced by their composition and by
light exposure.6-8
LPO products can be directly cytotoxic, and a relationship between elevated LPO and poor neonatal outcome has been reported in sick, very preterm infants.9-11
As free radicals are short-lived, they can be indirectly
evaluated either by their primary reaction products with
unsaturated fatty acids or by their secondary decomposition products such as hydroxypentenal, hydroxynonenal,
and malondialdehyde (MDA). MDA is highly cytotoxic
because of its ability to rapidly bind to proteins or nucleic
acids.12 The measurement of thiobarbituric acid reactive
substances (TBARS) is a widely used approach for the
evaluation of LPO.11-14 Unlike MDA, TBARS are not specific for LPO, because other aldehydes and nonlipid
materials present in biological samples may also form
thiobarbituric acid adducts.15 More specific methods are
available to evaluate MDA concentrations in serum and
in PN solutions.16 These measurements can be used to
optimize the composition of PN solutions and reduce the
amount of LPO products delivered to neonates.
In the current study, we aimed to evaluate the effect
of vitamins, trace elements, or iron on LPO in AIO
parenteral admixtures for preterm neonates.
Methods
MDA Concentrations in Parenteral Nutrition
The study protocol was designed to mimic routine conditions for the preparation and administration of PN solutions. In our neonatal intensive care unit (NICU), a
dedicated pharmacy unit manufactures the PN solutions
prescribed by healthcare providers (Fasonut, Montpellier).
From the prescription, software is used to produce manufacturing data, control data, and labeling. Solutions are
prepared according to a standardized and validated procedure. Good manufacturing practice recommendations are
used as a reference for production and quality control.
Each component is manually added to the solution using
syringes of appropriate size (from 2 to 60 mL). When the
volume of the added component is <0.2 mL, a 1:10 dilution ratio is used. The nutrients are mixed and introduced
using sterilizing filtration into transparent ethylene vinyl
acetate bags. These bags are sheltered from light using
individual dark cover packaging and taken to the NICU
within 2 hours. Between preparation and connection at
the bedside, these solutions are stored at 4°C to 8°C.
Then they are placed at the bedside without protection
from light and connected to the neonate’s feeding tube.
Nutrient solutions and tubing are changed every 24
hours.
For the purpose of this study, we evaluated a typical
AIO admixture providing the recommended amounts of
nutrients for a preterm infant weighing 1,500 g.17 AIO
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Peroxidation of Neonatal Parenteral Nutrition / Grand et al 507
admixtures contained carbohydrates (14 g/kg), lipids
(2 g/kg), amino acids (2.3 g/kg), and electrolytes as indicated in Table 1. To evaluate the influence of micronutrients, we added vitamins, trace elements, or iron to
admixtures (Table 1).
The bags were made at the pharmacy and imported to
the NICU under routine clinical conditions. Then they
were placed in a room with ambient light similar to those
in the NICU all day and night.
Each bag was connected to a drip line. Depending on
the situation evaluated, bags and tubes were protected
from (black plastic bags) or exposed to ambient light. The
dark packaging covering the bags was left in place (lightprotected) or removed (light-exposed). For the tubes, we
used either a transparent tube (Doran International,
Toussieu, France) or an opaque tube (Codan, Blagnac,
France). Infusion rate of PN solution was set at 0.1 mL/
min, which corresponds to 100 mL/kg/d.
To evaluate the influence of vitamins, trace elements,
and iron, various solutions were prepared. First, 36 control (C) solutions without vitamins, trace elements, or
iron (Vit–TE–Fe–) were evaluated: 18 were exposed to
ambient light (bags exposed and transparent tubes), and
18 were protected from light. Five other solutions were
prepared as follows:
•• Solution 1: 108 solutions containing vitamins
and trace elements but no iron (Vit+TE+Fe–):
54 were exposed to ambient light, and 54 were
protected from ambient light. There were more
solutions in this group than in the other groups
because we were particularly interested in this
mixture, as it is the solution most frequently
used in routine clinical practice.
•• Solution 2: 36 solutions containing vitamins as
the sole micronutrient, without trace elements or
iron (Vit+TE–Fe–): 18 were exposed to ambient
light and 18 were protected from ambient light.
•• Solution 3: 36 solutions containing trace
elements as the sole micronutrient, without
vitamins or iron (Vit–TE+Fe–): 18 were exposed
to ambient light, and 18 were protected from
ambient light.
•• Solution 4: 36 solutions containing iron as the
sole micronutrient, without vitamins or trace
elements (Vit–TE–Fe+): 18 were exposed to
ambient light, and 18 were protected from
ambient light.
•• Solution 5: 36 solutions containing vitamins,
trace elements, and iron (Vit+TE+Fe+): 18
were exposed to ambient light, and 18 were
protected from ambient light.
For each situation, a sample of the solution (1.5 mL) was
collected at the end of the infusion tube at the beginning
(H0) and 24 hours later (H24) and then stored at –20°C
until MDA concentration was assessed.
Measurement of MDA Concentration
Admixture samples were stored in the dark at –20°C until
measurement. MDA was measured by high-performance
liquid chromatography/mass spectrometry using a method
based on diaminonaphthalene derivatization.16 The quantification was carried out at 45°C with a dideuterated
MDA (d2-MDA) internal standard, on a 150 × 2 mm
Modulo-cart QS Uptishere 3 BioPII (Interchem, Villiers sur
Marne, France). The derivatives of MDA were detected at
m/z 195.2, and 197.2 the derivatives of d2-MDA were
detected at m/z. The mobile phase (ammonium acetate 5
mmol/L, adjusted at pH 1.8 with formic acid, containing
15% vol/vol of a 1:1 methanol/acetonitrile mixture)
enabled a full separation of acetaldehyde (m/z = 183.2)
and MDA derivatives.18 Between-run imprecision measured on commercial controls for 1 month (n = 18) was
4.9% at 308 nmol/L, and 4.1% at 1,682 nmol/L. As PN
solution are relatively “clean” samples, the method was
determined to be linear up to 10,000 nmol/L, with good
reproducibility.
Statistical Analysis
Characteristics of infants and MDA values were summarized by frequency and percentage for categorical variables and median and interquartile range for continuous
ones. MDA concentrations at H24 were compared
between groups (with or without vitamins, trace elements, or iron; light-protected or light-exposed) using
Wilcoxon nonparametric tests. Within each group, MDA
concentrations were compared between H0 and H24
using paired Wilcoxon tests. Finally, the impact of micronutrients was studied by comparing MDA concentrations.
All statistical tests were 2-sided, and P < .05 was considered statistically significant. The Bonferroni correction
was used for multiple comparisons. Statistical analyses
were performed using SAS 9 software (SAS Institute Inc,
Cary, NC).
Results
Parenteral Nutrition Study
In the control solution (Vit–TE–Fe–), MDA concentrations at H0 and H24 were similar in solutions protected
from light (H0: 247 [215; 426] nmol/L vs H24: 311 [215;
363] nmol/L; P = .54) and exposed to ambient light (H0:
279 nmol/L [212; 389] vs H24; 292 [226; 331] nmol/L;
P = 1.0) (Figure 1).
In solution 1 (Vit+TE+Fe–), MDA concentration at
H24 was significantly greater than at H0 in protected
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508 Journal of Parenteral and Enteral Nutrition / Vol. 35, No. 4, July 2011
a
6,000
5,500
5,000
MDA concentration (nmol/L)
4,500
a
4,000
3,500
a
3,000
2,500
2,000
1,500
1,000
500
0
Control Exp. Control Prot. Vit+TE+Fe−
Exp.
Vit+TE+Fe− Vit+TE−Fe− Vit+TE−Fe− Vit−OE+Fe− Vit−OE+Fe− Vit−OE−Fe+ Vit−OE−Fe+ Vit+TE+Fe+ Vit+TE+Fe+
Prot.
Exp.
Prot.
Exp.
Prot.
Exp.
Prot.
Exp.
Prot.
Figure 1. Malondialdehyde (MDA) concentrations at 24 hours (H24) in parenteral solutions protected from light (Prot.) or exposed
to light (Exp.). Solutions are with (+) or without (–) vitamins (Vit), trace elements (TE), iron or (Fe). Control admixtures: without
Vit, TE, or FE . Values are [interquartile range] expressed as median, range. MDA concentrations at H24 in all solutions were significantly different (P < .05) from control admixtures (Wilcoxon test). aSignificant difference (P < .05) between light-exposed and
light-protected admixtures (Wilcoxon test).
Table 2. Difference in Malondialdehyde (nmol/L) Concentrations Between H0 and H24
in Parenteral Solutions Exposed to or Protected From Ambient Light
Nutrients
Vit–TE–Fe– (control)
Vit+TE+Fe– (solution 1)
Vit+TE–Fe– (solution 2)
Vit–TE+Fe– (solution 3)
Vit–TE–Fe+ (solution 4)
Vit+TE+Fe+ (solution 5)
Exposed, nmol/L
13
1,043
598
153
301
2,469
[–103;39]
[637;1,376]
[332;767]
[26;316]
[10;568]
[1,803;2,736]
Protected, nmol/L
12
390
316
425
227
997
[–66;121]
[138;702]
[112;514]
[132;517]
[140;450]
[641;1714]
P
.559
<.001
.017
.071
.816
<.001
Values are given as median [interquartile range]. Parenteral solutions were either with (+) or without (–) vitamins (Vit), trace
elements (TE), or iron (Fe).
(H0: 1156 [671; 1365] nmol/L vs H24: 1462 [1,082;
2,022] nmol/L; P = .001) and light-exposed solutions
(H0: 956 [617; 1,280] nmol/L vs H24: 1,998 [1,808;
2,208] nmol/L; P < .001) (Figure 1). There was a significant increase in MDA concentration between H0
and H24 in these solutions when they were exposed to
light vs when they were protected from light (P <
.001) (Table 2). Bonferroni correction showed that
when both vitamins and trace elements were added to
solutions, the MDA concentration increased significantly between H0 and H24 compared with control
group. When solution 1 (Vit+TE+Fe–) was protected
from light, MDA concentration was higher at H24
than in the control group or in solution 3 Vit–TE+Fe–;
(P < .001), but there was no difference from solution
2 (Vit+TE–Fe–).
In solution 2, (Vit+TE–Fe–), MDA concentration at
H24 was significantly greater than at H0: in both lightprotected (H0: 784 [535; 1,081] nmol/L vs H24: 1,189
[872; 1,526] nmol/L; P = 0.01) and light-exposed solutions (H0: 399 [258; 812] nmol/L vs H24: 1,128 [845;
1,287] nmol/L; P < .001) (Figure 1). The increase in
MDA concentration between H0 and H24 was significantly greater in vitamin-containing solutions exposed
to light compared with solutions protected from light
(P = .017) (Table 2).
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Peroxidation of Neonatal Parenteral Nutrition / Grand et al 509
In solution 3 (Vit–TE+Fe–), MDA concentration at
H24 was significantly greater than at H0 in both lightprotected (H0: 810 [557; 914] nmol/L vs H24: 1114 [956;
1,356] nmol/L; P = .001) and exposed solutions (H0: 854
[517; 1104] nmol/L vs H24: 1,022 [833; 1,268] nmol/L;
P = .002) (Figure 1). The increase in MDA concentrations
between H0 and H24 tended to be greater in the solution
containing trace elements when exposed to light than
when protected from light, but the difference was not
statistically significant (P = .071) (Table 2).
In solution 4 (Vit–TE–Fe+), MDA concentration was
high at H0. When this solution was exposed to light,
MDA concentration at H24 was significantly higher than
at H0 (H0: 1,555 [961; 1,903] nmol/L vs H24, 1,817
[1,216; 2,017] nmol/L; P = .018). If these solutions were
protected from light, MDA concentrations was not statistically different between H0 (1,501 [1,044; 1,727] nmol/L)
and H24 (1,586 [1,265; 1,947] nmol/L) (P = .067, Figure 1).
The increases in MDA concentrations between H0 and
H24 in solutions containing iron were similar whether they
were exposed to or protected from light (P = .816; Table 2).
Influence of Vitamins Combined
With Trace Elements and Iron
In solution 5 (Vit+TE+Fe+), we observed the highest MDA
concentration at H0 (Figure 1) and the highest increase in
MDA concentration between H0 and H24. MDA was significantly reduced in solutions protected from light rather
than those exposed to light (P < .001).
Discussion
We observed that the simultaneous addition of multivitamins, trace elements, and iron saccharate in a typical PN
solution for preterm neonates induced a significant
increase in MDA concentration, particularly when all 3
micronutrients were present and when the solutions were
exposed to ambient light.
The effects of multivitamins on LPO are uncertain.
Lavoie et al1 reported an increase of hydroperoxides concentration in solutions containing lipids after the addition
of multivitamins (MVI Paediatric, Rhône-Poulenc, Canada).
These authors suggested that protection from light and
the administration of multivitamins together with lipids,
but separately from other nutrients, would limit peroxidation reactions and the destruction of vitamins, mimicking
the beneficial effect of photoprotection.7,19,20 In our study,
the addition of multivitamins (Cernevit, Clintec Parenteral
SA, Montargis, France) to PN solution had a deleterious
effect on LPO, which was significantly reduced when
admixtures were protected from light. Therefore, when it
is not possible to avoid exposing PN solutions to light, one
could propose to administer vitamins separately from the
PN solution. However, this separation would negate one of
the benefits of AIO admixtures by increasing manipulation of the central venous line. Photoprotection of these
admixtures from ambient light is easier to perform on a
routine basis.
Studies evaluating the effect of trace elements added to
PN solutions are scarce. In 2000, Steger et al21 reported that
hydroperoxide concentrations in AIO admixtures for adults
were significantly higher when trace elements were added,
suggesting that they should be added extemporaneously at
the time of administration or injected by a separate route.
Using another marker of peroxidation, we confirmed that
the presence of trace elements in AIO admixtures increased
peroxidation reactions, but this increase disappeared when
the solutions were protected from light. It could be partly
explained by the presence of iron gluconate in the Oligoéléments Pédiatriques used in the admixtures, but the iron
content is very small, and this is the only trace element solution available in France for infants and newborns.
Photoprotection is simpler to perform than extemporaneous
or separated administration of trace elements and requires
fewer manipulations of drip lines.
As digestive intolerance is frequent during the first
weeks of life and because intestinal absorption of iron is
very poor, the use of intravenous iron in AIO admixtures
has been proposed.22,23 Lavoie et al compared the effects
of free iron (Fe2+) and bound iron (Fe3+) (eg, iron dextran).
Free iron induced the formation of free radicals, whereas
bound iron inhibited the generation of peroxides in PN
solutions.24 In our study, we used iron saccharate, the only
intravenous iron presently available for infants in France
and in most European countries. We observed that the
addition of iron saccharate to AIO admixtures induced an
increase in LPO reactions, contrary to the results of
Lavoie et al19 with iron dextran. These authors promote
the administration of iron-dextran in PN solutions.19 Our
results suggest that this recommendation is probably not
appropriate when the iron source is iron saccharate.
Ascorbic acid can reduce ferric ions (Fe3+) to ferrous ions
(Fe2+) and decrease the generation of free oxygen radicals.
We observed that MDA concentrations in solutions with
iron were already high (median value ≈ 1,501 nmol/L) at
the beginning of AIO admixture administration, suggesting that LPO reactions occurred quite rapidly when iron
was present in PN solutions.
The results of this study indicate that it is possible to
administer vitamins and trace elements in AIO admixtures as long as they are protected from light, whereas it
is best to avoid the addition of iron in PN solutions, as
protection from light is not sufficient. The clinician
should provide iron by the oral route as soon as possible,
which requires the adoption of measures known to
improve digestive tolerance in preterm infants, including
trophic feeding and using human milk during the first
weeks of life.25
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510 Journal of Parenteral and Enteral Nutrition / Vol. 35, No. 4, July 2011
Although multivitamins, trace elements, and iron
seem to be capable of individually inducing significant
LPO reactions, these reactions are additive when all 3
micronutrients are present in AIO admixtures. The combination of vitamins and trace elements induces LPO
reactions of similar intensity to those seen when these
ingredients are added separately in the PN solution; these
reactions are much more important in solutions containing vitamins, trace elements, and iron, notably when
these solutions are exposed to light.
PN supplied as an AIO admixture in neonates has been
shown to be physically and chemically stable.26 Provided
that caregivers are cautious about the composition of PN
solutions, and as long as these solutions are protected from
light, the concentration of MDA infused is small. Khashu et
al27,28 recently showed that photoprotection has potential
biological and clinical benefits.
Our study shows that the addition of vitamins and
trace elements in PN solutions induces significant
increases in the concentration of peroxidation products,
which are lowered when admixtures are protected from
light. Conversely, it is recommended to avoid the addition
of iron saccharate in these solutions, even when they are
protected from light.
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