- Atul Malhotra, MD
Atul Malhotra, MD
- Kenneth M Moser Professor, Dept. of Medicine
- University of California, San Diego
- David R Schwartz, MD
David R Schwartz, MD
- Associate Professor of Clinical Medicine
- Section Chief, Critical Care
- NYU Medical Center
- Richard M Schwartzstein, MD
Richard M Schwartzstein, MD
- Professor of Medicine
- Harvard Medical School
Although supplemental oxygen is valuable in many clinical situations, excessive or inappropriate supplemental oxygen can be deleterious . 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".)
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 [7,8]. 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 .
Oxygen free radicals may also promote a deleterious inflammatory response, leading to secondary tissue damage and/or apoptosis [10-12]. 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 [13-15]. Data from animal models suggest possible roles for insulin growth factor 1  and angiopoietin 2  in the pathogenesis of hyperoxia-induced lung injury as well.
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 . Hyperoxia may also increase susceptibility to mucous plugging, atelectasis, and secondary infection by impairing both mucociliary clearance and the bactericidal capacity of immune cells [19-24].
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.
- Gilbert DL. Oxygen: An overall biological view. In: Oxygen and Living Processes, Gilbert DL (Ed), Springer-Verlag, New York 1981. p.376.
- Jenkinson SG. Oxygen toxicity. New Horiz 1993; 1:504.
- Deneke SM, Fanburg BL. Normobaric oxygen toxicity of the lung. N Engl J Med 1980; 303:76.
- Hedley-Whyte J. Causes of pulmonary oxygen toxicity. N Engl J Med 1970; 283:1518.
- Jackson RM. Pulmonary oxygen toxicity. Chest 1985; 88:900.
- 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.
- Freeman BA, Crapo JD. Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria. J Biol Chem 1981; 256:10986.
- Winslow RM. Oxygen: the poison is in the dose. Transfusion 2013; 53:424.
- Fridovich I. Oxygen toxicity: a radical explanation. J Exp Biol 1998; 201:1203.
- Waxman AB, Einarsson O, Seres T, et al. Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation. J Clin Invest 1998; 101:1970.
- 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.
- Mantell LL, Lee PJ. Signal transduction pathways in hyperoxia-induced lung cell death. Mol Genet Metab 2000; 71:359.
- 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.
- 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.
- Folz RJ, Abushamaa AM, 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.
- Kim TH, Chow YH, Gill SE, Schnapp LM. Effect of insulin-like growth factor blockade on hyperoxia-induced lung injury. Am J Respir Cell Mol Biol 2012; 47:372.
- Bhandari V, Choo-Wing R, Harijith A, et al. Increased hyperoxia-induced lung injury in nitric oxide synthase 2 null mice is mediated via angiopoietin 2. Am J Respir Cell Mol Biol 2012; 46:668.
- Heffner JE, Repine JE. Pulmonary strategies of antioxidant defense. Am Rev Respir Dis 1989; 140:531.
- Carvalho CR, de Paula Pinto Schettino G, Maranhão B, Bethlem EP. Hyperoxia and lung disease. Curr Opin Pulm Med 1998; 4:300.
- 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.
- 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.
- 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.
- Vlessis AA, Bartos D, Muller P, Trunkey DD. Role of reactive O2 in phagocyte-induced hypermetabolism and pulmonary injury. J Appl Physiol (1985) 1995; 78:112.
- 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.
- 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.
- 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.
- Dunn WF, Nelson SB, Hubmayr RD. Oxygen-induced hypercarbia in obstructive pulmonary disease. Am Rev Respir Dis 1991; 144:526.
- 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.
- Sassoon CS, Hassell KT, Mahutte CK. Hyperoxic-induced hypercapnia in stable chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 135:907.
- 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.
- Malhotra A, Schwartz DR, Ayas N, et al. Treatment of oxygen-induced hypercapnia. Lancet 2001; 357:884.
- Orem J. The nature of the wakefulness stimulus for breathing. Prog Clin Biol Res 1990; 345:23.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Berend N. Protective effect of hypoxia on bleomycin lung toxicity in the rat. Am Rev Respir Dis 1984; 130:307.
- 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.
- Lodato RF. Effects of normobaric hyperoxia on hemodynamics and O2 utilization in conscious dogs. Adv Exp Med Biol 1990; 277:807.
- 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.
- Büsing CM, Kreinsen U, Bühler 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.
- Lodato RF. Decreased O2 consumption and cardiac output during normobaric hyperoxia in conscious dogs. J Appl Physiol (1985) 1989; 67:1551.
- 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.
- Rothen HU, Sporre B, Engberg G, et al. Re-expansion of atelectasis during general anaesthesia: a computed tomography study. Br J Anaesth 1993; 71:788.
- 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.
- 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.
- 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.
- 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.
- Comhair SA, Erzurum SC. Antioxidant responses to oxidant-mediated lung diseases. Am J Physiol Lung Cell Mol Physiol 2002; 283:L246.
- Kolleck I, Sinha P, Rüstow 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.
- Bitterman N, Melamed Y, Ben-Amotz A. Beta-carotene and CNS oxygen toxicity in rats. J Appl Physiol (1985) 1994; 76:1073.
- Tang G, White JE, Gordon RJ, et al. Polyethylene glycol-conjugated superoxide dismutase protects rats against oxygen toxicity. J Appl Physiol (1985) 1993; 74:1425.
- 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.
- 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.
- 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.
- 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.