Authors:Atul Malhotra, MDRichard M Schwartzstein, MDSection Editor:Scott Manaker, MD,

PhDDeputy Editor:Geraldine Finlay, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2018. | This topic last updated: May 01, 2018.
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 "The
evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory
failure" and "Long-term supplemental oxygen therapy".)

CELLULAR INJURY — Hyperoxia is not precisely defined but significant elevations of the partial
arterial pressure of oxygen (PaO2) are found only when the fraction of inspired oxygen (FiO2)
is greater than 21 percent of atmospheric pressure. Adverse events may result from increased
oxygen tension in the alveoli, blood, or at the cellular level. Hyperoxia appears to produce
cellular injury through increased production of reactive oxygen intermediates (ROIs), such as
the superoxide anion, the hydroxyl radical, and hydrogen peroxide [7,8]. When the production
of these (ROIs) increases and/or the cell's antioxidant defenses are depleted, they can react
with and impair the function of essential intracellular macromolecules, resulting in cell death
[9].

Oxygen free radicals may also promote a deleterious inflammatory response, leading to
secondary tissue damage and/or apoptosis [10-12]. Much of the evidence supporting direct
cellular injury due to ROIs comes from studies in transgenic mice with altered superoxide
dismutase activity. Mice with augmented antioxidant mechanisms are relatively tolerant 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 [16] and
angiopoietin 2 [17] in the pathogenesis of hyperoxia-induced lung injury.

The respiratory tract is exposed to the highest concentrations of oxygen in the body, placing
airway lining cells and alveoli at the greatest risk for hyperoxic cytotoxicity [18]. 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].

CLINICAL CONSEQUENCES — High fractions of inspired oxygen (FiO2) have been associated
with several effects on lung tissue/gas exchange including diminished lung volumes and
hypoxemia due to absorptive atelectasis, accentuation/production 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 alveolar damage.

Absorptive atelectasis — High FiO2 results in washout of alveolar nitrogen (nitrogen is

replaced by oxygen, which is largely absorbed into the blood, resulting in a small alveolus
prone to collapse), which can result in alveolar closure, ie, atelectasis. Absorptive atelectasis is
theoretically more likely in the following circumstances:
●A low regional ventilation-perfusion ratio (where oxygen diffuses from alveoli to capillaries
faster than it is replenished by inhaled oxygen), decreasing alveolar volume, may result in
complete alveolar closure.

●Qualitative or quantitative surfactant abnormalities that promote alveolar collapse and

further reduce the ventilation-perfusion ratio

●A high rate of oxygen uptake, due to an increase in metabolic demand

●An impaired pattern of respiration that fails to correct atelectasis (eg, ventilation at low tidal
volumes and/or without intermittent sighs or "adequate" PEEP when using mechanical
ventilation)

Shunting resulting from absorptive atelectasis is minor in younger patients, but can rise to as
high as 11 percent in older, otherwise healthy volunteers breathing 100 percent oxygen for 30
minutes [25].

Once established, absorptive atelectasis is not directly reversed by a reduction of FiO2,

emphasizing the desirability of rapid titration of FiO2 to the lowest fraction necessary to
maintain an arterial oxygen saturation (SaO2) >90 percent [26].

Decrements in vital capacity of up to 20 percent have been noted after hyperoxic exposure in a
number of experiments [2,19]. This is presumably due to a combination of absorptive
atelectasis compounded by shallow breaths related to pain due to secondary pleural irritation.

Accentuation of hypercapnia — Hyperoxic hypercarbia describes the phenomenon of

increased partial pressure of arterial carbon dioxide (PaCO2) associated with increases in FiO2
predominantly described in individuals with chronic compensated respiratory acidosis; these
patients have limited ability to increase alveolar ventilation to compensate for rising PaCO2
and falling pH. In general, increased hypercapnia does not lead to CO2 narcosis and respiratory
failure as the relative rise in PaCO2 is small and these patients are acclimated to their higher
baseline level of PaCO2. (See "The evaluation, diagnosis, and treatment of the adult patient
with acute hypercapnic respiratory failure".)

Several mechanisms act in concert to produce hyperoxic hypercapnia, including [27-29]:

●The Haldane effect. This describes the rightward displacement of the CO2-hemoglobin
dissociation curve in the presence of increased oxygen tension; the increased oxyhemoglobin
results in dissociation of CO2 from hemoglobin, increasing blood CO2 levels. Since
oxyhemoglobin binds CO2 less avidly than deoxyhemoglobin, a patient with significant
hypoxemia given supplemental oxygen may experience a rise in PaCO2.

●An increase in dead space (ie, "wasted") ventilation. This probably reflects worsening
ventilation-perfusion matching and redistribution of blood flow from well-ventilated to poorly
ventilated alveoli due to a reversal of hypoxic pulmonary vasoconstriction as alveolar PO2 rises
with the supplemental oxygen; the lung unit remains poorly ventilated since supplemental
oxygen does not change the condition that produced the low ventilation. Carbon dioxide-
induced bronchodilation may also be important in mediating the increase in dead space [30].

●A modest decrease in minute ventilation, which also reduces alveolar ventilation, due to
decreased stimuli from peripheral chemoreceptors to the central respiratory center. (See
"Control of ventilation".)
●The anxiolytic and anti-dyspneic effects of supplemental oxygen can promote sleep,
particularly in patients who arrive in the emergency department sleep-deprived. The onset of
sleep is associated with loss of the drive to breathe associated with the reticular activating
system. When the awake and behavioral influences on breathing present during wakefulness
are absent, respiration is sustained solely by metabolic control mechanisms. This can result in
progressive hypercarbia [31,32].

●Hypoventilation decreases inspiratory flow demand, which reduces the amount of room air
entrained around a face mask or nasal cannula. This may increase the FiO2 delivered to the
patient, even if the flow rate from the oxygen source is unchanged [31]. The net effect is
augmentation of the above mechanisms which worsen hypercapnia. The effect on ventilatory
drive, increasing FiO2, sets up a dangerous vicious cycle, leading to progressive hypercapnia. If
not aware of the pathophysiology, increasing FiO2 in hypoxemic patients with reduced drive
may result in hypercapnic respiratory failure. As an example, in the postoperative patient,
when oxygen saturation falls due to hypoventilation, increasing the FiO2 further can lead to a
vicious spiral of worsening hypoventilation, hypercapnia, and hypoxemia which is then treated
with additional increases in supplemental oxygen, finally culminating in overt hypercapnic
hypoxemic respiratory failure. Mechanisms and management of hypercapnia are discussed
separately. (See "Mechanisms, causes, and effects of hypercapnia" and "The evaluation,
diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure".)

Airway injury — Many healthy volunteers experience substernal heaviness, pleuritic chest
pain, cough, and dyspnea within 24 hours of breathing pure oxygen; these symptoms are
probably due to a combination of tracheobronchitis and absorptive atelectasis [33]. Erythema
and edema of large airways can be observed bronchoscopically in most patients treated with a
FiO2 of 0.9 for six hours and are thought to reflect hyperoxic bronchitis [34]. In addition, the
concentration of reactive oxygen intermediates (ROIs) in exhaled gas increases after only one
hour of breathing 28 percent oxygen, regardless of the presence of underlying lung disease
[35].

Bronchopulmonary dysplasia (BPD), a disease seen in neonates following recovery from

neonatal respiratory distress syndrome, has been attributed to the effects of mechanical
ventilation and oxygen toxicity in the immature lung. BPD is characterized by epithelial
hyperplasia and squamous metaplasia in the large airways, thickened alveolar walls, and
peribronchial and interstitial fibrosis. Infants with BPD generally suffer respiratory distress and
require supplemental oxygen for up to six months. (See "Bronchopulmonary dysplasia:
Definition, pathogenesis, and clinical features".)

Parenchymal injury — Progressive worsening of airspace disease can be observed in

mechanically ventilated patients with acute respiratory distress syndrome (ARDS). Possible
mechanisms include progression of the underlying pulmonary process, development of
ventilator-associated pneumonia, ventilator-induced lung injury secondary to mechanical
forces, or diffuse alveolar damage (DAD) from oxygen toxicity. Determining the magnitude of
parenchymal injury due solely to oxygen therapy in humans is problematic because
confounders are always present. Much of the limited human data on hyperoxic pulmonary
injury are derived from healthy volunteers exposed to high FiO2; clinical relevance is
debatable.

Several studies involving patients in critical care units have attempted to assess the clinical
significance of pulmonary oxygen toxicity but have yielded conflicting results:
●One prospective study randomized 40 patients undergoing cardiac surgery to postoperative
treatment with either 100 percent oxygen delivered via an endotracheal tube for a mean of 24
hours, or to the minimum FiO2 required to maintain an arterial oxygen tension of 80 to 120
mmHg [36]. Despite the differences in FiO2 exposure, there was no difference in right-to-left
shunt fraction, effective compliance, or dead space to tidal volume ratio between the two
groups.

●A second report randomized 10 patients with irreversible brain damage to either 21 or 100
percent oxygen for a mean of 52 hours and in the hyperoxic group, noted increased right-to-
left shunt fraction, and increased dead space to tidal volume ratio [37]. However, postmortem
examination of the lungs revealed no major histopathologic differences (including no hyaline
membranes characteristic of early DAD) among the two treatment groups.

The physiologic deterioration in the hyperoxic patients in the second study may have reflected
progressive absorptive atelectasis, which was less prominent in the first series where patients
were exposed to hyperoxia for shorter periods, and had spontaneous respiratory efforts.
Alternatively, physiologic changes associated with brain injury or cardiac surgery may explain
the apparent differences in behavior of these two populations. (See "Neurogenic pulmonary
edema".)

●A retrospective study of 16 previously healthy, nonsmoking survivors of ARDS found that

treatment with an FiO2 >0.6 for more than 24 hours was both a sensitive and specific predictor
of a reduced diffusing capacity (DLCO) at one year [38]. Although there were potential biases
in this study based on severity of illness (patients with more biologically severe ARDS
presumably received higher concentrations of oxygen), the duration of FiO2 >0.6 was the only
variable which predicted the degree of diffusing abnormality.

Potentiation by bleomycin — Patients who receive bleomycin appear to be more susceptible

to DAD following oxygen exposure, based upon in vitro data and uncontrolled clinical
experience [39]. The typical presentation of combined bleomycin/oxygen toxicity involves a
patient with testicular cancer or Hodgkin lymphoma who, after receiving bleomycin, requires
high FiO2 at any later time point, eg, due to aspiration, pneumonia, or general anesthesia.
Following oxygen administration, the patient develops acute, subacute, or chronic worsening
of bilateral alveolar infiltrates with increasing dyspnea, nonproductive cough, and decreasing
lung compliance. (See "Bleomycin-induced lung injury".)

The diagnosis of this syndrome is established by the exclusion of other processes such as heart
failure, worsening pneumonia, ongoing aspiration, or alveolar hemorrhage. Lung injury
associated with amiodarone or external beam radiation may involve oxygen radicals in its
pathogenesis, and also may predispose individuals to hyperoxic complications. (See
"Amiodarone pulmonary toxicity" and "Radiation-induced lung injury".)

Extrapulmonary toxicity — The retinopathy of prematurity (previously called retrolental

fibroplasia) has been attributed to the toxic effects of oxygen. One cohort study of 101 infants
demonstrated a significant association between the duration of transcutaneously measured
PaO2 >80 mmHg and the incidence and severity of retinopathy [40]. Central nervous system
symptoms, including generalized tonic-clonic seizures, have been reported secondary to
hyperoxia but are unusual in the absence of hyperbaric therapy. (See "Retinopathy of
prematurity: Pathogenesis, epidemiology, classification, and screening".)

Hyperoxia may also alter cardiovascular function [41,42]. Increased oxygen tension can lead to
local coronary vasoconstriction, and microscopic foci of myocardial necrosis have been
observed in animal models [43]. Reductions in stroke volume and cardiac output, relative
bradycardia, and an increase in systemic vascular resistance may ensue, but the clinical
relevance of hyperoxia-related hemodynamic effects remains unclear [44].

Mortality — The impact of the end organ effects of hyperoxia on survival has been studied in
several populations and is discussed separately. (See "Overview of mechanical ventilation",
section on 'Fraction of inspired oxygen'.)

PREVENTION — There is no single threshold of fraction of inspired oxygen (FiO2) defining a

safe upper limit for prevention of oxygen toxicity, although clinical experience suggests that in
the absence of sensitizing agents such as bleomycin, FiO2 <0.6 is not likely to induce oxygen
toxicity. The relative importance of the duration and magnitude of hyperoxic exposure also has
not been clearly defined, although it is likely that the area under the FiO2 versus time curve is
the best predictive variable. Factors that are difficult to quantify, such as the adequacy of a
given patient's antioxidant defenses, probably also play a role in determining individual
susceptibility.

Reduction of FiO2 — Reducing the FiO2 to the lowest tolerable limit is a good principle for all
patients, in particular those likely to be at risk of hyperoxia-induced lung injury because of a
prolonged duration of oxygen therapy or prior therapy with bleomycin. In practical terms,
oxygen should be administered to achieve a minimal arterial oxygen tension (PaO2) of 60 to 65
mmHg (arterial oxygen saturation [SaO2] approximately 90 percent).

A number of therapeutic strategies can be employed in patients with ARDS to minimize the
need for a high FiO2 and thereby reduce the risk of oxygen toxicity. However, despite their
dramatic effect on FiO2 reduction in some cases, none of these therapies has been
unequivocally demonstrated to improve overall mortality in acute respiratory distress
syndrome (ARDS). Interventions of this type include:

●Administration of positive end-expiratory pressure (PEEP) to prevent alveolar derecruitment

and lower the right-to-left shunt fraction (see "Positive end-expiratory pressure (PEEP)")

●Titration of an "ideal PEEP" in conjunction with a protective ventilation strategy, which has
reduced mortality in one study, but has been somewhat controversial [45] (see "Mechanical
ventilation of adults in acute respiratory distress syndrome")

●Performance of additional alveolar recruitment maneuvers (eg, a sustained delivery of

continuous positive airway pressure of 40 cm H2O for 60 seconds) [45,46]

●Prone positioning [47] (see "Acute respiratory distress syndrome: Supportive care and
oxygenation in adults")

●Inverse-ratio or other alternative modes of ventilation (see "Modes of mechanical

ventilation")

●Inhaled nitric oxide [48,49] (see "Acute respiratory distress syndrome: Investigational or
ineffective therapies in adults")

●Extracorporeal membrane oxygenation [50] (see "Extracorporeal membrane oxygenation

(ECMO) in adults")

●Liquid ventilation (see "Liquid ventilation")

●Diuresis if pulmonary edema is possible.

●Bronchopulmonary hygiene if secretions are prominent.

In our practice, we begin to implement these measures as soon as it is evident that the patient
will require greater than 60 percent inspired oxygen for longer than six hours.

Augmentation of antioxidants — Because oxygen radicals lead to pulmonary toxicity,

enhanced defenses against these molecules theoretically should minimize or prevent lung
damage [51]. The potential importance of augmented antioxidant mechanisms is illustrated by
the relative tolerance to hyperoxia of transgenic mice with increased superoxide dismutase
activity [13].

Animal data suggest potentially beneficial roles for strategies that either inhibit oxidant
generation (eg, deferoxamine, allopurinol, tungsten) or provide supplemental antioxidants (eg,
alpha tocopherol, beta-carotene, N-acetylcysteine, dimethylthiourea) [18,52-56]. As an
example, one prospective randomized baboon study demonstrated decreased hyperoxic
pulmonary injury in animals randomized to aerosolized manganese superoxide dismutase [57].
A different study induced protection against hyperoxic lung injury in rats by transferring the
heme oxygenase-1 gene via a recombinant adenovirus vector [58]. Data on the efficacy of
these potential therapies in humans are lacking.

Immune modulators — Manipulation of the cytokine milieu may permit modification of the
deleterious inflammatory response provoked by hyperoxia. As an example, one study of
transgenic mice with increased lung expression of interleukin (IL)-11 found reduced hyperoxic
lung injury, possibly mediated through diminished hyperoxia-induced expression of IL-1 and
tumor necrosis factor [10]. The improved tolerance to hyperoxia occurred despite only small
changes in lung antioxidant concentrations.

SUMMARY AND RECOMMENDATIONS

●Hyperoxia is not precisely defined. Potential adverse clinical consequences of supplemental

oxygen therapy include absorptive atelectasis, accentuation of preexisting hypercapnia, airway
injury, parenchymal lung injury, and extrapulmonary toxicity. (See 'Clinical consequences'
above.)

●The term, "oxygen toxicity," generally refers to parenchymal lung injury due to supplemental
oxygen. (See 'Clinical consequences' above.)

●Oxygen toxicity is mediated by reactive oxygen intermediates (ROIs), which can promote
inflammation and induce cell death. (See 'Cellular injury' above.)

●There is no well-defined threshold fraction of inspired oxygen (FiO2) or duration of

supplemental oxygen therapy below which oxygen toxicity cannot occur. (See 'Prevention'
above.)

●Patients with any previous bleomycin exposure who are hypoxemic should receive the lowest
possible FiO2 compatible with tissue oxygenation goals (ie, avoidance of tissue hypoxia). The
potential for oxygen toxicity must be communicated to the anesthesiologist if a patient with
bleomycin exposure needs a surgical or endoscopic procedure. (See 'Reduction of FiO2'
above.)
●The FiO2 should be titrated to the lowest concentration required to meet oxygenation goals.
In our practice, we ideally aim for an arterial oxygen tension (PaO2) between 60 and 70 mmHg
and peripheral oxygen saturation between 90 and 96 percent; further increases in PaO2 add
relatively little to the oxygen content of the blood. But, clinical judgment should be used in
selecting a target oxygen saturation for an individual patient (eg, patients with coronary artery
disease or pulmonary hypertension may tolerate hypoxemia poorly). (See 'Reduction of FiO2'
above.)

●Additional strategies to maximize oxygenation and reduce FiO2 (eg, diuresis,

bronchopulmonary hygiene, prone positioning, inhaled nitric oxide, recruitment maneuvers
and/or optimal positive end-expiratory pressure [PEEP]) should be considered when FiO2
exceeds 60 percent for more than six hours. (See 'Reduction of FiO2' above.)

●The use of antioxidants to prevent oxygen toxicity remains experimental. (See 'Augmentation
of antioxidants' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge David R

Schwartz, MD, who contributed to an earlier version of this topic review.

REFERENCES
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 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 YC, et al. Aerosolized manganese SOD decreases
hyperoxic pulmonary injury in primates. II. Morphometric analysis. J Appl Physiol (1985) 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.
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