JPPT

Review Article

Effects of Light Exposure on Total Parenteral Nutrition and its

Implications in the Neonatal Population
David S. Hoff, PharmD1 and Amanda S. Michaelson, PharmD2

Pharmacy Department, Children’s Hospitals and Clinics of Minnesota, Minneapolis,1 and St. Paul,2 Minnesota

Total parenteral nutrition (TPN) is a necessary form of nutrition in neonates with functional or anatomical
disruption of the digestive tract. However, laboratory and human investigation have shown that exposure
of the TPN solution to light causes the formation of peroxides and other degradation products that are
quantifiable in experimental TPN solutions, laboratory animals, and neonates. Premature neonates are at a
higher risk for the development and progression of peroxide damage due to their relative lack of antioxi-
dant and free radical scavenger reserves. Furthermore, cell damage seen in a number of neonatal disease
states is exacerbated by the presence of peroxides that are generated via intrinsic pathologic processes and
from exogenous sources such as TPN. Numerous studies show that the formation of TPN photodegradation
products can be slowed or prevented by the application of various light protection mechanisms. While it is
not yet known if minimizing TPN associated photodegradation byproducts has a significant direct effect on
preventing or mitigating the overall clinical course of some neonatal disease states, it is becoming increasingly
clear that light protecting TPN can avoid specific metabolic complications in neonatal patients. It is prudent to
implement mechanisms that prevent photodegradation of TPN components from the manufacturer source
to the point of patient administration.

KEYWORDS degradation, lipid emulsion, neonate, peroxide, parenteral nutrition

J Pediatr Pharmacol Ther 2009;14:132–143

INTRODUCTION together to form TPN. The macromolecules

commonly included in TPN mixtures are water,
Until enteral nutrition is established, total amino acids, dextrose, and lipid emulsion. Mac-
parenteral nutrition (TPN) is an important romolecules are used for energy and as structural
means to meet the nutritional needs of premature ABBREVIATIONS ACC, acetyl-coA carboxylase; FMN,
neonates by increasing weight gain, protein ac- 5’-phosphate flavin mononucleotide ; MVP, multivitamin
cretion, positive nitrogen balance, and energy in- preparation; TBH, tertbutylhydroperoxide; TNA, all-in-one
take.1-7 TPN is often necessary to feed premature total nutrient admixture; SOD, superoxide dismutase; TPN,
neonates because they have limited nutritional total parenteral nutrition
reserves and immature, often erratic, gastrointes-
tinal function.7-9 It is also a common practice to components of cells. Micromolecules in TPN
rely on TPN while delaying or slowly introducing include vitamins, minerals and trace elements.
enteral feedings in premature neonates in order Micromolecules are added to TPN because they
to decrease the risk of necrotizing enterocolitis.10,11 are required to support metabolic activities,
A number of nutritional components are added such as enzymatic reactions, fluid balance and
regulation of electrophysiological processes.3
Some of these TPN components are susceptible
Address correspondence to: David S. Hoff, PharmD,
Pharmacy Department, Children’s Hospitals and Clinics to formation of peroxides, aldehydes, and other
of Minnesota, 2525 Chicago Avenue South, Minneapolis, degradation products.
MN 55404, email: [email protected] This review will provide a brief background of
© 2009 Pediatric Pharmacy Advocacy Group hydroperoxide and free radical reactions, outline

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TPN Photoprotection in Neonates JPPT
reasons for increased neonatal susceptibility antioxidant. Albumin, lactoferrin, and urate are
to radical damage, and summarize laboratory, other extracellular antioxidants.18
animal, and human data on light exposed TPN Sick and premature neonates often receive high
in order to highlight the potential health issues concentrations of peroxides in the first days of
associated with exposure of neonates to TPN life from endogenous and exogenous sources.
degradation products. Examples of endogenous sources include reper-
A free radical is a chemical species that has a fusion injury from hypoxia, acidosis, oxidative
single, unpaired, electron in the outer orbital of stress from birth trauma, mechanical ventila-
one of its atoms.12 Oxygen is a common biological tion, supplemental oxygen delivery, infection,
molecule that readily accepts electrons to form and inflammation.18,22 A significant exogenous
free radicals such as the superoxide anion, O2-, source of hydroperoxides is light exposed TPN.
and the peroxide ion, 2O2-.12 The peroxide ion However, many neonates do not have a proper
rapidly becomes protonated at physiological pH antioxidant response to this peroxide challenge
to form hydrogen peroxide, H2O2.12 Superoxide because of immature physiology. Neonates have
and H2O2 can become strong oxidizing agents in higher concentrations of bilirubin and lower
the presence of a transition metal, such as iron, concentrations of vitamin E, ß-carotene, and
by forming the reactive hydroxyl radical, OH-.12 glutathione compared to adults.23-25 Bilirubin has
The hydroxyl radical can combine with lipids protective antioxidant properties while deficien-
such as polyunsaturated fatty acids to form lipid cies in the antioxidants vitamin E, ß-carotene,
hydroperoxides and aldehydes, such as hydroxy- and glutathione are detrimental to antioxidant
pentenal, hydroxynonenal, nonadienal, decadi- activity. Superoxide dismutase activity is low in
enal, and malondialdehyde, which are all highly premature neonates compared to term neonates,
cytotoxic.12-17 This hydroxyl radical is also capable children and adults.26 This activity worsens with
of reacting with and damaging proteins and cell oxidative stress challenge. Apotransferrin and
components in the human body such as phos- ceruloplasmin have potent ferroxidase and ferric
pholipids, carbohydrates, metalloproteins, and ion sequestration properties, respectively. Their
DNA.12,13,18,19 Peroxidation can also cause a loss in antioxidant effect is approximately 200-500 times
quality and potency of TPN ingredients.20,21 Once more potent than vitamin E.27 However, both
initiated, the process of peroxide formation and of these antioxidants are also found in lower
oxidization will continue in biological systems concentrations in term neonates than adults and
until it is arrested by antioxidants. in premature neonates compared to term neo-
Free radical generation is adequately seques- nates.27,28 This may lead to more limited seques-
tered by antioxidants in the bodies of normal, tration of iron and copper, resulting in increased
healthy infants, children, and adults. Anti- catalysis of hydroxyl radicals.13 Increased radical
oxidants protect the human body from damage formation and reduced antioxidant scavenging
caused by free radicals. Vitamin E, vitamin C, and may exacerbate common disease states known
superoxide dismutase are the most important to present in premature neonates such as hy-
antioxidants in the human body.12 Vitamin E is poxic-ischemic encephalopathy, periventricular
the body’s most important extracellular lipid- leukomalacia, chronic lung disease, necrotizing
soluble antioxidant while vitamin C is the body’s enterocolitis, intraventricular hemorrhage, and
most important extracellular water-soluble an- retinopathy of prematurity.19,22,29
tioxidant.12 The superoxide dismutases are the Phototherapy lights commonly used in neo-
major intracellular antioxidant enzyme family nates with hyperbilirubinemia cause the forma-
in the body.12 Extracellular superoxide dismutase tion of lipid hydroperoxides to a greater extent
possesses only one three-thousandth of the ac- than ambient light alone, thereby increasing
tivity of intracellular superoxide dismutase.18 peroxide exposure to those neonates.30,31 Lipid
The superoxide dismutases are metalloprotein hydroperoxides may be responsible for increased
enzymes that catalyze the formation of superox- neonatal pulmonary vascular resistance and
ide to oxygen and H2O2.12 Hydrogen peroxide is vasoconstriction of umbilical veins. 30,32-34 The
converted to water by the intracellular enzymes vasoconstriction is thought to be caused by
glutathione peroxidase and catalase.12 Methio- lipid generated hydroperoxide inhibition of the
nine sulfoxide reductase is also an intracellular creation of prostaglandin I2 (PGI2), a vasodilator,

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JPPT Hoff DS, et al

from prostaglandin H2 and increased prostaglan- hours compared to yellow or black tubing, but
din F2α, a vasoconstrictor.34 it still generated significantly less peroxide than
the control solution. No difference in peroxide
METHODS formation was found between ambient light and
phototherapy among the systems studied. This
The references that support this review article study shows that color and transparency of light
were found by using a search conducted with the protection is important when choosing a product
MEDLINE database for published in vitro and for use in the pharmacy and on the patient care
in vivo research evaluating the effects of light on units. It also showed that yellow and black tub-
TPN. The search was conducted in August 2008. ing protected TPN solution the best, but orange
No time limit was put on the search. Search terms tubing still prevented a significant amount of per-
included: “pediatric,” “neonate,” “premature oxide formation. Yellow and orange tubing have
infant,” “children,” “total parenteral nutrition,” an advantage over black tubing because they are
“light,” “degradation,” “TPN,” “photoprotection” transparent, allowing the clinician to visualize air
and “light protection.” Other references were lo- bubbles and particulate matter in the line.
cated in the reference sections of the documents
obtained from the MEDLINE database search. Role of Oxygen in Peroxidation
The effect of oxygen exposure to TPN solu-
RESULTS tion is causative in the generation of peroxides.
One study compared peroxides generated from
Role of Light Protection Color in Peroxidation neonatal and adult lipid-free TPN with or with-
The color of light protection determines its abil- out oxygen washout by nitrogen and with and
ity to prevent the formation of peroxides in TPN without light exposure.36 The ferrous oxidation
and degradation of TPN components. Research of xylenol orange in methanol base (FOX-II) and
was conducted by a group of investigators that glutathione peroxidase assays were used to quan-
quantified the amount of peroxide generated by tify peroxides. Peroxide concentrations remained
five experimental TPN sets by varying the color less than 15 μmol/L in light exposed adult TPN
of IV tubing.35 A clear bag with clear tubing was solution, but light exposed neonatal TPN gen-
used as a control. The other four bags were cov- erated from 190 to 300 μmol/L of peroxides.
ered with opaque black plastic bags, but were Peroxide concentrations ranged from 60 to 130
connected to clear, orange, yellow, or black tub- μmol/L when neonatal TPN was protected from
ing. Lipid-free TPN was also compared to lipid- light. Removal of oxygen from a test solution
containing all-in-one total nutrient admixture of neonatal TPN inhibited peroxide formation.
(TNA). Both ambient light and phototherapy However, the effect was lost when the solution
were applied to the systems. The extent of per- was delivered through an IV infusion set. While
oxide formation in the presence of light over oxygen is an important cause of increased gen-
time was compared between the systems. The eration of peroxides when TPN is exposed to
investigators found that lipid-free TPN with a light, it would be difficult to consistently remove
clear bag and tubing had a 50% higher peroxide oxygen exposure from the system from the point
concentration than the light protected systems of compounding to patient delivery. This study
with colored tubing after 23 hours of light ex- showed that even if all of the air were withdrawn
posure. Peroxide concentrations did not differ from TPN and lipid bags to limit peroxide forma-
between the systems that used orange, yellow, or tion, the beneficial effect is lost when the solution
black tubing after 2 and 23 hours. The peroxide travels through IV tubing.
concentration in the TNA control solution with
a clear bag and tubing was significantly higher Role of Vitamins in Peroxidation
than in the lipid-free TPN with a clear bag and Several studies were conducted that analyti-
tubing. No difference was found in peroxide cally quantified vitamin degradation and perox-
formation in TNA systems with yellow and black ide formation in TPN solution upon continuous
tubing. However, the orange tubing used with exposure to light. One study was conducted to
the TNA solution was found to have greater than evaluate the effect of phototherapy and vitamin
a 50% rise in peroxide concentrations at 1 and 23 C on lipid hydroperoxide generation in lipid

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TPN Photoprotection in Neonates JPPT
emulsion.30 Lipid emulsion was prepared in a by the FOX-II assay. The lipid based emulsion
syringe connected to standard clear tubing. Sy- with FMN + vitamin C generated 12-fold more
ringes were glass, plastic, or plastic covered with peroxides than lipid alone and twice as much
aluminum foil. Tubing was exposed to either a peroxide as observed with the dextrose formu-
phototherapy spotlight or ambient room light lations. Peroxide formation of vitamin C and
throughout the study period. After 24 hours of FMN solutions in darkness remained low after
light exposure, all syringe reservoirs had an in- 24 hours. Vitamin C and FMN had a positive
crease in hydroperoxides by threefold (p<0.0005). concentration-dependent relationship on the gen-
Hydroperoxides increased an additional 65-fold eration of peroxides in dextrose solution exposed
from the syringe reservoir concentration when to light. Vitamin C provided a protective effect
exposed to phototherapy (p<0.0005). Hydroper- on peroxide generation in TPN in the absence
oxide formation was similar in the syringes that of FMN. Peroxide formation reached a plateau
were covered with aluminum foil and the sy- after 24 hours in systems studied up to 72 hours.
ringes that received vitamin C prior to exposure The findings from these two studies are con-
to ambient light. Vitamin E did not have an effect troversial because they used the FOX-II assay for
on hydroperoxide generation in lipid emulsion. quantification of peroxides from a lipid emulsion.
Two publications reported on experiments The FOX-II assay uses methanol that is intended
where a multivitamin preparation (MVP) with to draw lipid hydroperoxides from the aliphatic
vitamin C enhanced peroxidation when added phase of the experiment, but may still draw H2O2
to lipid emulsion. One analyzed how MVP in from aqueous components in the system. FOX is
TPN affected peroxide load in patients.37 The in- a non-specific measurement of all peroxides. The
vestigators compared TPN and TNA exposed to FOX-III, n-propanol based assay may draw less
6 hours of either daylight or darkness, with and H2O2 from the aqueous phase than the methanol
without MVP. General peroxide concentrations based FOX-II assay. Hydrogen peroxide gener-
were measured by the FOX-II assay. Exposure to ated and measured from either the FOX-II or
daylight for 6 hours had no effect on peroxide FOX-III assays may not be the result of lipid
content in TPN solutions not containing MVPs. peroxidation, but drawn unintentionally from
However, the authors did report that MVP added peroxidation of other, aqueous, components in
to TPN resulted in an immediate, 3-fold higher the experiment.39
peroxide content compared to either TPN or A study conducted by a different group of
TNA alone, with and without light exposure researchers used the FOX-III assay to evaluate
(p<0.001). The amount of peroxides in TNA solu- peroxide generation in a lipid emulsion with and
tion, with and without light exposure was greater without the addition of MVP.31 Lipid emulsion
than TPN. The amount of peroxide in TNA was without MVP generated approximately 1.5-fold
additive, not a compounding effect, compared more peroxides when exposed to phototherapy
to TPN. Eighty-eight percent of the peroxides light versus ambient light and significantly more
in the TNA admixture were H2O2. Amino acid peroxides under ambient light versus darkness
solution was found to have a protective effect (p<0.001). However, triglyceride hydroperoxide
on peroxide generation. In this study, the lesser formation was inhibited by the addition of MVP
concentrated amino acid solution was found to to light-exposed lipid emulsion, although ap-
generate a higher peroxide content than the more proximately 70% of the riboflavin (p<0.001) and
concentrated amino acid solution at a constant 11% of the vitamin C (p<0.01) was still degraded.
MVP concentration. Vitamin C loss increased to 80% after exposure
The other study found dextrose solutions with to 6 hours of phototherapy light.
vitamin C + 5’-phosphate flavin mononucleo- The same researchers published another study
tide (FMN) or FMN + polysorbates generated that further quantified lipid peroxide formation
peroxide concentrations that were greater than with three variations of the FOX assay compared
3-fold higher than the individual components to a catalase assay.39 The catalase assay is high
of the solution alone after 4 and 24 hours of performance liquid chromatography based and is
light exposure.38 FMN is the primary form of specific for lipid hydroperoxides because catalase
riboflavin (vitamin B2) found in the human body. degrades H2O2 in solution. The researchers found
General peroxide concentrations were measured that the FOX assays reported quite different

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JPPT Hoff DS, et al

amounts of peroxide depending on the amount of Different testing methods and research groups
MVP added to the solution with the FOX-I assay have confirmed these findings. Liberated per-
reporting higher peroxide concentrations than oxides may cause tissue damage. Degradation
the FOX-III assay and the FOX-II assay reporting of vitamin C and riboflavin may cause vitamin
much higher concentrations compared with the deficiencies in some patients.
FOX-I assay. The researchers also compared H2O2
concentrations in dextrose solution + MVP and Role of Trace Elements in Peroxidation
lipid emulsion + MVP either exposed to ambient The effect of trace elements on lipid emulsion
light or darkness. Hydrogen peroxide concentra- and TNA in light and darkness was reported
tions increased 40% less in lipid emulsion either in one publication.41 Lipid hydroperoxides in-
exposed to ambient light or darkness compared creased 6- to 9-fold (p<0.001) and pH decreased
to the dextrose + MVP solutions from 0 to 150 by 0.77 units (p<0.001) in the lipid emulsion
minutes. From these experiments, the research- mixed with trace elements kept in darkness
ers concluded that none of the FOX assays were compared to the control lipid emulsion. Lipid
reliable for accurately determining lipid hydro- hydroperoxides also increased significantly from
peroxide concentrations from the lipid phase in 0.04 to 0.19 mmol/L (p<0.01) and pH dropped
experiments of lipid emulsion containing MVP by 0.01 units in TNA mixed with trace elements
because of their variable activity when exposed kept under refrigeration in darkness compared
to MVP. They speculated that vitamin C may to control TNA. Lipid hydroperoxides increased
have interfered with the assays by either reducing significantly from 0.52 to 1.92 mmol/L (p<0.001)
ferric ions, generating H2O2 via autoxidation, or and pH decreased from 0.03 to 0.11 units in
because riboflavin may have reacted with oxygen TNA + trace elements versus TNA control, re-
in the presence of a reducing agent, producing spectively, at room temperature and exposed to
H2O2. The authors also concluded that MVP ambient light.
diminishes H2O2 generation if added to lipid
emulsion. Oxidative Stress and Nutrient Handling
One publication reported on the use of mass Investigators administered MVP in paren-
spectroscopy to measure vitamin C concentra- teral nutrition and lipid emulsion over 3 days in
tions in TPN after exposure to light for three newborn guinea pigs to determine if the mode
hours.40 The researchers documented degrada- of delivery of MVP affected nutrient disposition
tion byproducts in three types of solutions: or played a role in oxidant stress.42 The pups
MVP, vitamin C + riboflavin, and vitamin C + received TPN + MVP exposed to light, TPN +
H2O2 + Fe2+. All three solutions experienced ap- MVP protected from light, or lipid emulsion +
proximately a 50% reduction in vitamin C abun- MVP exposed to light. Urinary concentrations of
dance and developed the same five degradation creatinine, nitrogen, and vitamin C and hepatic
byproducts in the mass spectra fingerprint. The concentrations of vitamin A, vitamin E, vitamin
researchers conducted a separate experiment that C, isoprostanes, and glutathione were sampled.
compared the peroxide content of solutions of The investigators found that light exposed TPN
H2O2, vitamin C + H2O2, and vitamin C + H2O2 + + MVP was associated with a 40% higher con-
FeCl2. It showed that a similar peroxide concen- centration of urinary nitrogen (p<0.005) and a
tration was found in the H2O2 and vitamin C + 44% higher concentration of urinary vitamin
H2O2 solutions over time, but the peroxide con- C (p<0.05) compared to light protected TPN +
centration increased by greater than 60% within MVP. The hepatic vitamin C concentration was
30 minutes when Fe2+ was added to the vitamin 72% to 119% higher in the group that received
C + H2O2 solution, showing the importance of lipid emulsion + MVP compared to the other
iron as a transition metal. two groups (p<0.05). Hepatic concentrations of
In summary, the research conducted on mul- vitamin A, vitamin E, isoprostanes, and glutathi-
tivitamins show that vitamin C and riboflavin, one were similar between the groups. The light
in particular, are significantly involved in the protected TPN + MVP group and light exposed
formation of peroxides in light exposed TPN lipid emulsion + MVP group had similar urinary
solution, especially during phototherapy, and excretion of nitrogen and vitamin C. Urinary
are themselves significantly degraded by light. creatinine was similar between the groups. Total

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TPN Photoprotection in Neonates JPPT
peroxides were similar in the light exposed TPN concentrations (p<0.01), a marker of free radical
+ MVP group and lipid emulsion + MVP group attack, compared to the comparator light pro-
and 46% higher than the light protected TPN + tected solutions. Light exposed riboflavin-free
MVP group. The authors believed that vitamin C MVP solution and control solution had similar
protected MVP solution from lipid peroxidation. low scores of hepatic steatosis (p=NS), suggest-
ing an active role of riboflavin in the formation
Hepatic Effects of TPN Exposed to Light and of hepatic steatosis.
Peroxides The role of oxidant-antioxidant imbalance on
The hepatobiliary effects of protecting TPN decreased bile flow was determined by feeding
from light were studied in a number of inves- guinea pig pups 3 days of either light exposed
tigations in both the rat and guinea pig model. TNA, TNA + enteral feeding, 1% MVP solution,
However, the guinea pig model is believed to be 3% MVP solution, H2O2 solution, or control en-
more desirable because guinea pigs are the only teral feeding.43 Pups fed TNA with or without
animal species other than humans and primates enteral feedings had significantly heavier livers
that cannot synthesize vitamin C. Newborn and a 50% decrease in bile flow. Bile flow was
guinea pigs also have immature glutathione significantly lower in pups fed TNA versus 1%
synthesis that is similar to newborn humans.43 or 3% MVP solution even though the 3% MVP
In a study in the guinea pig model, H2O2 in solution had the highest amount of peroxides
dextrose + NaCl, tert-butylhydroperoxide (TBH) in solution in the study. Bile flow was similar
in dextrose + NaCl, MVP + dextrose + NaCl, between 0% MVP solution, 0% MVP solution +
or control solution of dextrose + NaCl was in- H2O2, and 3% MVP with sodium metabisulfite (to
fused over 4 days.44 Study animals and solution quench the peroxides) indicating that peroxide
were exposed to 12 hours of light per day. The content does not explain the reduction in bile
concentrations of H2O2 and TBH in the study flow seen with TNA.
solutions approximated the amounts found in Investigation into the effect of potentially toxic
MVP solution. After the infusions were com- byproducts from the interaction of riboflavin-
pleted, the hepatic glutathione content (p<0.01) induced H2O2 on vitamin C was studied in new-
and a free-radical sensitive marker, PGI2/total born guinea pigs.21 Researchers administered a
prostaglandin ratio (p<0.01), were both reduced control solution of amino acids with or without
in the groups administered solutions contain- riboflavin and with or without light exposure to
ing H2O2 and TBH. However, the solution that the pups for 3 days. Degradation of the amino
contained MVP did not statistically significantly acid formulation was significantly increased with
affect hepatic glutathione content or PGI2/total time (p<0.01) and the presence of light exposure
prostaglandin ratio compared to the control solu- (p<0.01) and riboflavin (p<0.01). H2O2 and pho-
tion. These findings show that peroxides oxidize toexcited riboflavin induced the transformation
membrane-bound prostaglandins and probably of dehydroascorbate into new, biologically ac-
consume protective glutathione, but MVI may tive peroxide and aldehyde molecules. High
be hepatoprotective. concentrations of the degradation molecules
Another study of guinea pig pups was de- were infused into the pups, causing an increase
signed to assess hepatic damage from light in hepatic acetyl-coA carboxylase (ACC) activity
exposed TPN or two types of MVP in control (p<0.01). ACC regulates hepatic fatty acid syn-
solution.45 Pups were randomized to intrave- thesis and mitochondrial oxidation. Increased
nously receive 4 days of either MVP in control hepatic ACC activity was not seen in pups that
solution (i.e., dextrose + NaCl) exposed to light, received light protected amino acid solution.
MVP in control solution protected from light, It is not clear from the evidence found in these
MVP in control solution exposed to light without investigations of guinea pigs if light exposed
riboflavin, TPN exposed to light, TPN protected MVP is hepatoprotective for oxidant damage
from light, or control solution. Pups that received in control solution, but histological and bio-
either light exposed MVP in control solution or chemical evidence shows that hepatic steatosis,
TPN were found to have more hepatic steatosis increased liver weight, and higher hepatic ACC
on histological examination (p<0.05), larger and isoprostane F2α concentrations result from
liver weight (p<0.05), and higher isoprostane F2α infusing TPN that has been exposed to light.

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JPPT Hoff DS, et al

These markers of damage are apparent in as little exposed MVP + control, light protected or ex-
as 3-4 days of receiving light exposed TPN and posed TPN, H2O2 + control, H2O2 + glutathione
TNA. Among the MVPs, riboflavin may provide + control, and 5% dextrose + 0.45% NaCl control.
a unique contributory role in the development of Light exposed MVP + control, light protected
hepatic steatosis. The effect of light exposure on TPN, and light exposed TPN pups had increases
TNA in bile flow was not conclusive since light of 67%, 93%, and 175%, respectively, in pulmo-
protected TNA was not used in the control arm. nary procollagen α1 (I) mRNA and 58%, 189%,
Rat studies of light exposed TPN report simi- and 244%, respectively, in pulmonary glutathione
lar findings of hepatotoxicity as in guinea pigs. compared to the light protected MVP group.
Light exposure to TPN was found to decrease These increases in procollagen α1 (I) mRNA and
bile flow and increase hepatic necrosis, portal glutathione were significantly higher in both TPN
tract inflammation, biliary concentrations of inor- groups compared to the light protected MVP
ganic phosphate, a marker of leaky cellular tight group (p<0.05) and higher in the light exposed
junctions, and biliary concentrations of oxidized TPN group compared to the light protected TPN
glutathione, an antioxidant that is produced pri- group (p<0.01). Light exposed MVP and higher
marily by the liver.46,47 potency H2O2 each had a similar increase in pro-
collagen α1 (I) mRNA (p<0.01) and glutathione
Pulmonary Effects of TPN Exposed to Light and (p<0.05) compared to control.
Peroxides Another study compared H2O2, MVP, and light
Several studies have been conducted to evalu- exposure on lung remodeling in newborn guinea
ate the effect of light exposed TPN on indicators pigs.51 TPN or MVP with or without light protec-
of pulmonary damage in newborn guinea pigs. tion, H2O2 with or without glutathione, MVP
One study measured the oxidant effect of light ex- with or without metabisulfite, vitamin C with or
posed solutions of MVP + control solution, TPN, without riboflavin, and control were compared.
TPN + MVP, and dextrose + NaCl + heparin con- Light exposed TPN solution had 18% fewer
trol in newborn guinea pig pups.48 After 4 days alveolar intercepts (p<0.01), a count of alveoli
of administration of study solution, the peroxide on a standardized microscopic preparation of
concentrations were similar in the MVP groups histological lung specimens, and a 3-fold higher
compared with a group that received H2O2 + con- percentage of apoptotic lung tissue (p<0.01) com-
trol. Pulmonary glutathione decreased by 25% in pared to light protected TPN. Similar findings
the MVP + control group (p<0.05) and increased were recorded for light exposed MVP compared
by 41% in the groups treated with TPN solution with light protected MVP. The alveolarization
(p<0.001). Pulmonary glutathione was measured index was also significantly lower in animals that
because it is a key antioxidant in the lungs, pos- received vitamin C plus riboflavin compared to
sessing antiradical and antiperoxide properties. the solutions not containing riboflavin.
The ratio of pulmonary (PGE2 + PGF2α)/total The degree of pulmonary fibrosis and alveolar
prostaglandins was increased compared to con- damage was studied in newborn guinea pigs that
trol in the MVP + control (p<0.001) and TPN + received 4 days of ambient light exposed TPN +
MVP groups (p<0.001), but statistically similar to MVP, lipid emulsion + MVP, or control solution
control in the TPN group. The rise in the (PGE2 in an effort to determine if the lipid emulsion
+ PGF2α)/total prostaglandins ratio is important adequately protected peroxide degradation of
because the enzyme that is responsible for 80% MVP.29 The researchers found that the TPN +
of the degradation of these prostaglandins is MVP group had higher pulmonary procollagen
inhibited by oxidation. A rise in the ratio may α1 (I) mRNA concentrations than the lipid emul-
indicate oxidative challenge in the lungs.49 sion + MVP group (p<0.05), but the lipid emul-
Pulmonary fibrosis and oxidation from light sion + MVP group also had significantly higher
exposed TPN elements were estimated by the pulmonary procollagen α1 (I) mRNA concentra-
measurement of pulmonary procollagen α1 (I) tions compared to the control group. Both groups
mRNA concentrations, a precursor of pulmonary had a similar lower number of alveolar intercepts
fibrosis, and pulmonary glutathione concentra- compared to controls (p<0.05), indicating loss of
tions in the lungs of newborn guinea pigs.50 Pups lung tissue.
were administered 4 days of light protected or Similar to the negative hepatic evidence found

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TPN Photoprotection in Neonates JPPT
in the guinea pig and rat models, light exposed protected TNA.14 MDA is a cytotoxic aldehyde
TPN has been shown to increase apoptotic lung oxidation byproduct. The MDA concentration of
tissue, decrease alveolar intercepts, increase pul- TNA solution increased from 152 to 335 nmol/L
monary procollagen α1 (I) mRNA, a precursor of (p<0.001) after being stored for 24 hours in dark-
pulmonary fibrosis, and increase pulmonary glu- ness, but equivalent solutions increased from 179
tathione and (PGE2 + PGF2α)/total prostaglandin to 13,880 nmol/L (p<0.001) after light exposure
ratio, indicating a pulmonary oxidant challenge. over the same time period. The average serum
Lipid emulsion + MVP also causes a decrease in MDA concentration measured in the enterally
alveolar intercepts and an increase in pulmonary fed newborns was 173 nmol/L. This implied
procollagen α1 (I) mRNA concentrations. Among that TNA causes an infusion of extra MDA into
the vitamins, light exposed riboflavin may have newborns above concentrations normally found
a unique and negative impact on the integrity of in the body. The exposure is much greater with
lung tissue. In summary, these investigations of light exposed TNA.
guinea pigs shows that pulmonary damage and One study measured antioxidant concentra-
a significant response to antioxidant challenge tions in 60 term and preterm infants that received
results in animals that receive light exposed TPN, enteral feeding, enteral feeding + TPN, and
MVP, and riboflavin solutions for even short TPN.53 Additional vitamin C (preterm, 25 mg/
periods of time. kg/day; term, 80 mg/day) was added to the TPN
solutions as an antioxidant. Plasma antioxidant
HUMAN RESEARCH concentrations were measured at baseline and on
the first and fifth days of study feeding. After the
A number of studies have been conducted that first and fifth study days, plasma MDA, super-
quantify peroxide and aldehyde byproducts, oxide dismutase (SOD), vitamin C, and vitamin
metabolic effects and clinical outcome of preterm E concentrations were not significantly differ-
infants that received light exposed TPN. In one ent in any of the groups compared to baseline.
study, investigators compared urinary peroxide However, term infants who were given enteral
excretion in 30 preterm infants, less than or equal feeding + TPN or TPN alone had higher MDA
to 32 weeks gestation at birth, who received concentrations before starting TPN compared to
10% dextrose, dextrose + amino acids, TPN, or the fifth study day, possibly indicating that the
TNA.52 Urinary peroxide concentrations were additional vitamin C was acting as an antioxidant
determined on day 0 with 10% dextrose and in the patients. No differences were found be-
again on days 1 and 2 of study solution. The tween term and preterm infants when evaluating
groups of infants that received light exposed SOD, vitamin E, and vitamin C concentrations,
TPN and TNA had similar higher urine perox- though preterm infants in the study had an older
ide concentrations compared to the dextrose + mean age (32 weeks gestational age at birth) than
amino acids group and the 10% dextrose baseline in other studies.
control (p<0.01). Photoprotection prevented the One group of researchers studied the effect of
rise in urinary peroxide excretion in the TPN light exposure on TPN and its effect on estab-
group. Patients that received light exposed TPN lishing minimal enteral nutrition in 128 preterm
+ MVP had higher urinary peroxide concentra- infants.54 Infants were randomized either to light
tions than light exposed TPN without MVP (14.7 protected TPN or light exposed TPN. Light pro-
vs. 74.5 micromol/L; p<0.05). The study findings tection was provided through the use of amber
suggested an inadequate peroxide quenching tubing and opaque black plastic coverings for the
mechanism in premature neonates, an active bag and syringe. Minimal enteral nutrition was
renal peroxide excretion mechanism, or both. No initiated by the use of a standardized protocol
correlation was found between urine peroxide and increased at the discretion of the clinicians.
concentrations and post-natal age, sex, use of The researchers found that infants in the light
oxygen supplementation, or phototherapy. protected TPN group had significantly faster
Another group of researchers compared daily advancement of minimal enteral nutri-
plasma malondialdehyde (MDA) concentra- tion (p<0.05) and cumulative feeding volumes
tions of 54 enterally fed newborn infants with (p<0.001) compared to the light exposed group
concentrations found in light exposed and light during the first week of the study. The study

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JPPT Hoff DS, et al

authors hypothesized that TPN light exposure (p<0.001). However, the number of patients
may have produced peroxides that, in turn, presenting with hyperglycemia and the number
caused mesenteric vasoconstriction and reduced of patients requiring insulin for hyperglycemia
feeding tolerance. was statistically similar between the groups.
The effect of light exposed TPN on the risk of Studies of light exposed TPN and TNA provide
chronic lung disease was studied in 77 premature evidence of slower advancement to minimal en-
neonates.55 Neonates were randomized to either teral nutrition and cumulative feeding volumes,
light protected or light exposed TPN from birth. increased urinary peroxides, and increased plas-
Light protection was applied to both the TPN ma triglycerides and glucose concentrations in
and lipid emulsion. A standardized protocol was preterm neonates compared to preterm neonates
used to advance TPN. Post hoc analysis found that received light protected TPN. Adding addi-
that light protected TPN was associated with a tional Vitamin C to TPN may reduce the plasma
30% relative reduction in chronic lung disease concentrations of MDA in patients. Research
or death compared with the light exposed TPN determining the effect of light exposed TPN on
group, but the result was not statistically sig- clinical outcomes such as chronic lung disease
nificant (p<0.2). A sample size of 300 would be has not yet been completed with an adequate
required to answer the question. Chronic lung sample size to determine if a clinical benefit of
disease and death was significantly more com- light protecting TPN exists.
mon in males compared to females as seen in
other reports. DISCUSSION
Variations in metabolic response were studied
in 45 premature infants randomized to either Free radicals, peroxides, and aldehydes are
light protected or light exposed TPN from birth.56 commonly found in the bodies of newborn
Light protection was applied to both the TPN animals and premature infants. A significant
and lipid emulsion. TPN advancement was exogenous source of these byproducts is adminis-
standardized according to a protocol. The effects tered to the patient via TPN. Laboratory research
of light exposure on TPN were assessed once shows that light protecting TPN with dark bags
the TPN reached the full rate (approximately 7 and with colored plastics limit peroxide and
days). The average peroxide concentration was MDA formation and degradation of TPN compo-
30% higher in light exposed TPN compared to nents. Furthermore, studies in laboratory animals
light protected TPN. However, no difference shows that light exposed TPN can cause hepatic
was found between the light exposed and light damage, steatosis, cholestasis, and pulmonary
protected TPN subjects with regard to average oxidant challenge, remodeling, apoptosis, and an
urinary nitrogen concentration. increased marker for pulmonary fibrosis. Human
Researchers investigated the impact of research has found increased urinary peroxide
light protection of TPN on plasma glucose and and plasma aldehyde concentrations, longer time
triglycerides over the first 9 days of life in 59 to minimal and cumulative enteral feeding, and
preterm infants.57 Infants were randomized to increased plasma glucose and triglycerides in
either light protected or light exposed TPN from preterm infants that received light exposed TPN.
birth. TPN and lipid dosing was increased up A drawback of achieving light protection of
to a pre-defined maximum rate. Study subjects TPN and lipid in clinical practice is the lack of
were excluded from data analysis if enteral availability of marketed light protection devices
feeding reached 5 mL/kg/day or more. Subject such as colored TPN and lipid bags and syringes.
demographics, macronutrient TPN intakes, and Instead, dark opaque and amber plastic bags are
amount of enteral feedings were similar between available for a low cost and may be used to facili-
the two groups. Plasma triglyceride concentra- tate protecting TPN and lipid bags and syringes
tions increased at a 2.5 times higher rate over time from light after preparation, during delivery to
in the light exposed group compared to the light the patient care unit, and during infusion into
protected group, achieving statistical significance the patient. Use of these coverings is adequate
on days 8 and 9 of life (p<0.05). Blood glucose to provide some light protection, but coverage is
concentrations over the first 9 days of life were not complete and the coverings take more time to
significantly higher in the light exposed group apply during the TPN preparation process than

140 J Pediatr Pharmacol Ther 2009 Vol. 14 No. 3 • www.jppt.org

TPN Photoprotection in Neonates JPPT
if the bags and syringes were available in light 2. Denne SC. Protein and energy require-
protection colors from vendors. Furthermore, ments in preterm infants. Semin Neonatol
dark plastic and foil that covers TPN and lipids 2001;6:377-382.
may cause a safety concern because they require 3. Chaudhari S, Kadam S. Total paren-
nurses and other practitioners to lift the cover- teral nutrition in neonates. Indian Pediatr
ing to view the pharmacy label that is affixed to 2006;43:953-964.
the container. Pharmacy labels could be directly 4. Thureen PJ, Hay WW Jr. Early aggressive
applied to the external surface of the TPN and nutrition in the preterm infant. Semin Neo-
lipid bags and syringes if the bags and syringes natol 2001;6:403-415.
were manufactured with light protection in the 5. Hay WW Jr. Nutritional requirements of
plastic. However, as opposed to TPN and lipid extremely low birthweight infants. Acta
bags and syringes, amber-orange colored IV tub- Paediatr Suppl 1994;402:94-99.
ing is available for purchase for light protection 6. van Lingen RA, van Goudoever JB, Luijen-
while still allowing the nurse to observe the IV dijk IHT, et al. Effects of early amino acid
line for air bubbles, precipitates, or leaks. The administration during total parenteral nu-
colored tubing offers a significant advantage trition on protein metabolism in pre-term
over older methods of tubing light protection infants. Clin Sci (Lond) 1992;82:199-203.
such as tubular amber plastic, aluminum foil, or 7. American Gastroenterological Association.
fabric coverings because these former methods American Gastroenterological Association
required extensive manual manipulation and medical position statement: parenteral nu-
they obscured the patency and integrity of the trition. Gastroenterology 2001;121:966-969.
IV fluid path. 8. Stewart CF, Hampton EM. Effect of matu-
ration on drug disposition in pediatric
CONCLUSION patients. Clin Pharm 1987;6:548-564.
9. Besunder JB, Reed MD, Blumer JL. Princi-
The absence of larger human clinical outcomes ples of drug biodisposition in the neonate. A
studies precludes light protection of TPN compo- critical evaluation of the pharmacokinetic-
nents from becoming a global recommendation at pharmacodynamic interface (Part 1). Clin
this time. However, it would seem prudent to use Pharmacokinet 1988;14:189-216.
this non-invasive approach, given the available 10. Bombell S, McGuire W. Delayed introduc-
data, to light protect TPN components from the tion of progressive enteral feeds to prevent
point of arrival in the pharmacy throughout the necrotizing enterocolitis in very low birth
duration of TPN administration on the patient weight infants. Cochrane Database Syst Rev
care unit until more conclusive human studies 2008;16:CD001970.
are forthcoming. 11. McGuire W, Bombell S. Slow advance-
ment of enteral feed volumes to prevent
DISCLOSURE The authors declare no conflicts or finan- necrotizing enterocolitis in very low birth
cial interest in any product or service mentioned in the weight infants. Cochrane Database Syst Rev
manuscript, including grants, equipment, medications, 2008;16:CD001241.
employment, gifts, and honoraria. 12. Graham EM, Mishra OP, Delivoria-Papa-
dopoulos M. Anti-oxidants and oxidative
ACKNOWLEDGMENT Portions of data that appear in this
manuscript were presented by Dr. Michaelson at the An-
stress injuries to the brain in the perinatal
nual Meeting of the American College of Clinical Pharmacy period. Semin Neonatol 1998;3:75-85.
in Denver, Colorado on October 16, 2007. 13. Pitkänen OM. Peroxidation of lipid emul-
sions: a hazard for the premature infant
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