Free Radicals in Neonatal Intensive Care

  • O. D. Saugstad
Part of the Update in Intensive Care and Emergency Medicine book series (UICM, volume 25)


The preterm baby is especially vulnerable to tissue injury. The eyes may be damaged by retinopathy of prematurity, the brain by intracranial hemorrhage and periventricular leukomalacia, the lungs by bronchopulmonary dysplasia, the ductus arteriosus may be persistent, and the intestine may suffer from necrotizing enterocolitis. Up to now most investigators have considered these conditions to be different diseases, but recently we have hypothesized that they are only different facets of the same disease, “The oxygen radical disease in neonatology” [1].


Oxygen Radical Xanthine Oxidase Bronchopulmonary Dysplasia Term Baby Retrolental Fibroplasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Saugstad OD (1988) Hypoxanthine as an indicator of hypoxia: Its role in health and disease through free radici production. Pediatr Res 23:143–150.PubMedCrossRefGoogle Scholar
  2. 2.
    Hossmann KA (1983) Neuronal survival and revival during and after cerebral ischemia. Am J Emerg Med 1:191–197.PubMedCrossRefGoogle Scholar
  3. 3.
    Kjellmer I (1988) Prenatal and intrapartum asphyxia.In: Levene MI, Bennett MJ, Punt J (eds) Fetal and neonatal neurology and neurosurgery. Churchill Livingstone, Edinburgh, London, Melbourne, New York, pp 357–369.Google Scholar
  4. 4.
    Latham F (1951) The oxygen paradox. Experiments on the effects of oxygen in human anoxia. Lancet 1:77–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Saugstad OD, Aasen AO (1980) Plasma hypoxanthine levels as a prognostic aid of tissue hypoxia. Europ Surg Res 12:123–129.CrossRefGoogle Scholar
  6. 6.
    Saugstad OD, Hallman M, Abraham J, Cochrane CG, Epstein B, Gluck L (1984) Hypoxanthine and oxygen induced lung injury: A basic mechanism of tissue damage? Pediatr Res 18:501–504.PubMedGoogle Scholar
  7. 7.
    Saugstad OD (1985) Oxygen radicals and pulmonary damage. Pediatr Pulmonol 1:167–175.PubMedCrossRefGoogle Scholar
  8. 8.
    Saugstad OD, Becher G, Grossmann M, Oddoy A, Merker G, Lachmann B (1987) Acute and chronic lung damage in guinea pigs induced by xanthine oxidase. Intensive Care Med 13:30–32.PubMedCrossRefGoogle Scholar
  9. 9.
    Saugstad OD, Hallman M, Becher G, Oddoy A, Lium B, Lachmann B (1988) Respiratory failure by intratracheal saline: Additive effect of xanthine oxidase. Biol Neonat 54:61–67CrossRefGoogle Scholar
  10. 10.
    Saugstad OD (1990) Oxygen toxicity in the neonatal period. Acta Paediatr Scand 79:881–892.PubMedCrossRefGoogle Scholar
  11. 11.
    Gilbert DL (1985) Oxygen an overall biological view. In: Gilbert DL (ed) Oxygen and living processes. Springer Verlag, New York, pp 376–92.Google Scholar
  12. 12.
    Wolfe WG, DeVries WC (1975) Oxygen toxicity. Ann Rev Med 26:203–217PubMedCrossRefGoogle Scholar
  13. 13.
    Kovachich GB, Haugaard N (1985) Biochemical aspects of oxygen toxicity in the metazoa. In: Gilbert DL (ed) Oxygen and living processes. Springer Verlag, New York, pp 210–34.Google Scholar
  14. 14.
    Schaefer KE (1985) Oxygen in closed environmental systems. In: Gilbert DL (ed) Oxygen and living processes. Springer Verlag, New York, pp 343–357.Google Scholar
  15. 15.
    Käfer ER (1971) Pulmonary oxygen toxicity. A review of the evidence for acute and chronic oxygen toxicity in man. Br J Anaesth 43:687–95.PubMedCrossRefGoogle Scholar
  16. 16.
    Holm BA, Matalon S, Finkelstein JN, Notter RH (1988) Type II pneumocyte changes during hyperoxic lung injury and recovery. J Appi Physiol 65:2672–2678.Google Scholar
  17. 17.
    Holm BA, Notter RH, Leary JF, Matalon S (1987) Alveolar epithelial changes in rabbits after a 21-day exposure to 60% O2. J Appi Physiol 62:2230–36.Google Scholar
  18. 18.
    Hansen TN, Gest AL (1984) Oxygen toxicity and other ventilatory complications of treatment of infants with persistent pulmonary hypertension. Clin Perinatol 11:653–72.PubMedGoogle Scholar
  19. 19.
    Huber GL, Drath DB (1985) Pulmonary oxygen toxicity. In: Gilbert DL (ed) Oxygen and living processes. Springer Verlag, New York, pp 273–342.Google Scholar
  20. 20.
    Yam J, Frank L, Roberts RJ (1987) Oxygen toxicity: Comparison of lung biochemical responses in neonatal and adult rats. Pediatr Res 12:115–19.Google Scholar
  21. 21.
    Saari H, Suomalainen K, Lindy O, Konttinen YT, Sorsa T (1990) Activation of latents human neutrophil collagenase by reactive oxygen species and serine proteases. Biochem Biophys Res Commun 171:979–987.PubMedCrossRefGoogle Scholar
  22. 22.
    Nogee LM, Wispe JR, Clark JC, Weaver TE, Whitsett JA (1991) Increased expression of pulmonary surfactant proteins in oxygen exposed rats. Am J Respir Cell Mol Biol 4:102–107.PubMedGoogle Scholar
  23. 23.
    Horowitz S, Dafni N, Shapiro DL, Holm BA, Notter RH, Quible DJ (1989) Hyperoxic exposure alters gene expression in the lung. Induction of tissue inhibitor and metalloprotei- nases mRNA and other mRNAs. J Biol Chem 264:7092–7095.PubMedGoogle Scholar
  24. 24.
    Northway WH, Rosan RC, Porter DY (1967) Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Eng J Med 276:357–68CrossRefGoogle Scholar
  25. 25.
    Gerschman R, Gilbert DL, Nyl SW, Dwyer P, Fen WO (1954) Oxygen poisoning and x-ray irradiation: a mechanism in common. Science 119:624–26.CrossRefGoogle Scholar
  26. 26.
    McCord JM, Fridovich I (1968) The reduction of cytochrome C by milk xanthine oxidase. J Biol Chem 243:5753–5760.PubMedGoogle Scholar
  27. 27.
    Babior BM, Kipnes RS, Curnutte JT (1973) Biological defense mechanisms. The production of superoxide - A potential bactericidal agent. J Clin Invest 52:741–744.PubMedCrossRefGoogle Scholar
  28. 28.
    Grisham MB, Hernandez LA, Granger DN (1986) Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 251: G567-G574.PubMedGoogle Scholar
  29. 29.
    Kugo M, Sano K, Uetani Y, Nakamura H (1989) Superoxide dismutase in polymorphonuclear leukocytes of term newborn infants and very low birth weight infants. Pediatr Res 26:227.231.Google Scholar
  30. 30.
    Sherman MP, D’Ambola JB, Aeberhard EE, Barrett CT (1988) Surfactant therapy of newborn rabbits impairs lung macrophage bactericidal activity. J Appl Physiol 65:137–145.PubMedGoogle Scholar
  31. 31.
    Sherman MP, Condiotti R (1987) Hyperoxia damages phagocytic defenses of neonatal rabbit lung. J Appl Physiol 62:684–690.PubMedGoogle Scholar
  32. 32.
    Crowell JW, Jones CE, Smith EE (1969) Effect of allopurinol on hemorrhagic shock. Am J Physiol 216:744–748.PubMedGoogle Scholar
  33. 33.
    Granger DN, Rutili G, McCord, JM (1981) Superoxide radicals in feline intestinal ischemia. Gastroenterology 81:22–29.PubMedGoogle Scholar
  34. 34.
    Saugstad OD (1996) Role of xanthine oxidase (XO) and its inhibitor in hypoxia-reoxygenation injury. Pediatrics in pressGoogle Scholar
  35. 35.
    Vettenranta K, Raivio KO (1990) Xanthine oxidase during human fetal development. Pediatr Res 27:286–288.PubMedCrossRefGoogle Scholar
  36. 36.
    Bratteby LE, Swanstrom S (1982) Hypoxanthine concentration in plasma during the first two hours after birth in normal and asphyxiated infants. Pediatr Res 16:152–155.PubMedCrossRefGoogle Scholar
  37. 37.
    Aasen AO, Saugstad OD (1979) Washing out of hypoxanthine in terminal endotoxin shock in dogs. Circ Shock 185:6:277–283.Google Scholar
  38. 38.
    Rootwelt T, Almaas R, Oyasaeter S, Moen A, Saugstad OD (1995) Release of xanthine oxidase to the systemic circulation during resuscitation from severe hypoxemia in newborn pigs. Acta Paediatr 84:507–511.PubMedCrossRefGoogle Scholar
  39. 39.
    Supnet MC, David-Cu R, Walther FJ (1994) Plasma xanthine oxidase and lipid hydroperoxide levels in preterm infant. Pediatr Res 6:283–287.Google Scholar
  40. 40.
    McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymatic function of erythro- cuprein (hemocuprein). J Biol Chem 244:6049–55.PubMedGoogle Scholar
  41. 41.
    Wayner DDM, Burton GW, Ingold KU, Barclay LRC, Locke SJ (1987) The relative contributions of vitamin E, urate, ascorbate and proteins to the total peroxyl radical-trapping antioxidant activity of human blood plasma. Biochim Biophys Acta 924:408–19.PubMedGoogle Scholar
  42. 42.
    Cutler RC (1986) Aging and oxygen radicals. In: AE Taylor, S. Matalon, PA Ward (eds) Physiology of oxygen radicals: American Physiology Society, Bethesda, pp 251–285.Google Scholar
  43. 43.
    Sullivan JL (1988) Iron, plasma antioxidants and the “Oxygen radical disease of prematurity”. Am J Dis Child 142:1341–1344.PubMedGoogle Scholar
  44. 44.
    Stocks J, Gutteridge JMC, Sharp RJ, Dormandy TL (1974) Assay using brain homogenate for measuring the antioxidant activity of biological fluids. Clin Sci Mol Med 47:215–222.PubMedGoogle Scholar
  45. 45.
    Stocks J, Gutteridge JMC, Sharp RJ, Dormandy TL (1974) The inhibition of lipid autoxidation by human serum and its relation to serum proteins and alpha tocopherol. Clin Sci Mol Med 47:223–233.PubMedGoogle Scholar
  46. 46.
    Gutteridge JMC, Stocks J (1981) Caeruloplasmin: physiological and pathological perspectives. CRC Crit Rev Clin Lab Sci 14:257–329.CrossRefGoogle Scholar
  47. 47.
    Hildebrand DC, Faluin Z, James E, Fahim M (1974) Ceruloplasmin and alkaline phosphatase levels in cord serum of term, preterm, and physiological jaundiced neonates. Am J Obstet Gynecol 118:950–954.Google Scholar
  48. 48.
    Scott PH, Berger HM, Kenward C, Scott T, Wharton RA (1975) Effect of gestational age and intrauterine nutrition of plasma transferrin and iron in the newborn. Arch Dis Child 50:796–798.PubMedCrossRefGoogle Scholar
  49. 49.
    Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235:1043–1046PubMedCrossRefGoogle Scholar
  50. 50.
    Stocker R, Glazer AN, Ames BN (1987) Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci 84:5918–5922.PubMedCrossRefGoogle Scholar
  51. 51.
    Bracci R, Buonocore G, Talluri B, Berni S (1988) Neonatal hyperbilirubinemia. Evidence for a role of the erythrocyte enzyme activities involved in the detoxification of oxygen radicals. Acta Paediatr Scand 77:349–356.PubMedCrossRefGoogle Scholar
  52. 52.
    Lindeman JHN, Van Zoeren-Grobben D, Schrijver J, Speek AJ, Poorthuis BJHM, Berger HM (1989) The total free radical ability of cord blood plasma in preterm and term babies. Pediatr Res 26:20–24.PubMedCrossRefGoogle Scholar
  53. 53.
    Haga P, Lunde G (1978) Selenium and vitamin E in cord blood from preterm and full term infants. Acta Paediatr Scand 67:735–739.PubMedCrossRefGoogle Scholar
  54. 54.
    Owens WC, Owens EU (1949) Retrolental fibroplasia in premature infants. II. Studies on the prophylaxis of the disease: the use of alpha tocopherol acetate. Am J Opthalmol 32:1631–1637.Google Scholar
  55. 55.
    Phelps DL, Rosenbaum AL, Isenberg SJ, Leake RD, Dorey FJ (1987) Tocopherol efficacy and safety for preventing retinopathy of prematurity: a randomized, controlled, double- masked trial Pediatrics 79:489–500.Google Scholar
  56. 56.
    Chiswick ML, Johnson M, Woodhall C et al (1983) Protective effect of vitamin E (DL- alpha-tocopherol) against intraventricular haemorrhage in premature babies. British Med J 287:81–84.CrossRefGoogle Scholar
  57. 57.
    Inan C, Kilic I, Kilinc K, Kalayci O, Kotiloglu E (1995) The effect of high fdose antenatal vitamin E on hypoxia-induced changes in newborn rats. Pediatr Res 38:685–689.PubMedCrossRefGoogle Scholar
  58. 58.
    Tapppel AL (1968) Will antioxidant nutrients slow aging processes? Geriatrics 23:97–105.Google Scholar
  59. 59.
    Packer JE, Slater TF, Wilson RL (1979) Direct observation of a free radical interaction between vitamin E and C. Nature 278:737–738.PubMedCrossRefGoogle Scholar
  60. 60.
    Frank L, Groseclose EE (1984) Preparation for birth into an 02-rich environment: The antioxidant enzymes in the developing rabbit lung. Pediatr Res 18:240–44.PubMedCrossRefGoogle Scholar
  61. 61.
    Hayashibe H, Asayama K, Dobashi K, Kato K (1990) Prenatal development of antioxidant enzymes in rat lung, kidney, and heart: marked increase in immunoreactive superoxide dismutase, glutathione peroxidase, and catalase in the kidney. Pediatr Res 27:472–475.PubMedCrossRefGoogle Scholar
  62. 62.
    Vlessis A, Mela-Riker L (1989) Perinatal development of heart, kidney, and liver mitochondrial antioxidant defense. Pediatr Res 26:220–226.PubMedCrossRefGoogle Scholar
  63. 63.
    Mishra OP, Delivoria-Papadopoulos (1988) Anti-oxidant enzymes in fetal guinea pig brain during development and the effect of maternal hypoxia. Develop Brain Res 42:173–179.CrossRefGoogle Scholar
  64. 64.
    Ripalda MJ, Rudolph N, Wong SL (1989) Developmental patterns of antioxidant defense mechanisms in human erythrocytes. Pediatr Res 26:366–369.PubMedCrossRefGoogle Scholar
  65. 65.
    Phylactos AC, Leaf AA, Costeloe K, Crawford MA (1995) Erythrocyte cupric/zink superoxide dismutase exhibits reduced activity in preterm and low-birthweight infants at birth. Acta Paediatr 84:1421–1425.PubMedCrossRefGoogle Scholar
  66. 66.
    Frank L, Sosenko IRS (1991) Failure of premature rabbits to increase antioxidant enzymes during hyperoxic exposure: increased susceptibility to pulmonary oxygen toxicity compared with term rabbits. Pediatr Res 29:292–296.PubMedGoogle Scholar
  67. 67.
    Frank L (1985) Effects of oxygen on the newborn. Fed Proc 44:2328–2334PubMedGoogle Scholar
  68. 68.
    Frank L, Bucher JR, Roberts RJ (1978) Oxygen toxicity in neonatal and adult animals of various species. J Appl Physiol 45:699–704.PubMedGoogle Scholar
  69. 69.
    Sullivan JL, Newton RB (1988) Serum antioxidant activity in neonates. Arch Dis Child 63:748–57.PubMedCrossRefGoogle Scholar
  70. 70.
    Goetzman BW (1986) Understanding bronchopulmonary dysplasia. Am J Dis Child 140:332–34.PubMedGoogle Scholar
  71. 71.
    O’Brodovich HM, Mellins RB (1985) Bronchopulmonary dysplasia. Unresolved neonatal acute lung injury. Am Rev Respir Dis 132:694–709.PubMedGoogle Scholar
  72. 72.
    Philips AGS (1975) Oxygen plus pressure plus time: The etiology of bronchopulmonary dysplasia. Pediatrics 55:44–50.Google Scholar
  73. 73.
    Johnson KJ, Fantone JC, Kaplan J, Ward PA (1981) In vivo damage of rat lungs by oxygen metabolites. J Clin Invest 67:983–993.PubMedCrossRefGoogle Scholar
  74. 74.
    Pitkanen OM, Hallman M, Andersson SM (1990). Correlation of free oxygen radical- influenced lipid peroxidation with outcome in very low birth weight infants. J Pediatr 116:760–764.PubMedCrossRefGoogle Scholar
  75. 75.
    Varsila E, Pitkanen OM, Hallman M, Andersson S (1994) Immaturity-dependent free radical activity in premature infants. Pediatr Res 36:55–59.PubMedCrossRefGoogle Scholar
  76. 76.
    Gladstone IM Jr, Levine RL (1994) Oxidation of proteins in neonatal lungs. Pediatrics 93:764–768.PubMedGoogle Scholar
  77. 77.
    Varsila E, Pesonen E, Andersson S (1995) Early protein oxidation in the neonatal lung is related to development of chronic lung disease. Acta Paediatr 84:1296–1299.PubMedCrossRefGoogle Scholar
  78. 78.
    Clement A, Chadelat K, Sardet A, Grimfeld A, Tournier G (1988) Alveolar macrophage status in bronchopulmonary dysplasia. Pediatr Res 23:470–473PubMedCrossRefGoogle Scholar
  79. 79.
    Cross KW (1973) Cost of preventing retrolental fibroplasia? Lancet 2:954–956.PubMedCrossRefGoogle Scholar
  80. 80.
    Lucey JF, Dangman B (1984) A reexamination of the role of oxygen in retrolental fibroplasia. Pediatrics 73:82–96.PubMedGoogle Scholar
  81. 81.
    Phelps DL (1982) Neonatal toxicity - Is it preventable? Pediatr Clin North Am 19:687–91.Google Scholar
  82. 82.
    Saugstad OD, Rognum TO (1988) High post mortem vitreous hypoxanthine levels in newborns with the respiratory distress syndrome (RDS). Pediatrics 31:395–398.Google Scholar
  83. 83.
    Parks DA, Granger DN (1986) Contributions of ischemia and reperfusion to mucosal lesion formation. Am J Physiol 250:G749-G753.PubMedGoogle Scholar
  84. 84.
    Gr0gaard B, Parks DA, Granger DN, McCord JM, Forsberg O (1982) Effects of ischemia and oxygen radicals on mucosal albumin clearance in intestine. Am J Physiol 242: G448-G454.PubMedGoogle Scholar
  85. 85.
    Hernandez LA, Grisham MB, Granger DN (1987) A role for iron in oxidant-mediated ischemic injury to intestinal microvasculature. Am J Physiol 253: G49-G53PubMedGoogle Scholar
  86. 86.
    Scheuch C, Berndt C, Gross J, Poulsen JP, Saugstad OD, Haberland A (1989) Influence of the hypoxanthine/xanthine oxidase system on striatal (3H) dopamine uptake. Biomed Biochim Acta 48:212–216.Google Scholar
  87. 87.
    Palmer C, Vannucci RC, Towfighi J (1990) Reduction of perinatal hypoxic-ischemic brain damage with allopurinol. Pediatr Res 27:332–336.PubMedCrossRefGoogle Scholar
  88. 88.
    Tate RM, Morris HG, Schroeder WR, Repine JE (1984) Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs. J Clin Invest 74:608–13.PubMedCrossRefGoogle Scholar
  89. 89.
    Clyman RI, Saugstad OD, Mauray F (1989) Reactive oxygen metabolites relax the lamb ductus arteriosus by stimulating prostaglandin production. Circ Res 64:1–8PubMedGoogle Scholar
  90. 90.
    Sanderud J, Norstein J, Saugstad OD (1991) Reactive oxygen metabolites produce pulmonary vasoconstriction in young pigs. Pediatr Res 29:543–547.PubMedCrossRefGoogle Scholar
  91. 91.
    Saugstad OD (1996) Mechanisms of tissue injury by oxygen radicals. Implications for neonatal disease. Acta Paediatr 85:1–4.PubMedCrossRefGoogle Scholar
  92. 92.
    Ramji S, Ahuja S, Thirupuram S, Rootwelt T, Rooth G, Saugstad OD (1993) Resuscitation of asphyxic newborn infants with room air or 100% oxygen. Pediatr Res 34:809–812.PubMedCrossRefGoogle Scholar
  93. 93.
    Poulsen JP, Oyasaeter S, Saugstad OD (1993) Hypoxanthine, xanthine and uric acid in newborn pigs during hypoxemia followed by resuscitation with room air or 100% oxygen. Crit Care Med 21:1058–1065.PubMedCrossRefGoogle Scholar
  94. 94.
    Rootwelt T, Løberg EM, Moen A, Øyasaster S, Saugstad OD (1992) Hypoxemia and reoxygenation with 21% or 100% oxygen in newborn pigs: changes in blood pressure, base deficit, and hypoxanthine and brain morphology. Pediatr Res 32:107–113.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • O. D. Saugstad

There are no affiliations available

Personalised recommendations