Parenteral nutrition and oxidant stress in the newborn: A narrative review.

There is strong evidence that oxidant molecules from various sources contaminate solutions of parenteral nutrition following interactions between the mixture of nutrients and some of the environmental conditions encountered in clinical practice. The continuous infusion of these organic and nonorganic peroxides provided us with a unique opportunity to study in cells, in vascular and animal models, the mechanisms involved in the deleterious reactions of oxidation in premature infants. Potential clinical impacts of peroxides infused with TPN include: a redox imbalance, vasoactive responses, thrombosis of intravenous catheters, TPN-related hepatobiliary complications, bronchopulmonary dysplasia and mortality. This is a narrative review of published data.

Shielding Parenteral Nutrition From Light Improves Survival Rate in Premature Infants.

BACKGROUND: Intravenous nutrition preparations that are not photoprotected generate oxidants, which are deleterious for cell survival. The question remains: are these observations of clinical relevance in individuals receiving parenteral nutrition (PN), especially in those who exhibit immature antioxidant defenses such as premature infants? OBJECTIVE: To review clinical trials reporting the effect of light-exposed vs light-protected PN to determine whether photoprotection reduces neonatal mortality in preterm infants. DATA SOURCE: Electronic databases, abstracts in relevant journals, and references in manuscripts between 1980 and 2014. SELECTION CRITERIA: Newborn, premature infants, PN, photoprotection, shielding from light, randomization, mortality, death. METHODS: Consensus for inclusion reached by 2 reviewers; meta-analysis of trials and observational studies reporting mortality at 36 weeks' gestational age or hospital discharge. RESULTS: Four trials meeting selection criteria, which involved a total of 800 newborn premature infants, were included. Across trials, gestational age (mean ± SD) ranged from 26 ± 1 to 31 ± 2 weeks, birth weight from 775 ± 161 to 1588 ± 366 g, and mortality from 5%-32%. Mortality in the light-protected group was half of that in the light-exposed group (95% confidence interval, 0.32-0.87) and twice as high in males compared with females (χ2, P = .01). CONCLUSION: Shielding PN from light has vital repercussions that call for action to provide photoprotected delivery systems and infusion sets in premature infants. Further studies should be extended to the increasing number of children and adults receiving long-term home PN to evaluate the effects of light protection on severe complications that impede their quality of life.

Influence of shielding TPN from photooxidation on the number of early blood transfusions in ELBW premature neonates.

OBJECTIVES: The smallest premature neonates often receive blood transfusions early in life. Nonrestrictive transfusion policies are linked to deleterious outcomes. Exposure of total parenteral nutrition (TPN) to ambient light generates oxidation products associated with haemolysis in vitro. Shielding TPN from light limits oxidation. Our hypothesis was protecting TPN from light decreases haemolysis and therefore the need for early blood transfusions. METHODS: Comparison of haemolysis between animals fed enterally and those receiving TPN, and exploratory case-control retrospective analysis of transfusion counts in premature infants receiving light-exposed or light-protected TPN. The statistical analysis was analysis of variance and longitudinal binomial regression model adjusting for potential covariables of transfusion counts. RESULTS: In animals, TPN is associated with higher (P<0.05) haemolysis compared with enteral feeds; photoprotection induces lower peroxide load with no effect on the level of haemolysis. In premature infants, light-exposed (n=76) or light-protected (n=57) populations exhibited similar clinical characteristics. Initial haematocrit, gestational age, and index of disease severity had a significant effect on the number of transfusions. When adjusting for these covariables, photoprotection was no longer significant. CONCLUSIONS: Even though peroxides are associated in vitro with haemolysis, shielding TPN from light to reduce infused peroxides does not significantly decrease the need for early transfusions in premature infants.

Determinants of oxidant stress in extremely low birth weight premature infants.

Early in life, premature neonates are at risk of oxidant stress. They often require total parenteral nutrition (TPN), which is, however, contaminated with oxidation products. Coadministration of parenteral multivitamins (MVP) with a lipid emulsion (LIP) prevents lipid peroxidation. We hypothesized that LIP+MVP induces a lower oxidant load compared to preparations in which MVP is administered with an amino acid solution (AA+MVP). The aim of this study was to compare markers of oxidant stress in premature neonates receiving LIP+MVP, either exposed to or protected from light, or AA+MVP. Antioxidant vitamins, the redox potential of glutathione, isoprostane, and dityrosine were measured in urine or blood sampled on days 7 and 10 from babies requiring low (<0.25) vs high (≥0.25) fractional inspired O(2). Oxygen supplementation induced a more oxidized redox potential and increased dityrosine with AA+MVP only. Adding MVP in the lipid rather than the amino acid moiety of TPN protects against the oxidant stress associated with O(2) supplementation. Photoprotection added no benefit. Blood transfusions were found to produce a pronounced oxidant load masking the beneficial effect of LIP+MVP. The impact of these findings relates to a strong association between a more oxidized redox potential and later bronchopulmonary dysplasia, a clinical marker of oxidant stress.

Inflammatory response in preterm infants is induced early in life by oxygen and modulated by total parenteral nutrition.

The i.v. lipid emulsion (LIP) is a source of oxidants, which may stimulate inflammation. Coadministration of parenteral multivitamins (MVP) with LIP prevents lipid peroxidation in light-exposed total parenteral nutrition (TPN). We hypothesized that this modality of TPN administration affects systemic inflammation, which may be modulated by exposure to oxygen. Premature infants were allocated to three TPN regimens: control regimen - MVP coadministered with amino acid/dextrose exposed to ambient light, LIP provided separately (n = 9) - LIP+MVP light exposed (LE): MVP coadministered with light-exposed LIP (n = 9) - LIP+MVP light protected (LP): MVP coadministered with light-protected LIP (n = 8). In LE and LP, amino acid/dextrose was provided separately. On reaching full TPN, infants were sampled for IL-6 and IL-8 in plasma and the redox potential of glutathione in whole blood (E, mV). Data were compared (ANOVA) in infants exposed to low (<0.25) versus high (> or =0.25) FiO2. Patients (mean +/- SD: birth weight 797 +/- 172 g; GA 26 +/- 1 wk) had similar clinical characteristics in TPN groups. Cytokine levels correlated positively (p < 0.01) with FiO2 and E. High FiO2 stimulated an increase (p < 0.01) in cytokines in control regimen, whereas these markers remained unaffected by oxygen in the LE and LP groups. The choice of a TPN admixture may have important consequences on the systemic inflammatory response triggered by an oxidant stress.

Neonatal exposure to oxidants induces later in life a metabolic response associated to a phenotype of energy deficiency in an animal model of total parenteral nutrition.

Failure to protect total parenteral nutrition (TPN) from ambient light exacerbates the generation of peroxides, which affects blood glucose and plasma triacylglyceride (TG) in neonates. Based on the concept that the origin of adult diseases can be traced back to perinatal life, it was hypothesized that neonatal exposure to peroxides may affect energy availability later in life. Three-day-old guinea pigs, fitted with a jugular catheter, were fed regular chow (sham) +/- i.v. 350 microM H2O2 (sham + H2O2) or nourished with light-protected TPN [TPN(-)L, 209 +/- 9 microM peroxides] or light-exposed TPN [TPN(+)L, 365 +/- 15 microM peroxides]. After 4 d, infusions were stopped and animals fed chow. Spontaneous ambulatory movements, fasting blood glucose, glucose tolerance, TG, hepatic activities of glucokinase, phosphofructokinase (key enzymes of glycolysis), and acetyl-CoA carboxylase (key enzymes of lipogenesis) were determined at 12-14 wk and compared by ANOVA (p < 0.05). Relative to sham, the animals from sham + H2O2, TPN(-)L and TPN(+)L groups had lower plasma TG explained for 36% by low phosphofructokinase activity; they had lower glucose tolerance, lower body weight, and lower physical activity. In conclusion, neonatal exposure to oxidant molecules such as peroxides has important consequences later in life on lipid and glucose metabolism leading to a phenotype of energy deficiency.

Vitamin A is systemically bioavailable after intratracheal administration with surfactant in an animal model of newborn respiratory distress.

Chronic lung disease (CLD) is a major cause of long-term morbidity in extremely LBW infants with respiratory distress syndrome. Parenteral vitamin A administration decreases the risk of CLD. We tested the hypothesis that intratracheal vitamin A administration with surfactant is systemically bioavailable without interfering with the functional properties of exogenous surfactant. Newborn piglets were ventilated with 100% FiO2 and sequential saline lavage induced respiratory distress syndrome. During lung injury induction, ventilator changes were allowed, but none were made following treatment allocation. Animals were assigned by chance in a blinded control trial to three groups: I=control; II=surfactant; III=surfactant+vitamin A. Hemodynamics, lung mechanics, and blood gases were measured following instrumentation, pre- and posttreatment for 4 h, at which time the liver was sampled for retinol determination. All parameters improved in animals receiving surfactant. A significant interaction existed between time and group for PaO2 and alveolar-arterial oxygen difference (A-aDO2). Hepatic levels of retinol were higher (p<0.001) in animals receiving retinyl acetate. Intratracheal administration of surfactant+vitamin A did not alter the beneficial effects of surfactant on lung compliance and gas exchange. Intratracheal Vitamin A was associated with rapid hepatic uptake. Further studies are warranted.

Early life events, sex, and arterial blood pressure in critically ill infants.

OBJECTIVE: To determine whether photo-protecting total parenteral nutrition in preterm infants influences arterial blood pressure differently according to gender. Blood pressure is influenced by complex mechanisms of vasomodulation. Oxidants are mediators and effectors in such reactions. Shielding total parenteral nutrition from light contributes to decrease the generation of peroxides. Girls may be better protected against an oxidant load than boys. We questioned whether shielding total parenteral nutrition may have cardiovascular effects that are influenced by gender. DESIGN: A post hoc subgroup analysis of the effect of shielding parenteral nutrition from light. SETTING: Neonatal intensive care unit. SUBJECTS: Preterm infants <1000 g with indwelling arterial catheters who received light exposed (n = 20) or light protected (n = 20) parenteral nutrition. INTERVENTIONS: Invasive monitoring, total parenteral nutrition. MEASUREMENTS AND MAIN RESULTS: Arterial blood pressure was recorded hourly and compared between light exposed and light protected over the first week of life; timed average maximum velocity (m/s) was measured in the superior mesenteric artery by Doppler; presence of ductus arteriosus was documented by cardiac ultrasound. Data were analyzed by analysis of variance. No differences were noted between light exposed and light protected in clinical determinants that may influence blood pressure. There was an interaction (p < .01) between gender and total parenteral nutrition on blood pressure. In girls (n = 17), systolic and diastolic blood pressures were higher (p < .01) and heart rate lower (p < .01) during light exposed. There was no effect on BP observed in boys (n = 23). The linear correlation between timed average maximum velocity and systolic blood pressure was positive (p < .05). There was no echocardographic difference in hemodynamic variables between boys (n = 21) and girls (n = 9) who had a patent ductus. CONCLUSION: Failure to shield total parenteral nutrition from light results in higher blood pressure in a selected population of critically ill female infants. This information adds to our understanding of the multiple determinants involved in optimizing arterial blood pressure in a critical care environment.

Surface activity of surfactant spiked with vitamin A.

BACKGROUND: Intramuscular injections of vitamin A decrease the risk of broncho-pulmonary dysplasia. Admixture of vitamin A with surfactant as a lipophilic vehicle might be a less invasive modality. AIM: Test physical properties of surfactant + vitamin A. METHODS: Miscibility and surface activity were tested in surfactant supplemented with retinyl-acetate, -palmitate, 13-cis-, or all-trans-retinoic acid. RESULTS: Retinol acetate (5000 IU/mL) demonstrated miscibility with surfactant when premixing with ethanol. Its surface activity was 40% lower compared to surfactant alone. CONCLUSION: These findings warrant preclinical studies to test whether administration of vitamin A in subjects requiring surfactant is associated with beneficial functional properties.

Shielding parenteral nutrition from light: does the available evidence support a randomized, controlled trial?

BACKGROUND: Exposure of total parenteral nutrition to ambient light induces the generation of peroxides, creating oxidant stress, which potentially compounds complications of prematurity. Photograph protection of total parenteral nutrition reduces the peroxide load and has been shown to be associated with nutritional and biochemical benefits in animals and humans. It is unclear whether this reduction in peroxides from total parenteral nutrition leads to a reduction in the complications of prematurity, such as bronchopulmonary dysplasia. Our hypothesis was that shielding total parenteral nutrition from ambient light is linked to clinical benefits. OBJECTIVE: The purpose of this work was to determine whether photograph protection of total parenteral nutrition (light protected), as compared with no photoprotection (light exposed), reduces the occurrence of bronchopulmonary dysplasia or death in preterm infants. METHODS: The Canadian Neonatal Network provided data for infants born in 2006 at <28 weeks' gestation admitted to level 3 NICUs in Canada. A retrospective analysis was performed comparing bronchopulmonary dysplasia and death in infants who received light-exposed or light-protected parenteral nutrition. Data were analyzed by using logistic regression models. RESULTS. Thirteen NICUs offered partial light-protected (total parenteral nutrition bag only, intravenous tubing exposed) and 13 offered light-exposed parenteral nutrition; not a single NICU offered complete light-protected parenteral nutrition (total parenteral nutrition bag plus intravenous tubing). The incidence of bronchopulmonary dysplasia or death was 66% with light-protected (n = 428) vs 59% with light-exposed (n = 438) parenteral nutrition. CONCLUSIONS: Partial photograph protection of total parenteral nutrition was not associated with a reduction in bronchopulmonary dysplasia or death as compared with no photograph protection; this relationship is confounded by covariates with strong associations with bronchopulmonary dysplasia. Partial photograph protection of total parenteral nutrition solutions confers no clinical benefit, while consuming valuable resources. A randomized, controlled trial is justified to determine whether there is a true "cause-and-effect" relationship between complete photoprotection of total parenteral nutrition and bronchopulmonary dysplasia or death.

Impact of shielding parenteral nutrition from light on routine monitoring of blood glucose and triglyceride levels in preterm neonates.

BACKGROUND: Premature infants are vulnerable to complications related to oxidative stress. Exposure to light increases oxidation products in solutions of total parenteral nutrition (TPN) such as lipid peroxides and hydrogen peroxide. Oxidative stress impairs glucose uptake and affects lipid metabolism. HYPOTHESIS: products of photo-oxidation contaminating TPN affect lipid metabolism. OBJECTIVE: Evaluate the effect of photoprotection of TPN in preterm infants on plasma glucose and triglyceride (TG) concentrations. DESIGN: Secondary analysis of a prospective study allocating preterm infants to light-exposed (LE, n = 32) or light-protected (LP, n = 27) TPN. SETTING: Level III NICU referral centre for patients of British Columbia. PATIENTS: Preterm infants requiring TPN. INTERVENTIONS AND OUTCOME MEASURES: TG and blood glucose measured during routine monitoring while on full TPN were compared between LE and LP. RESULTS: Clinical characteristics were similar between the two groups (gestational age 28+/-1 wk; birth weight: 1.0+/-0.1 kg). Nutrient intakes from TPN and from minimal enteral nutrition were comparable between LE and LP. Blood glucose was higher in preterm infants receiving LE (p<0.001). The accumulation of TG with increasing lipid intake was twice as high with LE accounting for significantly higher TG levels on days 8 and 9 (p<0.05). CONCLUSIONS: Failure to photoprotect TPN may cause alterations in intermediary metabolism. Shielding TPN from light provides a potential benefit for preterm infants by avoiding hypertriglyceridaemia allowing for increased substrate delivery.

Influence of lung oxidant and antioxidant status on alveolarization: role of light-exposed total parenteral nutrition.

Parenteral multivitamins (MVP) are linked to the generation of peroxides, which cause oxidant injury in lungs associated with alveolar remodelling linked to lung disease of prematurity. This study was to investigate the relationship between alveolar development and lung oxidant-antioxidant status as modulated by the mode of administration of multivitamins with total parenteral nutrition (TPN). Four groups of guinea pig pups received parenteral nutrition differing by 1) mode of MVP admixture: with amino acid solution (AA-MVP) or lipid emulsion (LIP-MVP); 2) light exposure: TPN exposed (LE) or shielded from light (LP). After 2 or 4 days of TPN, vitamins C and E, 8-isoprostaneF2alpha and alveolarization index were determined in lungs and GSSG/GSH in lungs and blood. Exposure to light and the mode of MVP admixture did not influence vitamin E and isoprostane levels. Blood glutathione redox potential was more oxidized in LE and LIP-MVP groups after 4-day infusions, whereas lung redox potential was more reduced in LE groups. LP and LIP-MVP had a beneficial effect, with higher number of alveoli. Globally, results indicate that in this model, alveolarization and modifications in lung redox potential are two independent events induced by light exposed TPN.

Variations in metabolic response to TPN are influenced more by sex than by light exposure.

BACKGROUND: Failure to protect total parenteral nutrition (TPN) solutions from ambient light induces the generation of peroxides, which contributes to the oxidation of several amino acids. We hypothesized that photo-protection improves the metabolic response to TPN. AIM: To study the effects of photo-protecting TPN on urinary nitrogen and vitamin C excretion and to evaluate in premature infants the influence of sex. PATIENTS AND METHODS: Premature infants were randomized to receive from birth light-exposed (LE) or light-protected (LP) TPN. Upon reaching full TPN, parenteral nutrient intakes were correlated with normalized urinary nitrogen and vitamin C concentrations. RESULTS: No differences were observed between LE and LP. However, sex-related differences were observed in nitrogen and vitamin C handling. In boys, 50% of the nitrogen loss was explained by parenteral amino acid intake, whereas in girls, no correlation was found. The inverse correlation observed between intake and urinary excretion only in girls suggests a state of greater vitamin C utilization in girls. CONCLUSIONS: These results demonstrate that sex-related differences in nitrogen/protein metabolism reported during enteral nutrition are seen during TPN as well. Sex is an important variable that will need to be taken into account in future studies evaluating the potential clinical effects of photo-protecting TPN.

In preterm neonates, is the risk of developing bronchopulmonary dysplasia influenced by the failure to protect total parenteral nutrition from exposure to ambient light?

Light-exposed total parenteral nutrition (TPN) generates peroxides that contribute to an oxidant load. Shielding TPN from light protects against lung remodelling. In preterm infants, photoprotection of TPN is associated with a 30% reduction in bronchopulmonary dysplasia in a post-hoc analysis. This analysis provides justification for a randomized controlled trial.

Shielding parenteral multivitamins from light increases vitamin A and E concentration in lung of newborn guinea pigs.

BACKGROUND & AIMS: Exposure of parenteral multivitamin preparation (MVP) to light generates peroxides. Light-exposed MVP induces an oxidant stress in lung but not in liver. This discrepancy suggests differences in handling of infused antioxidant vitamins between the two organs. HYPOTHESIS: antioxidant capacity of lung depends on the MVP concentration and light protection of infused solutions. METHODS: Protocol 1: four groups of three-day old guinea pigs received the base solution (5% dextrose + 0.45% NaCl) enriched with 0%, 1%, 2% and 3% MVP. Protocol 2: three further groups received the base solution + 2% MVP either light-exposed or light-protected or light-protected + 300 microM H2O2. After 4 days, lung and liver were sampled for vitamin determinations. Data were analyzed by ANOVA. RESULTS: In lung, vitamins A-C-E reached a plateau with 1% MVP. In liver, vitamin A and E increased according to their concentration in solutions. Light exposure and added-H2O2 were associated with lower vitamin E in lung and liver. Retinol was higher in lung and lower in liver of animals receiving light-protected compared to light-exposed solutions. CONCLUSIONS: Light protection of 1% MVP is a better way to improve the pulmonary oxidant-antioxidant balance than to increase MVP (>1%) in parenteral nutrition.

Photoprotection of parenteral nutrition enhances advancement of minimal enteral nutrition in preterm infants.

BACKGROUND: Light exposure of TPN generates peroxides which induce vasoconstriction. Mesenteric vasoconstriction may affect feeding tolerance. Since photo-protection of TPN decreases peroxide generation, we hypothesized that shielding TPN from light may improve the establishment of minimal enteral nutrition in preterm infants. METHODS: Infants were randomized to TPN being light exposed (LE) or protected (LP) from birth. Feeding volumes were monitored through 7 days of life in those initiated on minimal enteral nutrition (MEN). Comparisons between LP and LE were performed by ANOVA. RESULTS: Daily increments and cumulative volumes of enteral feeds (mL/kg birth weight/d) during the first week of life were significantly higher in LP (n = 18) than LE (n = 19). CONCLUSION: Photo-protection of parenteral nutrition enhances advancement of MEN in preterm infants. Further research is needed to substantiate these findings and determine whether this confers long-term nutritional advantages.

Doubling calcium and phosphate concentrations in neonatal parenteral nutrition solutions using monobasic potassium phosphate.

BACKGROUND: Premature infants require high intakes of Ca and P to mimic fetal accretion rates. With the current phosphate salt used, adequate amounts cannot be provided due to the precipitation of Ca and P in TPN solutions. OBJECTIVE: To compare monobasic potassium phosphate (monobasic regimen) and monobasic plus dibasic potassium phosphate (dibasic regimen) on calcium phosphate solubility in 5 amino acid products, and to determine whether solubility differences observed in these products can be explained by buffering capacity. METHODS: TPN solutions were prepared according to standard clinical practice. The following amino acid products were used at 3% concentrations: Primene, Vamin N, TrophAmine, Aminosyn-PF, and Travasol. Dextrose 10%, standard electrolytes, heparin, vitamins and trace elements were added. Calcium (as gluconate) and phosphate (as monobasic or dibasic regimen) were added in one-to-one molar ratios from 0-45 mmol/L. Solutions were inspected macroscopically and microscopically for precipitation under three conditions: immediately, 24 h after preparation at room temperature, and 3 h later in a 37 degrees C water bath. Buffering capacity was determined for each amino acid product by titrating with standardized 0.1 M NaOH. RESULTS: Variations in Ca:P solubility and buffer capacity exist between amino acid solutions. With Primene and Vamin no macroscopic or microscopic precipitation was detected up to 45 mmol/L using monobasic regimen, compared to 25 mmol/L using dibasic regimen with Trophamine. Buffer capacity did not account for the solubility differences observed between the five amino acid products, which were related to the pH of the final solution. CONCLUSIONS: These data will allow clinicians to double the current concentrations of calcium and phosphate in neonatal TPN solutions using monobasic regimen. Although this is particularly relevant to situations when fluid intake is restricted, the effect of the acid load needs to be investigated in extremely low birth weight infants.

Superfetation as a cause of growth discordance in a multiple pregnancy.

A triplet pregnancy is described, in which the diagnosis of in utero growth restriction is questioned after postnatal suspicion of superfetation, by using neurosonography and ophthalmic examination to aid gestational age assessment.

Reduced bile flow associated with parenteral nutrition is independent of oxidant load and parenteral multivitamins.

BACKGROUND: Reduction in bile flow is a characteristic of cholestasis related to parenteral nutrition. Light exposure of parenteral multivitamin preparations is the major source of peroxides contaminating parenteral nutrition solutions. They may contribute to local oxidative stress. Oxidants are reported to affect transport mechanisms across the hepatocyte membrane into bile. The authors hypothesize that an oxidant-antioxidant imbalance is involved in parenteral nutrition related cholestasis. The aim of this study was to investigate the roles of multivitamin preparations and peroxides on bile flow in newborn guinea pigs receiving parenteral nutrition. METHODS: Three-day-old guinea pigs were fed enterally or parenterally with solutions containing 8% dextrose/0.45% NaCl +/- multivitamin preparation +/- amino acids +/- lipids. The influence of the oxidant-antioxidant balance on bile flow was evaluated using 500 microM hydrogen peroxide and 1% and 3% multivitamin preparations +/- Na metabisulfite. Four days later, animals were anesthetized and bile flow was recorded over 2 hours. Glutathione determinations were performed on bile and liver samples. The percentage of oxidized glutathione, reflecting the redox status, was used as a marker of oxidative stress. Data were compared by analysis of variance with P < 0.05. RESULTS: Bile flow decreased first on initiating dextrose + NaCl infusion (a 25% decrease) and subsequently by adding amino acids (a further 30% decrease). Although antioxidant vitamins and peroxides modified the hepatic redox status, they did not influence bile flow. CONCLUSION: Although the composition of parenteral nutrition affects bile flow and the hepatic redox status, the oxidant-antioxidant imbalance in infused solutions is not the causal event in the installation of cholestasis.