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Oxygen toxicity

INTRODUCTION

Although supplemental oxygen is valuable in many clinical situations, excessive or inappropriate supplemental oxygen can be deleterious [1]. According to human and animal studies, high concentrations of inspired oxygen can cause a spectrum of lung injury, ranging from mild tracheobronchitis to diffuse alveolar damage (DAD) [2-6]. The latter is histologically indistinguishable from that observed in the acute respiratory distress syndrome (ARDS). The mechanisms and clinical consequences of oxygen toxicity are reviewed here. Specific issues related to the administration of oxygen are discussed separately. (See "Use of oxygen in patients with hypercapnia" and "Long-term supplemental oxygen therapy".)

CELLULAR INJURY

Hyperoxia is poorly defined, but probably exists whenever oxygen tension exceeds 21 percent of atmospheric pressure. It appears to produce cellular injury through increased production of reactive oxygen species, such as the superoxide anion, the hydroxyl radical, and hydrogen peroxide [7]. When the production of these reactive species increases and/or the cell's antioxidant defenses are depleted, oxygen radicals can react with and impair the function of essential intracellular macromolecules, resulting in cell death [8].

Oxygen free radicals may also promote a deleterious inflammatory response, leading to secondary tissue damage and/or apoptosis [9-11]. Support for the role of reactive oxygen species in producing cellular injury has come from studies in transgenic mice with altered superoxide dismutase activity. Mice with augmented antioxidant mechanisms have a relative tolerance to hyperoxia, while manganese superoxide dismutase knockout mice die shortly after birth with extensive mitochondrial injury within degenerating neurons and cardiac myocytes [12-14].

Lung tissue is exposed to the highest concentrations of oxygen in the body, placing cells that line the tracheobronchial tree and alveoli at the greatest risk for hyperoxic cytotoxicity [15]. Hyperoxia may also increase susceptibility to mucous plugging, atelectasis, and secondary infection by impairing both mucociliary clearance and the bactericidal capacity of immune cells [16-21].

CLINICAL CONSEQUENCES

High fractions of inspired oxygen (FiO2) have been associated with several pulmonary consequences: increased intrapulmonary right-to-left shunt fraction and diminished lung volumes due to absorptive atelectasis; accentuation of hypercapnia; and damage to airways and pulmonary parenchyma. The term "oxygen toxicity" is usually reserved for the last of these consequences, ie, tracheobronchial and pulmonary parenchymal damage.
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References Top
  1. Gilbert, DL. Oxygen: An overall biological view. In: Oxygen and Living Processes, Gilbert, DL (Ed), Springer-Verlag, New York, 1981, p. 376.
  2. Jenkinson, SG. Oxygen toxicity. New Horiz 1993; 1:504.
  3. Deneke, SM, Fanburg, BL. Normobaric oxygen toxicity of the lung. N Engl J Med 1980; 303:76.
  4. Hedley-Whyte, J. Causes of pulmonary oxygen toxicity. N Engl J Med 1970; 283:1518.
  5. Jackson, RM. Pulmonary oxygen toxicity. Chest 1985; 88:900.
  6. Davis, WB, Rennard, SI, Bitterman, PB, Crystal, RG. Pulmonary oxygen toxicity. Early reversible changes in human alveolar structures induced by hyperoxia. N Engl J Med 1983; 309:878.
  7. Freeman, BA, Crapo, JD. Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria. J Biol Chem 1981; 256:10986.
  8. Fridovich, I. Oxygen toxicity: A radical explanation. J Exp Biol 1998; 201:1203.
  9. Waxman, AB, Einarsson, O, Seres, T, et al. Targeted lung expression of interleukin-11 enhances murine tolerance of 100 percent oxygen and diminishes hyperoxia-induced DNA fragmentation. J Clin Invest 1998; 101:1970.
  10. Barazzone, C, Horowitz, S, Donati, YR, et al. Oxygen toxicity in mouse lung: Pathways to cell death. Am J Respir Cell Mol Biol 1998; 19:573.
  11. Mantell, LL, Lee, PJ. Signal transduction pathways in hyperoxia-induced lung cell death. Mol Genet Metab 2000; 71:359.
  12. White, CW, Avraham, KB, Shanley, PF, Groner, Y. Transgenic mice with expression of elevated levels of copper-zinc superoxide dismutase in the lungs are resistant to pulmonary oxygen toxicity. J Clin Invest 1991; 87:2162.
  13. Lebovitz, RM, Zhang, H, Vogel, H, et al. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci U S A 1996; 93:9782.
  14. Folz, RJ, Abushamaa, AA, Suliman, HB. Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia. J Clin Invest 1999; 103:1055.
  15. Heffner, JE, Repine, JE. Pulmonary strategies of antioxidant defense. Am Rev Respir Dis 1989; 140:531.
  16. Carvalho, CR, de Paula, Pinto Schettino G, Maranhao, B, Bethlem, EP. Hyperoxia and lung disease. Curr Opin Pulm Med 1998; 4:300.
  17. Huber, GL, Porter, SL, Burley, SW, et al. The effect of oxygen toxicity on the inactivation of bacteria by the lung. Chest 1972; 61:Suppl:66S.
  18. Suttorp, N, Simon, LM. Decreased bactericidal function and impaired respiratory burst in lung macrophages after sustained in vitro hyperoxia. Am Rev Respir Dis 1983; 128:486.
  19. Sackner, MA, Hirsch, JA, Epstein, S, Rywlin, AM. Effect of oxygen in graded concentrations upon tracheal mucous velocity. A study in anesthetized dogs. Chest 1976; 69:164.
  20. Vlessis, AA, Bartos, D, Muller, P, Trunkey, DD. Role of reactive O2 in phagocyte-induced hypermetabolism and pulmonary injury. J Appl Physiol 1995; 78:112.
  21. Griffith, DE, Garcia, JG, James, HL, et al. Hyperoxic exposure in humans. Effects of 50 percent oxygen on alveolar macrophage leukotriene B4 synthesis. Chest 1992; 101:392.
  22. Wagner, PD, Laravuso, RB, Uhl, RR, West, JB. Continuous distributions of ventilation-perfusion ratios in normal subjects breathing air and 100 per cent O2. J Clin Invest 1974; 54:54.
  23. Santos, C, Ferrer, M, Roca, J, et al. Pulmonary gas exchange response to oxygen breathing in acute lung injury. Am J Respir Crit Care Med 2000; 161:26.
  24. Dunn, WF, Nelson, SB, Hubmayr, RD. Oxygen-induced hypercarbia in obstructive pulmonary disease. Am Rev Respir Dis 1991; 144:526.
  25. Aubier, M, Murciano, D, Milic-Emili, J, et al. Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis 1980; 122:747.
  26. Sassoon, CS, Hassell, KT, Mahutte, CK. Hyperoxic-induced hypercapnia in stable chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 135:907.
  27. Robinson, TD, Freiberg, DB, Regnis, JA, Young, IH. The role of hypoventilation and ventilation-perfusion redistribution in oxygen-induced hypercapnia during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161:1524.
  28. Malhotra, A, Schwartz, DR, Ayas, N, et al. Treatment of oxygen-induced hypercapnia. Lancet 2001; 357:884.
  29. Orem, J. The nature of the wakefulness stimulus for breathing. Prog Clin Biol Res 1990; 345:23.
  30. Comroe, JH, Dripps, RD, Dumke, PR, Deming, M. The effect of inhalation of high concentrations of oxygen for 24 hours on normal men at sea level and at a simulated altitude of 18,000. JAMA 1945; 128:710.
  31. Sackner, MA, Landa, J, Hirsch, J, Zapata, A. Pulmonary effects of oxygen breathing; A 6-hour study in normal men. Ann Intern Med 1975; 82:40.
  32. Carpagnano, GE, Kharitonov, SA, Foschino-Barbaro, MP, et al. Supplementary oxygen in healthy subjects and those with COPD increases oxidative stress and airway inflammation. Thorax 2004; 59:1016.
  33. Singer, MM, Wright, F, Stanley, LK, et al. Oxygen toxicity in man. A prospective study in patients after open-heart surgery. N Engl J Med 1970; 283:1473.
  34. Barber, RE, Hamilton, WK. Oxygen toxicity in man. A A/Barber RE, Lee J, Hamilton WK: Oxygen toxicity in man. A prospective study in patients with irreversible brain damage. N Engl J Med 1970; 283:1478.
  35. Elliott, CG, Rasmusson, BY, Crapo, RO, et al. Prediction of pulmonary function abnormalities after adult respiratory distress syndrome (ARDS). Am Rev Respir Dis 1987; 135:634.
  36. Berend, N. Protective effect of hypoxia on bleomycin lung toxicity in the rat. Am Rev Respir Dis 1984; 130:307.
  37. Flynn, JT, Bancalari, E, Snyder, ES, et al. A cohort study of transcutaneous oxygen tension and the incidence and severity of retinopathy of prematurity. N Engl J Med 1992; 326:1050.
  38. Lodato, RF. Effects of normobaric hyperoxia on hemodynamics and O2 utilization in conscious dogs. Adv Exp Med Biol 1990; 277:807.
  39. Ganz, W, Donoso, R, Marcus, H, Swan, HJ. Coronary hemodynamics and myocardial oxygen metabolism during oxygen breathing in patients with and without coronary artery disease. Circulation 1972; 45:763.
  40. Busing, CM, Kreinsen, U, Buhler, F, Bleyl, U. Light and electron microscopic examinations of experimentally produced heart muscle necroses following normobaric hyperoxia. Virchows Arch A Pathol Anat Histol 1975; 366:137.
  41. Lodato, RF. Decreased O2 consumption and cardiac output during normobaric hyperoxia in conscious dogs. J Appl Physiol 1989; 67:1551.
  42. Amato, MB, Barbas, CS, Medeiros, DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:347.
  43. Rothen, HU, Sporre, B, Engberg, G, et al. Reexpansion of atelectasis during general anaesthesia: a computed tomography study. Br J Anaesth 1993; 71:788.
  44. Albert, RK. The prone position in acute respiratory distress syndrome: Where we are, and where do we go from here. Crit Care Med 1997; 25:1453.
  45. Dellinger, RP, Zimmerman, JL, Taylor, RW, Straube, RC. Placebo and inhaled nitric oxide mortality the same in ARDS clinical trial. Crit Care Med 1998; 26:619.
  46. Dellinger, RP, Zimmerman, JL, Taylor, RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: Results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med 1998; 26:15.
  47. Lewandowski, K, Rossaint, R, Pappert, D, et al. High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation. Intensive Care Med 1997; 23:819.
  48. Comhair, SA, Erzurum, SC. Antioxidant responses to oxidant-mediated lung diseases. Am J Physiol Lung Cell Mol Physiol 2002; 283:L246.
  49. Kolleck, I, Sinha, P, Rustow, B. Vitamin E as an antioxidant of the lung: mechanisms of vitamin E delivery to alveolar type II cells. Am J Respir Crit Care Med 2002; 166:S62.
  50. Bitterman, M, Melamed, Y, Ben-Amotz, A. Beta-carotene and CNS oxygen toxicity in rats. J Appl Physiol 1994; 76:1073.
  51. Tang, G, White, JE, Gordon, RJ, et al. Polyethylene glycol-conjugated superoxide dismutase protects rats against oxygen toxicity. J Appl Physiol 1993; 74:1425.
  52. Turrens, JF, Crapo, JD, Freeman, BA. Protection against oxygen toxicity by intravenous injection of liposome- entrapped catalase and superoxide dismutase. J Clin Invest 1984; 73:87.
  53. Dennery, PA, Spitz, DR, Yang, G, et al. Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2. J Clin Invest 1998; 101:1001.
  54. Welty-Wolf, KE, Simonson, SG, Huang, YCT, et al. Aerosolized manganese SOD decreases hyperoxic pulmonary injury in primates. II. Morphometric analysis. J Appl Physiol 1997; 83:559.
  55. Otterbein, LE, Kolls, JK, Mantell, LL, et al. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J Clin Invest 1999; 103:1047.
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