PERSPECTIVE

Targeting Normoxemia in Acute Respiratory Distress Syndrome May

Cause Worse Short-Term Outcomes because of Oxygen Toxicity
Neil R. Aggarwal and Roy G. Brower
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Abstract coexisting lung inammation increases susceptibility to oxygen

It was suggested that targeting normoxemia (PaO2 85110 mm Hg) in
patients with acute respiratory distress syndrome (ARDS) might
prevent neurocognitive dysfunction in survivors. However, targeting
normoxemia may cause detrimental effects to the lungs from oxygen
toxicity. Some have suggested that oxygen is not harmful to the lungs
at FIO2 (fraction of inspired oxygen) levels less than 0.60.7, but
contrasting evidence in normal humans suggests that there can be
untoward effects of moderate FIO2 levels. Furthermore, in
experimental models of the acute respiratory distress syndrome,
toxicity. Coexisting lung inammation may lower the threshold for
oxygen toxicity in patients with ARDS or in other acute illnesses in
the lung. Moreover, physicians frequently prescribe higher FIO2 levels
than are necessary to achieve their arterial oxygenation goal, further
increasing the risk of oxygen toxicity. Targeting normoxemia in
patients with ARDS may prevent some long-term neurocognitive
decits in survivors, but it may increase lung inammation and cause
worse short-term clinical outcomes. We advocate for a clinical trial in
patients with ARDS to determine more appropriate goals for arterial
oxygenation.

(Received in original form July 4, 2014; accepted in final form September 22, 2014 )
Correspondence and requests for reprints should be addressed to Neil R. Aggarwal, M.D., Johns Hopkins University School of Medicine, Pulmonary and Critical
Care Medicine, Johns Hopkins Asthma & Allergy Center, Room 4B.68, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: naggarw1@jhmi.edu
Ann Am Thorac Soc Vol 11, No 9, pp 14491453, Nov 2014
Copyright 2014 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.201407-297PS
Internet address: www.atsjournals.org

In their article in the Annals, Mikkelsen
and colleagues suggest that targeting
normoxemia (PaO2 85110 mm Hg) in
patients with acute respiratory distress
syndrome (ARDS) might prevent
neurocognitive dysfunction in survivors
(1). Normoxemia might be good for
neurocognition in the long term, but it may
be unfavorable for ARDS survival in the
short term because of oxygen toxicity. We
surmise that Mikkelsen and colleagues may
be understating the potential short-term
risks of a high fraction of inspired oxygen
(FIO2) in patients with ARDS. It is tempting
to try to normalize variables such as PaO2,
but like everything we do in medicine, there
are risks.
The primary goal of this perspective
is to provide evidence that in targeting
normoxemia, patients may be exposed
to unnecessarily high FIO2 levels that
exacerbate lung injury. In support of this
idea, we highlight uncertainty in our
understanding of human oxygen toxicity, as
evidence suggests that oxygen can be toxic
to the lungs of normal humans even at
moderate concentrations (FIO2 0.50.6) (2).
Furthermore, experimental models
demonstrate that coexisting lung
inammation such as sepsis increases
susceptibility to oxygen toxicity (3, 4).
Work also suggests that hyperoxia can lead
to worse outcomes in other acute
conditions including cardiac arrest (5) and
chronic obstructive pulmonary disease
(COPD) exacerbation (6). In addition,
with the National Institutes of Health
(Bethesda, MD) focus on prevention and
early treatment of acute lung injury,
understanding the relevance of oxygen
toxicity in these susceptible populations
will be important in the design of future
studies. We stress the need for
a prospective study to establish more
appropriate goals for arterial oxygenation
in patients with ARDS.
What Is a Safe FIO2?
A safe level and duration of oxygen
exposure has not been established even
in normal humans. Animal studies
demonstrate a spectrum of susceptibility
to oxygen across and within species.
Determinants of oxygen-induced tissue
injury include age as well as the oxygen
concentration and duration of oxygen
exposure (7). Humans and other primates
are thought to have similar susceptibilities
to oxygen toxicity. However, studies in
primates demonstrate interspecies
differences in susceptibility. In one study,
rhesus monkeys required more than 5 days
of exposure to greater than 90% oxygen
before they developed symptoms, and the
average exposure time to death was 10 days
(8). In a study in which primates were
exposed to an FIO2 of 1.0, mortality rates
by Day 6 were 57% in baboons compared
with 33% in rhesus monkeys (9).

Perspective 1449

Many clinicians believe that FIO2 levels
lower than 0.60.7 are safe. This conclusion
may be based primarily on studies, in
normal humans, with subjective end points
that lacked a rigorous assessment of lung
inammation and barrier function, and
on studies in patients with coexisting
respiratory disease or potentially harmful
concurrent exposures. In a study by
Comroe and colleagues, healthy volunteers
complained of chest discomfort and cough
when exposed to FIO2 levels greater than
0.75 for only 24 hours (10). Exposures to
moderate oxygen concentrations (0.5 ,
FIO2 , 0.75) commonly used in patients
with ARDS were not tested in this study.
Moreover, lung inammation, vascular
permeability, and barrier function were not
assessed. Studies by Sevitt (11) and Nash
and colleagues (12) demonstrate evidence
supporting the potential harm of FIO2 levels
less than 0.6, but it is difcult to conclude
that harm occurred only as a result of
excess oxygen because of existing
respiratory pathology or exposure to
mechanical ventilation. More recently,
Grifth and colleagues exposed normal
subjects to an FIO2 of 0.50 for a mean of 44
hours. They demonstrated increased lung
inammation and impaired endothelial and
epithelial barrier function compared with
room air exposure (2). We still do not know
the minimal concentration of oxygen and
duration of exposure sufcient to induce
lung damage in normal humans.
Patients Frequently Receive
More Oxygen Than Is Needed
to Achieve Arterial
Oxygenations Goals
Evidence suggests that many patients with
acute respiratory failure are exposed to
excess oxygen. In the ARDS Network,
a frequent violation of the ventilator
management protocols was a lack of
response to PaO2 above the goal range (13).
Providers usually respond quickly when
PaO2 or oxyhemoglobin saturation falls
below the goal range, but they are slow to
respond when arterial oxygenation exceeds
the goal range. This appears to be related to
clinician behavior, and may also be based
on a lack of understanding of oxygen
toxicity in humans (14, 15). A number of
factors have likely contributed to the
practice of permitting excessively high PaO2
values, including a focus on avoiding
1450
hypoxemia and a culture that has not
highlighted the importance of precise
control (1416).
Other studies in patients with acute
respiratory failure also demonstrate
a tendency to err on the side of excessive
oxygen exposure. de Graaff and colleagues
assessed the response of intensive care unit
(ICU) physicians to hyperoxemia, dened
in their study as a PaO2 greater than 120 mm
Hg (.16 kPa), among mechanically
ventilated patients receiving supplemental
oxygen. In this population, the FIO2 was
reduced in only 25% of instances over
a 24-hour period (17). Because arterial
blood gases were obtained an average of
nine times in 24 hours, physicians had
numerous opportunities to reduce FIO2, but
minimal action was taken in response to
PaO2 levels that exceeded normoxemia.
Suzuki and colleagues assessed physician
responses to oxyhemoglobin saturations
greater than or equal to 99% in patients
with acute respiratory failure. When the
starting FIO2 was greater than or equal to
0.6, it was reduced in more than 95% of
instances. However, when the starting FIO2
was 0.5, no changes were made 57% of the
time. When the starting FIO2 was 0.4, it
was not changed 76% of the time and was
actually increased 5% of the time (18). This
study strongly suggests that physicians
accept FIO2 levels less than 0.6 as safe even
in patients with acute respiratory failure.
Even after an ICU adopted a conservative
oxygen therapy (oxygen saturation as
determined by pulse oximetry [SpO2] goal
9092%) approach to avoid unnecessary
exposures to oxygen, nearly half of SpO2
levels were well above the upper limit of
the goal range (19). Despite signicant
nonadherence, two-thirds less oxygen was
used in the conservative group without
adverse effects. Thus, many patients are
exposed to FIO2 levels that are higher than
necessary to achieve a goal arterial
oxygenation range.
Physicians may miss opportunities to
avoid unnecessary exposures to high FIO2
levels because they frequently rely on pulse
oximetry to monitor arterial oxygenation.
In practice we assume normoxemia when
SpO2 is high-normal (.95%), but the actual
PaO2 can exceed normoxemia (80100
mm Hg) and extend into hyperoxemia (.120
mm Hg). In a study by Rice and colleagues
in patients with ARDS, for a given SpO2/
FIO2, the range of corresponding PaO2/FIO2
ratios was wide (20). For example, at an
AnnalsATS Volume 11 Number 9 | November 2014
PERSPECTIVE
SpO2/FIO2 of approximately 180, the PaO2/
FIO2 varied from less than 100 to more than
300, suggesting numerous instances of
unnecessarily high PaO2.
Adjusting FIO2 or positive end-
expiratory pressure (PEEP) can be an
effective strategy to increase PaO2. However,
in a study of patients with ARDS, Rachmale
and colleagues demonstrate that clinicians
frequently elect to raise FIO2 before raising
PEEP (21). They dened excessive oxygen
use as an FIO2 greater than 0.50 when SpO2
values exceeded 92%. In the 48 hours
after intubation, excessive oxygen use
occurred in 74% of ventilated patients for
a median of 17 hours. Patients receiving
excessive FIO2 had signicantly lower PEEP
levels compared with those treated without
excessive FIO2 (5 vs. 8 mm Hg). The
discrepancy between excessive FIO2 and
lower PEEP exposure suggests that
clinicians may adjust PEEP and FIO2 on the
basis of their perceptions of the potential
risks and benets of both, and consider the
potential harm of higher PEEP to outweigh
the potential harm of higher FIO2.
Are Unnecessary FIO2 Levels
Safe in Acute Respiratory
Failure?
By erring on the safe, high side of a PaO2
range, patients with acute respiratory
failure are exposed to unnecessarily high
and potentially harmful oxygen
concentrations. In the study by Rachmale
and colleagues, increasing durations of
exposure to excessive oxygen were
associated with worsening oxygenation
indices. Excessive oxygen exposure was also
associated with longer durations of
mechanical ventilation, and longer ICU and
hospital lengths of stays (21). A study by de
Jonge and colleagues suggested a direct
association between hospital mortality and
higher FIO2 values in the rst 24 hours
after initiation of mechanical ventilation.
This was to be expected in patients with
correspondingly low PaO2 values (low
PaO2/FIO2 ratio). However, a higher FIO2 was
also associated with increased mortality in
patients with high PaO2 values (high
PaO2/FIO2), suggesting that oxygen toxicity
contributed to in-hospital mortality (22).
In contrast to the studies by Rachmale
and de Jonge, a study by Eastwood and
colleagues did not demonstrate an
association between excessive oxygen use
 PERSPECTIVE
in the rst 24 hours and increased hospital
mortality (23). To date, studies evaluating the
effects of hyperoxia in patients with ARDS
have been predominantly observational,
making it difcult to draw any specic
conclusions about the effects of excess oxygen.
Exposures to Moderate FIO2
Levels Can Exacerbate
Lung Inammation
In response to high levels of oxygen
exposure or other sources of oxidative stress,
mammalian adaptation includes production
of more antioxidant enzymes such as
superoxide dismutase, catalase, and
glutathione peroxidase, which reduce
reactive oxygen species (ROS) to water.
However, patients with ARDS may be more
susceptible to the harmful effects of oxygen
because their adaptive responses are
impaired by lung inammation and damage.
By quantifying uorescent products of lipid
peroxidation in the alveolar uid, Grifth
and colleagues suggested that there was
a signicant increase in oxidative stress after
exposure to an FIO2 of 0.5 for 44 hours in
healthy humans (2). Mitochondria in
cells exposed to hyperoxia are a signicant
source of ROS. Despite a linear relationship
between oxygen concentration and the
rate of mitochondrial superoxide anion
(O2$) production, the release of hydrogen
peroxide (H2O2) from lung mitochondria
occurs at a faster rate when FIO2 exceeds 0.6
(2426). The authors suggested that FIO2
greater than 0.6 exceeds a threshold of
mitochondrial antioxidant defenses.
Independent of FIO2, ROS are generated by
lung inammatory processes. Coupled with
reduced production from damaged lung
cells, lung antioxidant enzyme reservoirs
may be depleted in the setting of lung
inammation. Thus, patients with ARDS
may be more susceptible to oxygen toxicity
than normal patients. Turrens and
colleagues demonstrated that early delivery
of catalase and superoxide dismutase
containing liposomes prolonged survival in
rats exposed to 100% oxygen (27). Delayed
administration, that is, after the onset of
lung inammation and exposure to toxic
concentrations of oxygen, may explain the
negative results of clinical studies that
have tested the therapeutic effects of
antioxidant therapy in ARDS (2830).
There is now a shift toward prevention
and early treatment of ARDS (PETAL;
Perspective
http://grants.nih.gov/grants/guide/rfa-les/
RFA-HL-14-014.html). Varying somewhat
on the basis of patient population,
a signicant percentage (2080%) of
patients develop ARDS more than 24 hours
after hospital admission (3135). As
a result, there is growing interest in
recognizing and reducing second-hit lung
insults, such as mechanical ventilation with
higher tidal volumes and unnecessary blood
product transfusions, that may increase the
incidence of in-hospital ARDS in patients
at high risk. Hyperoxia, even at moderate
FIO2 levels, may be a second hit. Sinclair and
colleagues exposed rabbits to 4 hours of
mechanical ventilation, using tidal volumes
of 25 ml/kg with room air or 50% oxygen.
There was a signicant reduction in the
PaO2/FIO2 and signicant increases in
histologic lung injury, alveolar neutrophils,
and alveolarcapillary permeability in
rabbits that received 50% oxygen (4).
Using another experimental model in
which acute lung injury evolves more
slowly, we exposed mice to intratracheal
low-dose LPS followed 12 hours later with
60 or 27% oxygen for 1 to 3 days. There
was synergistic augmentation of lung
injury, demonstrated by increased alveolar
neutrophils and alveolar protein (Figure 1)
in mice exposed to intratracheal LPS plus
60% oxygen compared with mice exposed
to intratracheal LPS plus room air,
intratracheal LPS plus 27% oxygen, or
intratracheal H2O plus 60% oxygen (3).
Alveolar macrophages collected from mice
exposed to intratracheal LPS plus 60%
oxygen produced higher levels of ROS and
proinammatory cytokines compared with
500
BAL Protein (g/mL)
400
300
200
100
0
W W+O2
(60%)
Day 4 after IT LPS (L) or Water (W)
Figure 1. Murine bronchoalveolar (BAL) protein was measured in lavage fluid on Day 4 after
intratracheal (IT) instillation of LPS or water followed 12 hours later by exposure to room air or oxygen
(27 or 60%) (n = 58 in each group, *P , 0.05 compared with all other groups). Adapted from
Reference 3.
mice exposed to intratracheal LPS or 60%
oxygen alone. Therefore, 60% oxygen,
but not 27% oxygen, was sufcient to
induce oxygen toxicity and augment lung
injury when coupled with mild lung
inammation.
Lower Arterial Oxygen Goals:
Difcult to Achieve, But Should
Be Evaluated
Training physicians to maintain
normoxemia with more rigorous oxygen
titration is possible, but this will likely be
a slow process even within the protocol of
a clinical trial. In a study comparing titrated
oxygen therapy versus usual oxygen therapy
to patients with COPD exacerbations,
Austin and colleagues demonstrated
reduced adherence by health care personnel
in the titrated oxygen group with an
oxyhemoglobin saturation goal of 8892%
(6). However, over an 8-year period, Li and
colleagues were successful in implementing
hospital-wide changes in physician
management, and demonstrated a signicant
50% reduction in the incidence of in-hospital
ARDS by using noninvasive, protocol-based
interventions (36). Changes in physician
behavior included lung-protective ventilation
in patients without ARDS, goal-directed uid
therapy, and early antibiotic administration.
Changing physician behavior to limit
excessive oxygen by using protocols to
achieve and maintain a goal PaO2 or SpO2
range could positively affect patient
outcomes, but may be challenging given the
severity of illness in ARDS. However, in
*
LPS L+O2 L+O2
(60%) (27%)
1451
 PERSPECTIVE

a prospective trial, Suzuki and colleagues
demonstrated safety and feasibility in
adopting a lower arterial oxygen saturation
goal in patients with ARDS (19). We
hypothesize that implementing a protocol
to frequently monitor oxygenation and
target mild permissive hypoxemia (PaO2
5580, SpO2 8892%) could lead to better
outcomes in patients with ARDS and those
at increased risk for ARDS. We suggest
a modied range for SpO2 compared with
that used by the ARDS Network in part
because an SpO2 of 9395% may be
unnecessary to maintain a PaO2 greater than
60 in the majority of patients, and because
clinicians frequently allow higher oxygen
saturation levels than the goal range.
Furthermore, minimizing excessive oxygen
may reduce the progression to ARDS
among patients with early acute lung
injury (EALI) dened as having an
ARDS risk factor, bilateral inltrates,
and receiving oxygen at more than 2
L/minute (37).
Excessive Oxygen Is
Detrimental in Other Acute
Conditions
Excessive oxygen appears to increase
mortality in several other acute conditions.
In the rst 24 hours after cardiac arrest,
a higher maximal PaO2 (254 mm Hg,
interquartile range 172363) was associated
with increased in-hospital mortality and
worse neurological status compared with
a lower maximal PaO2 (198 mm Hg,
interquartile range 152.5282) (38). Austin
and colleagues demonstrated that among
patients with a presumed acute COPD
exacerbation, compared with control
patients treated empirically with 810 L of
O2 per minute, titrating oxygen to a goal
oxyhemoglobin saturation of 8892% was
associated with a reduction in overall
mortality of 58%, and a reduction of 78%
among those with conrmed COPD (6). In
a retrospective cohort study in patients with
stroke who received mechanical ventilation,
hyperoxia (PaO2 > 300 mm Hg) was
associated with higher mortality (39).
Smaller observational studies in patients
with myocardial infarction suggest that
there was a detrimental effect of hyperoxia
on infarct size (40) and hemodynamic
proles (41). A meta-analysis suggested an
increased pooled risk ratio of death in
patients who received oxygen therapy
(46 L) within the rst 24 hours after
conrmed or suspected acute myocardial
infarction when compared with those
treated with room air (42). Thus, data
from other acute inammatory diseases
strengthens the need to test the effects of
excess oxygen exposure in patients with
EALI or ARDS.
Normalizing Physiological
Variables: A Risky Proposition
In the management of critically ill patients,
many studies suggest that normalization of
variables is associated with worse outcome.
The ARDS Network demonstrated that low
tidal volume ventilation signicantly
reduced mortality in patients with ARDS
even though it induced more hypercapnia
and respiratory acidosis (43). Hebert and
colleagues demonstrated that a liberal red
cell transfusion strategy with a goal Hb
1012 g/dl increased hospital mortality
compared with restricted transfusion
strategy with a goal Hb of 79 g/dl among
patients with APACHE scores less than
20 (44). Similar results regarding liberal
transfusion strategies were demonstrated by
Lacroix in critically ill children (45). Much
of what we do in medicine has associated
risk. Many physicians have an irresistible
urge to normalize physiological variables,
believing that correcting abnormal variables
will improve outcome. But sometimes, we
can do more harm than good. We should
not assume that normalization of arterial
oxyhemoglobin saturation would be
benecial toward clinical outcomes.
Conclusion
Short-term mortality and long-term
neurocognitive dysfunction may be
competing risks. We agree with Mikkelsen
and colleagues as to the potential advantages
and disadvantages of lower and higher
arterial oxygenation goals (1). However, we
need rst to determine whether targeting
normoxemia leads to excess oxygen and
higher mortality before we assess what is
best for long-term neurocognitive function
in survivors. Safe levels and durations of
FIO2 exposure have not been established in
normal humans, those with acute lung
inammation at risk for ARDS, or those
with ARDS. Studies of patients with acute
respiratory failure demonstrate that
patients frequently receive FIO2 levels that
are greater than those necessary to achieve
the goal PaO2 or SpO2. Various observational
reports thus far have been inconsistent
regarding effects of excessive oxygen
exposure in patients with respiratory
failure. We need more rigorous, prospective
studies to determine optimal oxygenation
strategies. We agree that a clinical trial is
necessary to assess whether a concerted,
protocol-driven effort to maintain patients
with EALI or ARDS in the range of mild
hypoxemia or even normoxemia may
minimize the risk of excess oxygen on lung
toxicity and positively affect survival from
this devastating illness. n
Author disclosures are available with the text
of this article at www.atsjournals.org.
Acknowledgment: The authors thank David
Hager, M.D., Ph.D., and David Pearse, M.D., for
critical review of the manuscript.

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