Urinary Metabolites of Oxidative Stress and Nitric Oxide in Preterm and Term Infants

Background: Many neonatal diseases have been associated with oxidative stress and altered nitric oxide status. Objective: To determine the effects of clinical interventions on the levels of urinary peroxides, a marker of oxidative stress, and urinary nitrate/nitrites, indices of nitric oxide production and metabolism, in the first 72 h of life in premature infants. Methods: A single, spot urine sample was collected from 82 premature and 20 healthy term infants within the first 72 h of life. The peroxide levels were quantified using a fluorometric method, and nitrate/nitrite levels were quantified by chemiluminescence. Results: Premature infants had a median peroxide level of 10.0 µmol/mmol creatinine (Cr) (interquartile range 4.8–20.0 µmol/mmol Cr). These values were significantly higher than term infants (median 5.0 µmol/mmol Cr, interquartile range 2.7–10.0 µmol/mmol Cr). Urinary nitrate/nitrite levels were not significantly different between preterm (220.5 µmol/mmol Cr, interquartile range 161–287 µmol/mmol Cr) and healthy term infants (244 µmol/mmol Cr, interquartile range 194–316 µmol/mmol Cr). For urinary peroxides, infants on TPN had significantly higher urinary peroxide levels than infants who were not on TPN at the time of urine collection (p = 0.006). Administration of indomethacin was associated with lower levels of urinary nitrate/nitrites (p = 0.0003). Both effects remained significant after controlling for gestational age, degree of respiratory distress and day of urine collection. Conclusion: Monitoring the level of both peroxides and nitrate/nitrite may offer added information about the degree of oxidative stress experienced by a newborn but needs to account for clinical and therapeutic interventions.

[1]  O. Aalen,et al.  Resuscitation of newborn infants with 21% or 100% oxygen: follow-up at 18 to 24 months. , 2003, Pediatrics.

[2]  H. Tamai,et al.  New Evidence for the Involvement of Oxygen Radicals in Triggering Neonatal Chronic Lung Disease , 1996, Pediatric Research.

[3]  T. Sulpice,et al.  Limiting lipid peroxidation in the nonischemic zone of infarcted rat hearts by indomethacin improves left ventricular function without affecting myocardial healing and remodeling. , 1996, American heart journal.

[4]  L. Ignarro,et al.  Production and excretion of nitrate by human newborn infants: neonates are not little adults. , 2000, Nitric oxide : biology and chemistry.

[5]  M. Gladwin,et al.  Methodologies for the Sensitive and Specific Measurement of S -nitrosothiols, Iron-nitrosyls, and Nitrite in Biological Samples , 2003, Free radical research.

[6]  B. Halliwell,et al.  Hydrogen peroxide in human urine: implications for antioxidant defense and redox regulation. , 1999, Biochemical and biophysical research communications.

[7]  J. Dzik,et al.  Nitric oxide metabolites in the urine of full‐term and preterm infants , 2002, Pediatrics international : official journal of the Japan Pediatric Society.

[8]  H. Tamai,et al.  Susceptibility of Neonatal Lipoproteins to Oxidative Stress , 1991, Pediatric Research.

[9]  P. Chessex,et al.  Multivitamin solutions for enteral supplementation: a source of peroxides. , 2002, Nutrition.

[10]  G. Buonocore,et al.  Oxidative Stress in Preterm Neonates at Birth and on the Seventh Day of Life , 2002, Pediatric Research.

[11]  M. Jacob,et al.  Indomethacin induces free radical-mediated changes in renal brush border membranes , 2005, Archives of Toxicology.

[12]  T. Krediet,et al.  Nitric Oxide Production and Plasma Cyclic Guanosine Monophosphate in Premature Infants with Respiratory Distress Syndrome , 2002, Neonatology.

[13]  N. Uzuner,et al.  Urinary nitrite excretion in low birth weight neonates with systemic inflammatory response syndrome. , 1997, Biology of the neonate.

[14]  O. Saugstad.  The role of oxygen in neonatal resuscitation. , 2004, Clinics in perinatology.

[15]  A. Pulimood,et al.  Indomethacin-induced renal damage: role of oxygen free radicals. , 2004, Biochemical pharmacology.

[16]  H. Schulman,et al.  The Postnatal Hypotransferrinemia of Early Preterm Newborn Infants , 1976, Pediatric Research.

[17]  R. Haugland,et al.  A stable nonfluorescent derivative of resorufin for the fluorometric determination of trace hydrogen peroxide: applications in detecting the activity of phagocyte NADPH oxidase and other oxidases. , 1997, Analytical biochemistry.

[18]  H. Tsukahara,et al.  Assessment of endogenous nitric oxide formation in newborns: measurement of urinary nitrite and nitrate concentrations. , 1997, Biology of the neonate.

[19]  M. Miller,et al.  Urinary nitrite excretion in premature infants: effects of transfusion or indomethacin , 1993, Acta paediatrica.

[20]  R. Wu,et al.  Cyclooxygenase-2 Inhibitors Attenuate Angiotensin II–Induced Oxidative Stress, Hypertension, and Cardiac Hypertrophy in Rats , 2005, Hypertension.

[21]  P. Chessex,et al.  Photoprotection of solutions of parenteral nutrition decreases the infused load as well as the urinary excretion of peroxides in premature infants. , 2001, Seminars in perinatology.

[22]  N. Rudolph,et al.  Developmental Patterns of Antioxidant Defense Mechanisms in Human Erythrocytes , 1989, Pediatric Research.

[23]  F. Kelly.  Free radical disorders of preterm infants. , 1993, British medical bulletin.

[24]  M. Tobin,et al.  Urine hydrogen peroxide during adult respiratory distress syndrome in patients with and without sepsis. , 1994, Chest.

[25]  J. Mehta,et al.  Cyclooxygenase inhibition decreases nitric oxide synthase activity in human platelets. , 1997, American journal of physiology. Heart and circulatory physiology.

[26]  M. Hallman,et al.  Immaturity-Dependent Free Radical Activity in Premature Infants , 1994, Pediatric Research.

[27]  S. Lorch,et al.  Oxygen Tension and Inhaled Nitric Oxide Modulate Pulmonary Levels of S-Nitrosocysteine and 3-Nitrotyrosine in Rats , 2004, Pediatric Research.

[28]  T. Rognum,et al.  High postmortem levels of hypoxanthine in the vitreous humor of premature babies with respiratory distress syndrome. , 1988, Pediatrics.

[29]  P. Chessex,et al.  Increased urinary peroxides in newborn infants receiving parenteral nutrition exposed to light. , 2000, The Journal of pediatrics.

[30]  B. Ames,et al.  Biomarkers of oxidative stress study III. Effects of the nonsteroidal anti-inflammatory agents indomethacin and meclofenamic acid on measurements of oxidative products of lipids in CCl4 poisoning. , 2005, Free radical biology & medicine.

[31]  B. Warner,et al.  Urinary Nitrite and Nitrate Concentrations in Patients with Idiopathic Persistent Pulmonary Hypertension of the Newborn and Effect of Extracorporeal Membrane Oxygenation , 1995, Pediatric Research.

[32]  M. Vento,et al.  Resuscitation of Depressed Newborn Infants with Ambient Air or Pure Oxygen: A Meta-Analysis , 2005, Neonatology.

[33]  B. Ames,et al.  Original Contribution Biomarkers of oxidative stress study III. Effects of the nonsteroidal anti-inflammatory agents indomethacin and meclofenamic acid on measurements of oxidative products of lipids in CCl 4 poisoning , 2005 .