Philippe Chessex

Influence of Bilirubin on the Antioxidant Capacity of Plasma in Newborn Infants

In vitro, bilirubin is a strong antioxidant, but in vivo its capacity to act as a scavenger of toxic oxygen radicals remains poorly documented. The aim of this study was to evaluate of bilirubin had antioxidant properties in jaundiced infants. The antioxidant capacity of neonatal plasma was measured in Trolox equivalents (TEAC, mmol/l) and correlated in vitro with plasma bilirubin concentrations (r2 = 0.99). Plasma TEAC was compared before and after exchange transfusions for neonatal hyperbilirubinemia (250-435 mumol/l). The antioxidant properties of the paired blood samples before and after exchange transfusions (TEAC: 1.67 +/- 0.12 vs. 1.37 +/- 0.09 mmol/l, n = 11) varied in proportion to the serum bilirubin levels. The changes in other antioxidants were not large enough to account for the magnitude of change in antioxidant capacity. Therefore, in vivo, the plasma antioxidant capacity of jaundiced newborn infants is related to the level of bilirubin.

Association between hypothermia and mortality rate of premature infants—Revisited

The incidence of hypothermia (axillary temperature less than 35 degrees C) on admission of an infant to a neonatal intensive care unit was retrospectively analyzed in 559 very-low-birth-weight (less than 1500 gm) newborn infants. The smaller infants were at greater risk of hypothermia. Only in the larger neonates was mortality related to hypothermia, which suggests that this known association bears little cause-effect relationship.

Antiperoxide activity of sodium metabisulfite: A double-edged sword

Sulfites are chemical substances that are used widely in the pharmaceutical industry to reduce or prevent oxidation. Sodium metabisulfite (Na2S2O5) is still present in several parenteral amino acid solutions. Since intravenous lipid emulsions are contaminated by hydroperoxides, we evaluated whether metabisulfite had an antioxidant activity against hydroperoxides. In vitro, Na2S2O5 inhibited the oxidant activity of H2O2, tert-butyl-, and cumene hydroperoxides. The antioxidant capacity of metabisulfite was supported in vivo by the lower (P < 0.01) excretion of malondialdehyde, a stable end product of lipid peroxidation, in babies receiving metabisulfite in their parenteral nutrition. However, for concentrations outside the range found in solutions for parenteral nutrition, the reduction of hydroperoxides by Na2S2O5 could transform this compound into an oxidant, like a sulfite radical. It is suggested that metabisulfite has antiperoxide properties that, under specific conditions, contribute to the generation of toxic oxidants.

DEVELOPMENT OF GLUTATHIONE SYNTHESIS AND GAMMA -GLUTAMYLTRANSPEPTIDASE ACTIVITIES IN TISSUES FROM NEWBORN INFANTS

Following the observation that the level of glutathione in leukocytes from human newborn infants was lower in preterm and in male infants, a study was designed to document the level of activities of glutathione synthesis and gamma-glutamyltranspeptidase during the development of preterm and term newborn infants. Measurements were performed in leukocytes from tracheal aspirates of oxygen dependent infants, and in leukocytes from cord blood. Contrary to the common belief concerning the development of antioxidant activity, the biosynthesis of glutathione was active in leukocytes from preterm infants; and by two days of life the activity of gamma-glutamyltranspeptidase reached 3 times the level of that seen in cord blood. Our results suggest that the maturity of these enzymes was not the limiting step in maintaining cellular glutathione levels. This represents new information concerning the maturation of a central antioxidant in tissue derived from preterm and term human newborn infants at risk of oxidant stress. This implies that sources of cysteine crossing freely the cellular membrane could be used by tissues of term and preterm infants to produce glutathione.

Energy expenditure and severity of respiratory disease in very low birth weight infants receiving long-term ventilatory support

We attempted to determine whether the hypermetabolism of infants with bronchopulmonary dysplasia was detectable during assisted ventilation. Respiratory gas exchange variables were measured with a metabolic gas monitor in 10 infants under similar nutritional conditions. Oxygen consumption increased linearly with the need for ventilatory support (R2 = 0.75), as documented by the ventilatory index.

Peroxide-like oxidant response in lungs of newborn guinea pigs following the parenteral infusion of a multivitamin preparation

The multivitamin solution is a major component responsible for the photo-induced generation of peroxides in parenteral nutrition. The lung is a target of oxidant injury; however, the specific role of infused peroxides is unknown. The aim of this study was to determine if parenteral multivitamins induce in the lung an oxidant challenge similar to that of peroxides. Newborn guinea pigs were infused with dextrose plus relevant concentrations of H(2)O(2) (0,250,500 microM) or multivitamins (0,1%), as well as parenteral nutrition supplemented with multivitamins (0,1%). After 4 days, total glutathione, glutathione-related enzymes, and oxidant-sensitive eicosanoids were measured in the lungs. Peroxides as well as multivitamins led to a significant decrease in glutathione and the activity of glutathione synthase, indicating that infused peroxides were not entirely transformed into free radicals, which would have stimulated glutathione synthesis. The multivitamin solution induced a response in oxidant-sensitive eicosanoids similar to the response to peroxides, suggesting an oxidant stress that was not alleviated by the antiradical properties of its components. The effects on prostaglandins occurred independently from the stimulation in glutathione levels induced by parenteral nutrition. The multivitamin solution carries an oxidant load and causes effects similar to those of peroxides in the lungs of newborn guinea pigs.

Total parenteral nutrition in the newborn infant: Energy substrates and respiratory gas exchange*

The hypothesis that a high-fat parenteral regimen was beneficial for respiratory gas exchanges, in comparison with a high-glucose regimen, was tested in a paired crossover design. Ten parenterally fed newborn infants with no respiratory problems received two 5-day isoenergetic and isonitrogenous regimens that differed in their nonprotein source of energy; the level of fat intake (low fat (LF) 1 gm.kg-1.day-1; high fat (HF) 3 gm.kg-1.day-1) varied inversely with that of glucose. Continuous transcutaneous PO2 (tcPO2) and PCO2 (tcPCO2), respiratory gas exchange (indirect calorimetry), and plasma arachidonate metabolites were measured at the end of each regimen. Oxygen consumption and resting energy expenditure were not affected by modification of the source of energy. However, carbon dioxide production (VCO2) was higher during LF than during HF (6.9 +/- 0.2 vs 6.2 +/- 0.1 ml.kg-1.min-1; p less than 0.01), as was the respiratory quotient (1.08 +/- 0.02 vs 0.96 +/- 0.02; p less than 0.001). Despite the differences in VCO2, the tcPCO2 was not affected, suggesting adequate pulmonary compensation during LF, as documented by the higher minute ventilation (160 +/- 7 vs 142 +/- 5 ml.kg-1.min-1; p less than 0.01). The lower tcPO2 during the HF regimen (73.8 +/- 2.8 vs 68.8 +/- 2.6 mm Hg; p less than 0.015) indicated a disturbance at the alveolocapillary level induced by the lipid emulsion. No differences were found in circulating levels of prostaglandins and thromboxanes. The substitution of glucose for lipid did not modify fat storage (2.1 +/- 0.3 vs 2.1 +/- 0.3 gm.kg-1.day-1). We conclude that the supposed beneficial effect of a fat emulsion on respiratory gas exchange is questionable.

Effect of amino acid composition of parenteral solutions on nitrogen retention and metabolic response in very-low-birth weight infants

To evaluate the influence of amino acid preparations on the metabolic response of parenterally fed immature newborn infants, nitrogen retention and plasma amino acid concentrations were compared in very-low-birth-weight infants given two parenteral regimens differing only by the composition of the infused amino acids (Travasol 10% blend B and Vamin 7%). The intakes of fluid, nitrogen, and calories were comparable. The nitrogen retention was 72% +/- 7% with Vamin and 65% +/- 6% with Travasol. The differences in plasma amino acid concentrations were consistent with the composition of the amino acid solutions. During the infusion of Vamin the increased intake of aromatic amino acids resulted in high plasma levels of tyrosine (256 +/- 233 mumol/L, range 67 to 894 mumol/L). The infusion of Travasol resulted in high plasma levels of methionine (114 +/- 39 mumol/L, range 53 to 260 mumol/L) and an elevated load of glycine, which was accompanied by an abnormally high urinary loss of this amino acid. Despite these metabolic imbalances, the growth rate over the whole study was adequate. These results emphasize the importance of the composition of amino acid solutions on the metabolic response of the very immature preterm infant.

Gender-related response to a tert-butyl hydroperoxide-induced oxidation in human neonatal tissue.

Reports of gender-related differences in the activity of enzymes involved in the metabolism of intracellular antioxidants, led us to verify whether the prostaglandin response to tert-butyl hydroperoxide (TBH) differed according to the sex of infants. Segments of human umbilical veins were perfused in the presence or absence of TBH (0.25 mmol/l, and 1.0 mmol/l). Because TBH is quenched in the cell by glutathione peroxidase, total glutathione concentrations and production of glutathione-dependent prostaglandins (PGE2 and PGF2 alpha) as well as membrane-derived eicosanoids (PGI2 and thromboxane) were measured in the eluate. In veins from boys, TBH induced a sustained response for glutathione only, which was increased (p < 0.05). In female-derived tissue, the hydroperoxide induced a different response according to the dose of TBH. At 0.25 mmol/l, a drop (p < 0.005) in PGF2 alpha was associated with a rise (p < 0.001) in thromboxane. At 1.0 mmol/l, TBH had an opposite effect--there was a rise (p < 0.01) in PGE2 and PGI2. The prostaglandin concentration were not proportional to the oxidative stimulus, suggesting a critical level of TBH at which the oxidative state differs in tissues derived from boys or girls.

The increase in vasomotor tone induced by a parenteral lipid emulsion is linked to an inhibition of prostacyclin production

The aim of the study was to verify whether the infusion of a lipid emulsion causes a rise in vascular pressure related to an imbalance in the production of vasoconstricting and vasodilatating eicosanoids. Segments of umbilical veins were perfused with and without 1.5 microM indomethacin (cyclooxygenase inhibitor) in solutions differing only in their lipid content (control vs. lipid). The lipid-induced higher pressure (p < 0.05) was associated with an inhibition (p < 0.05) in the output of the vasodilatator PGI2, and an increase (p < 0.01) in the production of the vasoconstrictor PGF2 alpha. Indomethacin abolished differences in pressure, but produced a rise (p < 0.01) in vascular tone of both the control and lipid-containing solutions by inhibiting PGI2 synthesis. Prostacyclin was the only eicosanoid significantly correlated (p < 0.01) to vascular tone. The lipid emulsion was therefore linked to the inhibition of the conversion of PGH2 to PGI2. The ensuing greater PGH2 availability would result in vivo, in the increased synthesis of vasoconstricting eicosanoids. The lipid-containing solution produced vasoactive responses similar to those reported with tert-butyl hydroperoxide, suggesting that hydroperoxides contaminating commonly used lipid emulsions could be causing a prostanoid-dependent vasoconstriction.