Published June 27, 2023

NEJM Evid 2023; 2 (7)

DOI: 10.1056/EVIDra2300111

REVIEW ARTICLE

Oxygen Therapy Part 2 — Indications and Toxicity

Matthew L. Wemple, M.D.,1 Kai E. Swenson, M.D.,2 and Erik R. Swenson, M.D.1

Abstract
C.Corey Hardin, M.D., Ph.D.
The first part of this article1 discusses the history, physiology, and evaluation for oxygen Editor
therapy. In this second part, we discuss the acute and chronic indications for oxygen, the
delivery of supplemental oxygen (outside of invasive and noninvasive positive-pressure
ventilation), and its potential adverse effects and toxicity.

Acute Indications for Oxygen Therapy

I
ndications for acute, short-term supplemental oxygen therapy are listed in Table 1.2-4
When a patient presents with respiratory distress, supplemental oxygen is often
administered even before an assessment of hypoxemia is made. The clearest indica-
tion for oxygen is arterial hypoxemia when the partial presssure of arterial oxygen (PaO2)
is less than 60 mm Hg, which normally corresponds to an arterial oxygen saturation (SaO2)
or peripheral oxygen saturation (SpO2) of 89 to 90%. When PaO2 drops below 60 mm Hg,
oxygen saturation may drop precipitously, leading to a much lower arterial oxygen content
and possibly tissue hypoxia.

Supplemental oxygen may be indicated in a few clinical scenarios other than arterial hyp-
oxemia. Patients with severe anemia, trauma, and critical surgical illness may benefit from
enhanced arterial oxygen content by virtue of a much higher dissolved O2 content to
reduce tissue hypoxia. In patients with carbon monoxide (CO) poisoning, supplemental
oxygen increases dissolved blood oxygen content, displaces CO bound to hemoglobin, and
increases the percentage of oxyhemoglobin. With the administration of pure oxygen, the
half-life of carboxyhemoglobin is 70 to 80 minutes compared with 320 minutes when
breathing ambient air.5 Under hyperbaric conditions, with pure oxygen, the half-life is
shortened to under 10 minutes. Hyperbaric oxygen is generally used when carboxyhemo-
globin levels are high (>25%) and there is cardiac ischemia or alterations in sensorium.6

Several other disorders may benefit from administration of supplemental oxygen, although
supportive data are lacking or equivocal. Oxygen therapy is often used in cluster headaches,7 The author affiliations are listed
at the end of the article.
sickle cell pain crises,8 palliative relief of dyspnea without hypoxemia,9 and pneumothorax
and pneumomediastinum10 to facilitate resorption of pleural air.11,12 Some evidence suggests Dr. Swenson can be contacted
that intraoperative hyperoxia may reduce the incidence of surgical site infections.13 However, at eswenson@uw.edu or at VA
Puget Sound Health Care System,
administration of supplemental oxygen does not appear to be effective in reducing postopera- 1660 South Columbian Way,
tive nausea/emesis.14 Therapeutic uses of hyperbaric oxygen are discussed elsewhere.15 Seattle, WA 98108.

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 Table 1. Indications for Acute Oxygen Therapy.*

Accepted Indications Questionable Indications

PaO2 below normal range, usually <60 mm Hg or SaO2<90%
Acute myocardial infarction and stroke without hypoxemia

Hypoxemia strongly suspected, such as respiratory distress (confirm
Dyspnea without hypoxemia (palliative)
hypoxemia as soon as possible)

Severe trauma
Sickle cell pain crisis

Low–cardiac output states with metabolic acidosis
Pneumothorax and pneumomediastinum
* PaO2 denotes partial pressure of arterial oxgen; and SaO2, arterial oxygen saturation.

These two trials suggest that supplemental oxygen for more

Indications for Long-Term Oxygen
Therapy
Use of long-term oxygen therapy (LTOT) has been grow-
ing as our ability to deliver oxygen in outpatient settings
has improved. Criteria for administering LTOT have be-
come well established. LTOT is frequently used in the
context of chronic obstructive pulmonary disease (COPD).
Table 2 outlines the guidelines of the American Thoracic
Society (ATS) for LTOT in chronic lung disease.16
Supportive data for LTOT come from two major studies in
patients with hypoxemic COPD. The first is the Nocturnal
Oxygen Therapy Trial (NOTT), performed in 1980, in
which patients were randomly assigned to either nocturnal
(at least 12 hours) or continuous oxygen.17 Patients who
received nocturnal oxygen alone had higher mortality at
12 and 24 months. The second, in 1981, is the British Med-
ical Research Council Domiciliary trial,18 in which patients
were randomly assigned to receive either no oxygen or at
least 15 hours/day of supplemental oxygen. As with the
NOTT, mortality was significantly higher in the no-oxygen
group. Both trials studied patients in a stable state on max-
imal therapy and nonsmoking who had PaO2 of less than
55 or less than 60 mm Hg if they had polycythemia or cor
pulmonale.
than 15 hours/day is better than no oxygen at all and that
continuous oxygen is better than nocturnal-only therapy.
The entry criteria for these trials form the basis of the cur-
rent Medicare criteria and ATS guidelines for LTOT. Extrap-
olating to other hypoxemic cardiopulmonary diseases is
reasonable, but trials are lacking. In patients with COPD
whose hypoxemia does not meet resting criteria or who
have only exercise-induced hypoxemia, a recent multicenter
trial found no mortality or quality-of-life differences.19
Finally, nocturnal supplemental oxygen is sometimes pre-
scribed in patients with significant desaturation while sleep-
ing. There is currently no clear evidence to support this
practice in COPD.20,21 For patients with nocturnal desatura-
tion from obstructive sleep apnea or obesity hypoventilation
syndrome, noninvasive positive-pressure ventilation, rather
than supplemental oxygen, constitutes primary therapy.22
Another consideration is determining the need for supple-
mental oxygen during air travel. Most commercial aircraft
are generally pressurized to an equivalent altitude of around
8000 feet, resulting in an inspired oxygen tension of
approximately 108 mm Hg. In patients with lung disease,
this reduced inspired oxygen tension (PiO2) will result in
hypoxemia. Prior to travel, the patient should have a thor-
ough medical evaluation, including an arterial blood gas

Table 2. Indications for Chronic Oxygen Therapy — American Thoracic Society Guidelines.*

Prescription Indication Criteria Quality of Evidence

Long-term oxygen therapy >15 h/d Severe chronic resting
hypoxemia
Long-term oxygen therapy >15 h/d Resting hypoxemia with
qualifiers
PaO2<55 mm Hg or SaO2<88% Strong recommendation, moderate-
quality evidence
PaO2=56–59 mm Hg or Strong recommendation, moderate-
SaO2=89% þ one of the quality evidence
following:

Cor pulmonale

Hct>55%

P pulmonale on ECG

Ambulatory oxygen Severe exertional hypoxemia PaO2<55 mm Hg or SaO2<88% Conditional recommendation, low-
with exertion quality evidence
* ECG denotes electrocardiogram; Hct, hematocrit; PaO2, partial pressure of arterial oxygen; and SaO2, arterial oxygen saturation.

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test. For patients whose PaO2 is greater than or equal to
70 mm Hg (SpO2>95%) at ground level, their in-flight PaO2
will likely exceed 50 mm Hg, which is generally considered
adequate for minimal physical activity. For patients with a
more marginal SpO2 or PaO2, a 6-minute walk test may be
considered23 or a hypoxia simulation test may be performed,
usually done by breathing 15% oxygen, and if hypoxemia
results, the necessary corrective liter flow by nasal cannulae
may be added.24 Review articles addressing testing options
and recommended liter flow rates to achieve adequate oxy-
genation are available.25
Techniques of Oxygen
Administration
When choosing an oxygen delivery device, the clinician
must consider the degree of hypoxemia; the patient’s
minute ventilation; the oxygen flow that the device can
deliver; its adjustability; and its precision, comfort, and cost.
Delivery devices utilized in the acute setting may be divided
into low-flow and high-flow delivery systems. The required
flow depends on the patient’s degree of hypoxemia and ven-
tilation. Patients with a high minute ventilation or who are
profoundly hypoxemic require high-flow devices. Patients
with more moderate degrees of hypoxemia may only need
low-flow systems, which are generally more comfortable.
LOW-FLOW SYSTEMS
Low-flow systems deliver only a fraction of the patient’s
minute ventilation as pure oxygen. The maximum oxygen
flow in these systems is 15 l/minute. Because a patient’s
tidal volume and inspiratory flow rate vary breath to
breath, the fraction of inspired oxygen for any given
breath is impossible to predict.26 Nasal cannulae allow
comfortable oxygen delivery at 2 to 6 l/minute with unim-
peded communication and oral intake. This flow creates
an anatomic reservoir of oxygen in the nasopharynx from
which the patient draws during inspiration. Oxygen masks
can deliver higher flow rates than nasal cannulae; they
entrain less ambient air and therefore can generate a
higher fraction of inspired oxygen (FIO2). The flow rate of
a simple mask should never be less than 5 l/minute; below
this level, carbon dioxide (CO2) rebreathing may occur,
along with an increased resistance to inspiration. A reser-
voir mask is like a simple mask but has an attached reser-
voir of 600 to 800 ml. Reservoir masks include partial
rebreather and nonrebreather types. When using a non-
rebreathing reservoir mask, oxygen flow should be set
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high enough to prevent deflation of the reservoir bag —
usually approximately 15 l/minute. Typically, these masks
provide a maximum FIO2 of 0.8 to 0.9, but FIO2 may be
even lower (0.6 to 0.8) with very high minute ventilation
and inspiratory flow rates.27
HIGH-FLOW SYSTEMS
High-flow oxygen devices deliver an accurate and con-
stant oxygen percentage by high flows of pure oxygen or
nitrogen-oxygen admixtures that exceed the patient’s ven-
tilation, sometimes by a factor of four. A Venturi mask
consists of a mask, a jet nozzle, and entrainment ports.
Oxygen is delivered under pressure through the jet nozzle,
which entrains ambient air through entrainment ports.
Depending upon the entrainment port size, jet nozzle size,
and oxygen flow rate, a predictable FIO2 can be delivered.
Over the past decade, high-flow nasal cannulae (HFNC)
have been developed that deliver much higher flow rates
than simple nasal cannulae, allowing delivery of up to
60 l/minute of heated, humidified oxygen. Physiological
benefits of HFNC include elimination of interface dead
space, washout of CO2 from the nasopharynx, improved
thoracoabdominal synchrony, less work of breathing, and a
positive end-expiratory pressure up to 4 cm water (H2O).28 In
hypoxemic respiratory failure, systematic reviews and meta-
analyses have shown a lower rate of intubation with the use
of HFNC O2 compared with conventional O2 therapy.29,30
Similarly, when used immediately following extubation in
patients at high risk, the rates of reintubation for HFNC are
comparable with those noninvasive positive-pressure ventila-
tion and are lower compared with conventional O2 therapy.31
When evaluating patients on HFNC, the ratio of oxygen sat-
uration (ROX) index has been proposed as an easy-to-use
calculation to assess the likelihood of HFNC failure and the
need for invasive mechanical ventilation. The ROX index is
defined as the ROX as measured by SpO2/FIO2 to respira-
tory rate, with an ROX index of greater than 4.88 minutes/
breath associated with a lower risk of intubation.32 When
deciding on proceeding to intubation for patients, clinicians
should keep in mind the risk of potential self-induced lung
injury in the setting of respiratory failure with the high work
of breathing.33
Oxygen Toxicity
Concerns about oxygen toxicity were raised in 1775 by Priest-
ley,34 who wrote presciently that pure oxygen “might not
3
be so proper for us in the usual healthy state of the body.”
J. Lorrain Smith in 1899 described pathologic changes in
mice exposed to hyperbaric oxygen,35 writing that “the effect
was uniformly fatal, and the immediate cause of death was
inflammation of the lungs … and the lungs were found post-
mortem to be extremely congested … the alveoli were to a
great extent filled with an exudate.”
Biochemical Basis of Oxygen
Toxicity
Oxygen toxicity is caused by the production of reactive
oxygen species (ROS), which are oxygen-derived free radi-
cals with a single unpaired orbital electron that react with
proteins, lipids, and nucleic acids to alter their structure
and cause cellular damage. Small amounts of ROS are gen-
erated in normal mitochondrial metabolism and serve as
signaling molecules. ROS are also used by immune cells
for pathogen killing. ROS include superoxide, hydrogen
peroxide (H2O2), and hydroxyl radical. Invariably, exces-
sive generation of ROS overcomes cellular defenses,36,37
causing death or mutagenesis.
To limit ROS generation–mediated damage, protective cellu-
lar antioxidant defenses neutralize free radicals. Superoxide
dismutase converts superoxide to H2O2, which in turn, is
converted to H2O and to O2 by catalase and glutathione per-
oxidase. Glutathione is an important molecule in limiting
damage from ROS. Glutathione reductase and glucose-6-
phosphate dehydrogenase regenerate glutathione, enabling
its recycling as an antioxidant. Other antioxidant molecules
include a-tocopherol (vitamin E), ascorbate (vitamin C), ceru-
loplasmin, and cysteine. Human lung tissue contains a high
concentration of extracellular antioxidants and superoxide
dismutase isoforms, which allow exposure to a higher con-
centration of oxygen than other tissues without development
of toxicity, but even these defenses can be overwhelmed.38-40
Hyperoxia-induced, ROS-mediated lung damage occurs in
two phases.41 First, there is an exudative phase, character-
ized by alveolar type 1 and endothelial cell death, intersti-
tial edema, and exudative neutrophilic alveolar filling. A
proliferative phase follows with the proliferation of endo-
thelial cells and type 2 pneumocytes, which cover the
previously exposed basement membrane. Recovery from
oxygen injury is characterized by fibroblast proliferation
and interstitial scarring but with preservation of fairly
normal-appearing capillary endothelium and alveolar
epithelium.
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Clinical Manifestations of
Pulmonary Oxygen Toxicity
The exposure level at which toxicity occurs has not been
clearly identified. Clinical toxicity is generally absent when
the FIO2 is less than 0.5. In early human studies, it was
found that exposure to nearly 100% oxygen resulted in
paresthesias, nausea, and tracheobronchitis, and decreases
in vital capacity, diffusing capacity, lung compliance, PaO2,
and pH.42-44 Other relevant concerns over oxygen toxicity
include absorption atelectasis, oxygen-induced hypercap-
nia, acute respiratory distress syndrome (ARDS), and new-
born bronchopulmonary dysplasia (BPD).45-47
ABSORPTION ATELECTASIS
Nitrogen, an inert gas, does not diffuse into the blood at
any appreciable rate compared with O2 and thus acts to
maintain alveolar patency. When 100% oxygen is used,
the absence of nitrogen promotes alveolar collapse in low
_
alveolar ventilation-perfusion ratio (V=Q ) regions as the
oxygen uptake rate exceeds the rate at which fresh gas
can be delivered. Atelectasis can develop quickly48-50 and
particularly during surgery, when a decrease in the func-
tional residual capacity of the lungs with anesthesia and
paralysis promotes small airway and alveolar collapse.50
OXYGEN-INDUCED HYPERCAPNIA
Patients with severe COPD are prone to worsening hyper-
capnia during exacerbations when exposed to high levels
of inspired oxygen. This hypercapnia has been attributed
to suppression of the hypoxic drive to breathe in the set-
ting of a blunted hypercapnic drive.51 However, two other
mechanisms contribute to varying degrees in any given
patient.
Hypoxemia in patients with COPD is the result of low par-
_
tial pressure of alveolar oxygen (PAO2) in low V=Q regions.
_
To minimize the effects of these low V=Q regions in con-
tributing to hypoxemia, two responses of the pulmonary
circulation, hypoxic pulmonary vasoconstriction (HPV) and
hypercapnic pulmonary vasoconstriction, divert blood flow to
better-ventilated regions. When PAO2 is increased by supple-
mental oxygen, HPV is markedly reduced, increasing perfu-
sion to these regions and thus generating units of even lower
_
V=Q ratio, now oxygen enriched, but less able to eliminate
CO2. The increase in perfusion to these units comes at the
expense of better-ventilated units, which now do not elimi-
nate as much CO2 as before, leading to hypercapnia.52
4
An additional cause is reduction of the Haldane effect, which
is the increased capacity of deoxygenated blood to carry
more CO2 than oxygenated blood. As hemoglobin becomes
deoxygenated, it binds more protons (Hþ) and CO2 as carba-
mates. As deoxyhemoglobin concentration falls with oxygen
therapy, CO2 and Hþ buffering capacity are reduced, dimin-
ishing venous blood’s CO2 transport capacity with a resultant
rise in PaCO2.52
When administering supplemental O2 to those with chronic
CO2 retention or at risk, especially when they are very hyp-
oxemic and exhausted, careful titration of FIO2 to achieve
an SpO2 goal of 88 to 90% is important. Many case reports
have reported poor outcomes with unregulated FIO2, but
this was incontrovertibly shown in a randomized study in
patients with acute COPD exacerbations en route to the hos-
pital. Those randomly assigned to supplemental O2 titrated
to achieve an SpO2 in the range of 88 to 92% compared
with unrestricted O2 had a lower mortality of 2 versus 7%.53
ARDS AND BPD
Oxygen toxicity has long been implicated in the pathophysi-
ology of ARDS. In nonhuman mammals, exposure to 100%
oxygen leads to diffuse alveolar damage and, eventually,
death. However, unequivocal evidence of oxygen toxicity in
patients with severe pulmonary disease is difficult to distin-
guish from damage caused by the underlying disease. Fur-
thermore, many inflammatory diseases evoke upregulation
of antioxidant defenses. Thus, many studies have failed to
show an association between excessive oxygen exposure
and development of acute lung injury or ARDS.54,55
Premature newborns with hyaline membrane disease, a dis-
order caused by surfactant deficiency and characterized by
alveolar collapse and inflammation, often require high levels
of oxygen supplementation.56 Oxygen toxicity is considered
a major factor in the pathogenesis of BPD and occurs even
in those not requiring mechanical ventilation.56 Newborns
are particularly prone to hyperoxic damage, because their
cellular antioxidant defenses are not fully developed; this
effect is best established in retinopathy of prematurity, a dis-
order associated with repetitive hypoxic/hyperoxic stress.
Potentiation of Pulmonary
Oxygen Toxicity
Several drugs may potentiate oxygen toxicity. Oxygen
increases bleomycin ROS generation and is deactivated by
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bleomycin hydrolase, an otherwise ubiquitous enzyme not
expressed in the lung. In hamsters, high oxygen fractions
augment bleomycin-induced lung injury,57 and case re-
ports describe ARDS in patients previously treated with
bleomycin who had exposure to a high FIO2 periopera-
tively.58-60 However, one prospective trial failed to show
an association between high levels of oxygen exposure,
past bleomycin exposure, and significant postoperative
pulmonary dysfunction.61 Another potentiator of oxygen
toxicity is paraquat, a commercial herbicide.62-64 There-
fore, in managing patients with paraquat poisoning and
bleomycin exposure, FIO2 should be minimized as much
as possible. Other drugs that may potentiate oxygen toxic-
ity include disulfiram and nitrofurantoin.65,66 Protein and
nutritional deficiencies67 lead to hyperoxic damage, possi-
bly by a lack of thiol-containing amino acids, which are
crucial to glutathione synthesis, and deficiencies in antiox-
idant vitamins A and E.68,69
Oxygen Toxicity in Other
Organ Systems
Hyperoxia can produce toxicity beyond the lungs. An asso-
ciation between increased mortality and hyperoxia after
successful cardiopulmonary resuscitation (CPR) was sug-
gested by a large multicenter, retrospective cohort study,70
which found that patients who were hyperoxic and had a
PaO2 greater than 300 mm Hg following CPR had an odds
ratio for in-hospital death of 1.8 (95% confidence interval
[CI], 1.8 to 2.2) compared with patients who had normoxia
or hypoxia. The increased mortality was attributed to ROS-
mediated hyperoxic reperfusion injury worsening postarr-
est central nervous system functioning. A recent study also
described increased mortality in patients with hyperoxemia
immediately following emergency department intubation,
which correlated strikingly with the degree in elevation
of PaO2.71
With brain injury and stroke, there appears to be no benefit
in providing oxygen to patients who were not hypoxemic.
In a study conducted at a single trauma center, higher mor-
tality and lower Glasgow coma scores on discharge were
noted in patients with traumatic brain injuries exposed to
hyperoxia (PaO2>200 mm Hg) compared with normoxia.72
Another study of patients treated with hyperbaric oxygen
showed worse neurologic outcomes.73 In a large multicen-
ter trial of in-hospital provision of supplemental oxygen to
patients who were not hypoxemic (saturation of >96%)
5
with acute stroke, there was no benefit on mortality or
functional outcome by providing oxygen.74
In the case of acute myocardial infarction (AMI), supple-
mental oxygen is a commonly used therapy, although its use
in this setting is controversial. When treating patients with
AMI who are hypoxemic, oxygen is indicated, because it can
be lifesaving. However, without hypoxemia, the benefit of
traditional supplemental oxygen is unclear. A double-blind
randomized trial conducted in the late 1970 s compared
oxygen therapy (6 l/minute) with no oxygen therapy in
157 patients with uncomplicated AMI.75 In patients who
received oxygen, higher rates of sinus tachycardia and a
greater rise in myocardial enzymes were noted but with no
difference in mortality. In patients with nonhypoxemic ST
segment elevation AMI,76 there was no benefit of nasal can-
nula oxygen at 8 l/minute compared with ambient air. In
another study of 6 l/minute versus ambient air, the 1-year
mortality and rate of rehospitalization with AMI were no dif-
ferent.77 In patients with out-of-hospital cardiac arrest, there
was no benefit targeting oxygen saturation to 98 to 100%
over 90 to 94%.78 The potential deleterious effects of hyper-
oxia in AMI include coronary vasoconstriction, maldistribu-
tion of microcirculatory blood flow, increase in functional
O2 shunting, a reduction in oxygen consumption, and more
ROS damage in areas undergoing successful reperfusion.
Finally, clinical trials and meta-analyses have examined
the appropriate SpO2 target for critically ill inpatients. A
single-center, open-label randomized trial in 434 patients
in the intensive care unit (ICU) compared conservative
oxygen therapy (goal SpO2 of 94 to 98%) with conven-
tional therapy (accepting SpO2 values to 97 to 100%).
Patients randomly assigned to conservative oxygen ther-
apy had improved ICU mortality and a lower rate of
shock, liver failure, and bacteremia.79 A subsequent meta-
analysis examined results from 25 clinical trials that
enrolled over 16,000 inpatients with varying diagnoses,
including stroke, trauma, sepsis, myocardial infarction,
and emergency surgery. Results from this meta-analysis
also showed an increased hospital mortality in patients
receiving a liberal oxygen strategy (relative risk, 1.21; 95%
CI, 1.03 to 1.43).80 However, two subsequent large trials
failed to show an effect of a conservative oxygenation
strategy on ventilator-free days in patients with lung dis-
ease81 or 28-day survival in those with ARDS.82 More
recently, a study of 2541 patients receiving mechanical
ventilation found that targeting oxygen supplementation
to three different SpO2 ranges (88 to 92%, 92 to 96%, and
96 to 100%) did not affect the number of days alive and
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free of mechanical ventilation, mortality, cardiac arrest,
arrhythmia, myocardial infarction stroke, or pneumotho-
rax at 28 days.83 On the basis of these data, the British
Thoracic Society guidelines advocate for a target SpO2
range of 94 to 98% in most adult inpatients. This is rea-
sonable because this range (given the –2 to 3% error of
pulse oximetry) yields a safe but adequate PaO2 range of
65 to 100 mm Hg. In patients at risk for hypercapnic respi-
ratory failure, the range from 88 to 92% is a safer target to
avoid O2-induced hypercapnia.84
Conclusion
Oxygen has successfully revolutionized medical care since
the early half of the 20th century. Oxygen therapy may
improve oxygen delivery and reverse tissue ischemia. The
role of supplemental oxygen in the management of out-
patients with chronic, severe, pulmonary and cardiac diseases
is broad. In the outpatient setting, supplemental oxygen may
considerably improve quality of life in those patients willing
to adapt to its use. Despite the widespread availability of sup-
plemental oxygen and its relative ease of use, oxygen must
be considered a drug with a therapeutic window, above which
the potential for significant toxicity exists.
Disclosures
Author disclosures are available at evidence.nejm.org.
Author Affiliations
1
Division of Pulmonary, Critical Care and Sleep Medicine, VA Puget
Sound Health Care System, University of Washington, Seattle
2
Division of Pulmonary and Critical Care Medicine, Massachusetts
General Hospital, Harvard Medical School, Boston
References
1. Wemple ML, Swenson K, Swenson E. Oxygen therapy part 1 — his-
tory, physiology, and evaluation. NEJM Evid 2023;2(5). DOI: 10.
1056/EVIDra2300005.
2. Kallstrom TJ. AARC Clinical Practice Guideline: oxygen therapy for
adults in the acute care facility — 2002 revision & update. Respir
Care 2002;47:717-720 (https://www.aarc.org/wp-content/uploads/
2014/08/06.02.717.pdf).
3. O’Driscoll BR, Howard LS, Davison AG. BTS guideline for emer-
gency oxygen use in adult patients. Thorax 2008;63: Suppl 6:vi1-
vi68. DOI: 10.1136/thx.2008.102947.
4. Fulmer JD, Snider GL. American College of Chest Physicians
(ACCP) — National Heart, Lung, and Blood Institute (NHLBI) Con-
ference on oxygen therapy. Arch Intern Med 1984;144:1645-1655.
DOI: 10.1001/archinte.1984.00350200157023.
6
 5. Weaver LK, Howe S, Hopkins R, Chan KJ. Carboxyhemoglobin
half-life in carbon monoxide-poisoned patients treated with 100%
oxygen at atmospheric pressure. Chest 2000;117:801-808. DOI: 10.
1378/chest.117.3.801.
6. Hampson NB, Piantadosi CA, Thom SR, Weaver LK. Practice
recommendations in the diagnosis, management, and prevention of
carbon monoxide poisoning. Am J Respir Crit Care Med 2012;186:
1095-1101. DOI: 10.1164/rccm.201207-1284CI.
7. Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of
cluster headache: a randomized trial. JAMA 2009;302:2451-2457.
DOI: 10.1001/jama.2009.1855.
8. Miller ST, Kim H-Y, Weiner D, et al. Inpatient management of
sickle cell pain: a ‘snapshot’ of current practice. Am J Hematol
2012;87:333-336. DOI: 10.1002/ajh.22265.
9. Abernethy AP, Currow DC, Frith P, Fazekas BS. Prescribing palliative
oxygen: a clinician survey of expected benefit and patterns of use. Pal-
liat Med 2005;19:168-170. DOI: 10.1177/026921630501900219.
10. Kim KS, Jeon HW, Moon Y, et al. Clinical experience of spontane-
ous pneumomediastinum: diagnosis and treatment. J Thorac Dis
2015;7:1817-1824. DOI: 10.3978/j.issn.2072-1439.2015.10.58.
11. Chadha TS, Cohn MA. Noninvasive treatment of pneumothorax
with oxygen inhalation. Respiration 1983;44:147-152. DOI: 10.1159/
000194541.
12. Hill RC, DeCarlo DP Jr, Hill JF, Beamer KC, Hill ML, Timberlake
GA. Resolution of experimental pneumothorax in rabbits by oxygen
therapy. Ann Thorac Surg 1995;59:825-827. DOI: 10.1016/0003-
4975(95)00007-8.
13. Cohen B, Schacham YN, Ruetzler K, et al. Effect of intraoperative
hyperoxia on the incidence of surgical site infections: a meta-analysis.
Br J Anaesth 2018;120:1176-1186. DOI: 10.1016/j.bja.2018.02.027.
14. Markwei MT, Babatunde IO, Kutlu-Yalcin E, et al. Perioperative
supplemental oxygen and postoperative nausea and vomiting: sub-
analysis of a trial, systematic review, and meta-analysis. Anesthesi-
ology 2023;138:56-70. DOI: 10.1097/ALN.0000000000004428.
15. Tibbles PM, Edelsberg JS. Hyperbaric-oxygen therapy. N Engl J
Med 1996;334:1642-1648. DOI: 10.1056/NEJM199606203342506.
16. Jacobs SS, Krishnan JA, Lederer DJ, et al. Home oxygen therapy for
adults with chronic lung disease. An official American Thoracic
Society clinical practice guideline. [published correction appears
in Am J Respir Crit Care Med. 2021;203:1045-1046]. Am J Respir
Crit Care Med 2020;202:e121-e141. DOI: 10.1164/rccm.202009-
3608ST.
17. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal
oxygen therapy in hypoxemic chronic obstructive lung disease: a
clinical trial. Ann Intern Med 1980;93:391-398. DOI: 10.7326/
0003-4819-93-3-391.
18. Medical Research Council Working Party. Long term domiciliary
oxygen therapy in chronic hypoxic cor pulmonale complicating
chronic bronchitis and emphysema. Report of the Medical Research
Council Working Party. Lancet 1981;1:681-686.
NEJM EVIDENCE
NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from evidence.nejm.org on July 3, 2023. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society.
19. Albert RK, Au DH, Blackford AL, et al. A randomized trial of long-
term oxygen for COPD with moderate desaturation. N Engl J Med
2016;375:1617-1627. DOI: 10.1056/NEJMoa1604344.
20. Lacasse Y, Tan A-Y M, Maltais F, Krishnan JA. Home oxygen in
chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2018;197:1254-1264. DOI: 10.1164/rccm.201802-0382CI.
21. Lacasse Y, S
eri
es F, Corbeil F, et al. Randomized trial of nocturnal
oxygen in chronic obstructive pulmonary disease. N Engl J Med
2020;383:1129-1138. DOI: 10.1056/NEJMoa2013219.
22. Kushida CA, Littner MR, Hirshkowitz M, et al. Practice parameters
for the use of continuous and bilevel positive airway pressure
devices to treat adult patients with sleep-related breathing disor-
ders. Sleep 2006;29:375-380. DOI: 10.1093/sleep/29.3.375.
23. Chetta A, Castagnetti C, Aiello M, et al. Walking capacity and fit-
ness to fly in patients with chronic respiratory disease. Aviat Space
Environ Med 2007;78:789-792.
24. Gong H Jr, Tashkin DP, Lee EY, Simmons MS. Hypoxia-altitude
simulation test. Evaluation of patients with chronic airway obstruc-
tion. Am Rev Respir Dis 1984;130:980-986.
25. Mohr LC. Hypoxia during air travel in adults with pulmonary dis-
ease. Am J Med Sci 2008;335:71-79. DOI: 10.1097/MAJ.0b013e31
815f1e35.
26. Wagstaff TAJ, Soni N. Performance of six types of oxygen delivery
devices at varying respiratory rates. Anaesthesia 2007;62:492-503.
DOI: 10.1111/j.1365-2044.2007.05026.x.
27. Duprez F, Dupriez F, De Greef J, et al. Performance of different
low-flow oxygen delivery systems. Respir Care 2022;67:322-330.
DOI: 10.4187/respcare.09312.
28. Nishimura M. High-flow nasal cannula oxygen therapy in adults:
physiological benefits, indication, clinical benefits, and adverse
effects. Respir Care 2016;61:529-541. DOI: 10.4187/respcare.04577.
29. Ni Y-N, Luo J, Yu H, et al. Can high-flow nasal cannula reduce
the rate of endotracheal intubation in adult patients with acute
respiratory failure compared with conventional oxygen therapy and
noninvasive positive pressure ventilation?: a systematic review and
meta-analysis. Chest 2017;151:764-775. DOI: 10.1016/j.chest.2017.
01.004.
30. Ferreyro BL, Angriman F, Munshi L, et al. Association of noninva-
sive oxygenation strategies with all-cause mortality in adults with
acute hypoxemic respiratory failure: a systematic review and meta-
analysis. JAMA 2020;324:57-67. DOI: 10.1001/jama.2020.9524.
31. Munshi L, Mancebo J, Brochard LJ. Noninvasive respiratory support
for adults with acute respiratory failure. N Engl J Med 2022;387:
1688-1698. DOI: 10.1056/NEJMra2204556.
32. Roca O, Caralt B, Messika J, et al. An index combining respiratory
rate and oxygenation to predict outcome of nasal high-flow ther-
apy. Am J Respir Crit Care Med 2019;199:1368-1376. DOI: 10.
1164/rccm.201803-0589OC.
33. Weaver L, Das A, Saffaran S, et al. High risk of patient self-
inflicted lung injury in COVID-19 with frequently encountered
7
 spontaneous breathing patterns: a computational modelling study.
Ann Intensive Care 2021;11:109. DOI: 10.1186/s13613-021-00904-7.
34. Priestley J. Experiments and observations on different kinds of air.
London: J. Johnson, 1775.
35. Becker-Freysang H. Physiological and pathophysiological effects
of increased oxygen tension. In: USAF School of Aviation Medicine.
German aviation medicine in World War II. Vol. 1. Washington,
DC: Department of the Air Force, 1950:493-514.
36. Frank L, Bucher JR, Roberts RJ. Oxygen toxicity in neonatal and
adult animals of various species. J Appl Physiol 1978;45:699-704.
DOI: 10.1152/jappl.1978.45.5.699.
37. Freeman BA, Crapo JD. Biology of disease: free radicals and tissue
injury. Lab Invest 1982;47:412-426.
38. Cantin AM, North SL, Hubbard RC, Crystal RG. Normal alveolar
epithelial lining fluid contains high levels of glutathione. J Appl
Physiol (1985) 1987;63:152-157. DOI: 10.1152/jappl.1987.63.1.152.
39. Oury TD, Chang LY, Marklund SL, Day BJ, Crapo JD. Immunocyto-
chemical localization of extracellular superoxide dismutase in
human lung. Lab Invest 1994;70:889-898.
40. Carlsson LM, Jonsson J, Edlund T, Marklund SL. Mice lacking
extracellular superoxide dismutase are more sensitive to hyperoxia.
Proc Natl Acad Sci USA 1995;92:6264-6268. DOI: 10.1073/pnas.92.
14.6264.
41. Matute-Bello G, Frevert CW, Martin TR. Animal models of acute
lung injury. Am J Physiol Lung Cell Mol Physiol 2008;295:L379-
L399. DOI: 10.1152/ajplung.00010.2008.
42. Dolezal V. The effect of longlasting oxygen inhalation upon respira-
tory parameters in man. Physiol Bohemoslov (1956) 1962;11:149-158.
43. Caldwell PR, Lee WL Jr, Schildkraut HS, Archibald ER. Changes in
lung volume, diffusing capacity, and blood gases in men breathing
oxygen. J Appl Physiol 1966;21:1477-1483. DOI: 10.1152/jappl.1966.
21.5.1477.
44. Sackner MA, Landa J, Hirsch J, Zapata A. Pulmonary effects of oxy-
gen breathing. A 6-hour study in normal men. Ann Intern Med
60. Gilson AJ, Sahn SA. Reactivation of bleomycin lung toxicity follow-
1975;82:40-43. DOI: 10.7326/0003-4819-82-1-40.
45. Carvalho CR, de Paula Pinto Schettino G, Maranh~ao B, Bethlem
EP. Hyperoxia and lung disease. Curr Opin Pulm Med 1998;4:300-
304. DOI: 10.1097/00063198-199809000-00010.
46. Hayes D Jr, Feola DJ, Murphy BS, Shook LA, Ballard HO. Patho-
genesis of bronchopulmonary dysplasia. Respiration 2010;79:425-
436. DOI: 10.1159/000242497.
47. Downs JB. Has oxygen administration delayed appropriate respira-
tory care? Fallacies regarding oxygen therapy. Respir Care 2003;
48:611-620.
48. Joyce CJ, Williams AB. Kinetics of absorption atelectasis during
anesthesia: a mathematical model. J Appl Physiol (1985) 1999;86:
1116-1125. DOI: 10.1152/jappl.1999.86.4.1116.
49. Beno^ıt Z, Wicky S, Fischer J-F, et al. The effect of increased FIO2
before tracheal extubation on postoperative atelectasis. Anesth
NEJM EVIDENCE
NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from evidence.nejm.org on July 3, 2023. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society.
Analg 2002;95:1777-1781. DOI: 10.1097/00000539-200212000-
00058.
50. Hedenstierna G, Edmark L. Mechanisms of atelectasis in the peri-
operative period. Best Pract Res Clin Anaesthesiol 2010;24:157-169.
DOI: 10.1016/j.bpa.2009.12.002.
51. Davies CE, Mackinnon J. Neurological effects of oxygen in chronic
cor pulmonale. Lancet 1949;254:883-885. DOI: 10.1016/S0140-
6736(49)91459-2.
52. Abdo WF, Heunks LMA. Oxygen-induced hypercapnia in COPD:
myths and facts. Crit Care 2012;16:323. DOI: 10.1186/cc11475.
53. Austin MA, Wills KE, Blizzard L, Walters EH, Wood-Baker R.
Effect of high flow oxygen on mortality in chronic obstructive pul-
monary disease patients in prehospital setting: randomised con-
trolled trial. BMJ 2010;341:c5462. DOI: 10.1136/bmj.c5462.
54. Barber RE, Lee J, Hamilton WK. Oxygen toxicity in man — a pro-
spective study in patients with irreversible brain damage. N Engl J
Med 1970;283:1478-1484. DOI: 10.1056/NEJM197012312832702.
55. Singer MM, Wright F, Stanley LK, Roe BB, Hamilton WK. Oxygen
toxicity in man — a prospective study in patients after open-heart
surgery. N Engl J Med 1970;283:1473-1478. DOI: 10.1056/NEJM197
012312832701.
56. Clark RH, Gerstmann DR, Jobe AH, Moffitt ST, Slutsky AS, Yoder
BA. Lung injury in neonates: causes, strategies for prevention, and
long-term consequences. J Pediatr 2001;139:478-486. DOI: 10.
1067/mpd.2001.118201.
57. Meadors M, Floyd J, Perry MC. Pulmonary toxicity of chemotherapy.
Semin Oncol 2006;33:98-105. DOI: 10.1053/j.seminoncol.2005.11.005.
58. Tryka AF, Skornik WA, Godleski JJ, Brain JD. Potentiation of
bleomycin-induced lung injury by exposure to 70% oxygen. Mor-
phologic assessment. Am Rev Respir Dis 1982;126:1074-1079.
59. Nygaard K, Smith-Erichsen N, Hatlevoll R, Refsum SB. Pulmonary
complications after bleomycin, irradiation and surgery for esophageal
cancer. Cancer 1978;41:17-22. DOI: 10.1002/1097-0142(197801)41:
1<17::AID-CNCR2820410105>3.0.CO;2-Q.
ing oxygen administration. A second response to corticosteroids.
Chest 1985;88:304-306. DOI: 10.1378/chest.88.2.304.
61. Donat SM, Levy DA. Bleomycin associated pulmonary toxicity: is
perioperative oxygen restriction necessary? J Urol 1998;160:1347-
1352. DOI: 10.1016/S0022-5347(01)62533-3.
62. Gawarammana IB, Buckley NA. Medical management of paraquat
ingestion. Br J Clin Pharmacol 2011;72:745-757. DOI: 10.1111/j.
1365-2125.2011.04026.x.
63. Hoet PHM, Demedts M, Nemery B. Effects of oxygen pressure and
medium volume on the toxicity of paraquat in rat and human type
II pneumocytes. Hum Exp Toxicol 1997;16:305-310. DOI: 10.1177/
096032719701600602.
64. Huang NC, Lin SL, Hung YM, Hung SY, Chung HM. Severity
assessment in acute paraquat poisoning by analysis of APACHE II
score. J Formos Med Assoc 2003;102:782-787.
8
65. Forman HJ, York JL, Fisher AB. Mechanism for the potentiation of
oxygen toxicity by disulfiram. J Pharmacol Exp Ther 1980;212:452-455.
66. Boyd MR, Catignani GL, Sasame HA, Mitchell JR, Stiko AW. Acute
pulmonary injury in rats by nitrofurantoin and modification by vita-
min E, dietary fat, and oxygen. Am Rev Respir Dis 1979;120:93-99.
67. Deneke SM, Gershoff SN, Fanburg BL. Potentiation of oxygen tox-
icity in rats by dietary protein or amino acid deficiency. J Appl Phy-
siol 1983;54:147-151. DOI: 10.1152/jappl.1983.54.1.147.
68. Cohen-Addad N, Bollinger R, Chou J, Poland R. Vitamin A defi-
ciency and pulmonary oxygen toxicity: morphometric studies in the
murine lung. Pediatr Res 1988;23:76-80. DOI: 10.1203/00006450-
198801000-00017.
69. Yamaoka S, Kim H-S, Ogihara T, et al. Severe vitamin E deficiency
exacerbates acute hyperoxic lung injury associated with increased
oxidative stress and inflammation. Free Radic Res 2008;42:602-
612. DOI: 10.1080/10715760802189864.
70. Kilgannon JH, Jones AE, Shapiro NI, et al. Association between arterial
hyperoxia following resuscitation from cardiac arrest and in-hospital
mortality. JAMA 2010;303:2165-2171. DOI: 10.1001/jama.2010.707.
71. Page D, Ablordeppey E, Wessman BT, et al. Emergency depart-
ment hyperoxia is associated with increased mortality in mechani-
cally ventilated patients: a cohort study. Crit Care 2018;22:9. DOI:
10.1186/s13054-017-1926-4.
72. Brenner M, Stein D, Hu P, Kufera J, Wooford M, Scalea T. Association
between early hyperoxia and worse outcomes after traumatic brain
injury. Arch Surg 2012;147:1042-1046. DOI: 10.1001/archsurg.2012.1560.
73. Rusyniak DE, Kirk MA, May JD, et al. Hyperbaric oxygen therapy
in acute ischemic stroke: results of the Hyperbaric Oxygen in Acute
Ischemic Stroke Trial Pilot Study. Stroke 2003;34:571-574. DOI: 10.
1161/01.STR.0000050644.48393.D0.
74. Roffe C, Nevatte T, Sim J, et al. Effect of routine low-dose oxygen
supplementation on death and disability in adults with acute stroke.
The Stroke Oxygen Study randomized clinical trial. JAMA 2017;318:
1125-1135. DOI: 10.1001/jama.2017.11463.
NEJM EVIDENCE
NEJM Evidence is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from evidence.nejm.org on July 3, 2023. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
For personal use only. No other uses without permission. Copyright © 2023 Massachusetts Medical Society.
75. Rawles JM, Kenmure AC. Controlled trial of oxygen in uncompli-
cated myocardial infarction. BMJ 1976;1:1121-1123. DOI: 10.1136/
bmj.1.6018.1121.
76. Stub D, Smith K, Bernard S, et al. Air versus oxygen in ST-
segment–elevation myocardial infarction. Circulation 2015;131:
2143-2150. DOI: 10.1161/CIRCULATIONAHA.114.014494.
77. Hofmann R, James SK, Jernberg T, Lindahl B, et al. Oxygen ther-
apy in suspected acute myocardial infarction. N Engl J Med 2017;
377:1240-1249. DOI: 10.1056/NEJMoa1706222.
78. Bernard SA, Bray JE, Smith K, et al. Effect of lower vs higher oxy-
gen saturation targets on survival to hospital discharge among
patients resuscitated after out-of-hospital-arrest: the EXACT ran-
domized clinical trial. JAMA 2022;328:1818-1826. DOI: 10.1001/
jama.2022.17701.
79. Girardis M, Busani S, Damiani E, et al. Effect of conservative vs
conventional oxygen therapy on mortality among patients in an
intensive care unit: the Oxygen-ICU randomized clinical trial.
JAMA 2016;316:1583-1589. DOI: 10.1001/jama.2016.11993.
80. Chu DK, Kim LH-Y, Young PJ, et al. Mortality and morbidity in
acutely ill adults treated with liberal versus conservative oxygen
therapy (IOTA): a systematic review and meta-analysis. Lancet
2018;391:1693-1705. DOI: 10.1016/S0140-6736(18)30479-3.
81. Mackle D, Bellomo R, Bailey M, et al. Conservative oxygen therapy
during mechanical ventilation in the ICU. N Engl J Med 2020;382:
989-998. DOI: 10.1056/NEJMoa1903297.
82. Barrot L, Asfar P, Mauny F, et al. Liberal or conservative oxygen
therapy for acute respiratory distress syndrome. N Engl J Med
2020;382:999-1008. DOI: 10.1056/NEJMoa1916431.
83. Semler MW, Casey JD, Lloyd BD, et al. Oxygen-saturation targets
of critically ill adults receiving mechanical ventilation. N Engl J
Med 2022;387:1759-1769. DOI: 10.1056/NEJMoa2208415.
84. O’Driscoll BR, Howard LS, Earis J, Mak V. BTS guideline for oxy-
gen use in adults in healthcare and emergency settings. Thorax
2017;72: Suppl 1:ii1-ii90. DOI: 10.1136/thoraxjnl-2016-209729.
9