Opinion
EDITORIAL
Oxygen in the ICU
Too Much of a Good Thing?
Niall D. Ferguson, MD, MSc
Oxygen gas was discovered and described in the 1770s
by Scheele, Priestley, and Lavoisier and shortly thereafter
its therapeutic potential for patients with respiratory ill-
ness was appreciated.1 Oxy-
gen has become a mainstay of
Related article treatment for acutely ill pa-
tients, with emphasis fre-
quently placed on the importance of avoiding hypoxemia.2
Modern clinical practice guidelines for critically ill patients3
generally target the normal levels for the partial pressure of
arterial oxygen (PaO2) and the oxyhemoglobin saturation in ar-
terial blood (SaO2), which range from 89 through 100 mm Hg
and 95% through 97%, respectively, depending on patient age.4
Avoiding hypoxemia is sensible from a physiological stand-
point because the focus is on maintaining adequate oxygen de-
livery to vital tissues. Oxygen saturation is 1 of only 3 variables,
along with cardiac output and hemoglobin concentration, that
can be manipulated to achieve this goal. In addition, data from
adults with acute respiratory distress syndrome (ARDS) sug-
gest that lower levels of oxygenation in the intensive care unit
(ICU) are associated with worse long-term cognitive and neu-
ropsychological outcomes.5,6 Furthermore, randomized trials
of permissive hypoxemia in neonates aimed at reducing reti-
nopathy of prematurity resulted in higher mortality in the lower
oxygen group.7-9 Given these concerns about potential dan-
gers, clinicians often are reassured when the oxygen satura-
tion is closer to 100%.10
Despite these sentiments, however, data increasingly
suggest that too much oxygen may also have adverse effects.
That high levels of inspired oxygen can cause lung injury me-
diated through superoxides and free radical formation has
been known for some time.11,12 More recently, toxicity related
to hyperoxia has been observed in a number of other clinical
situations including cardiac arrest, 13 acute myocardial
infarction,14 and brain injury.15 In the critical care unit, a before-
after study also suggested improved outcomes with avoid-
ance of hyperoxia.16
This background provides the context for the single-
center randomized clinical trial (RCT) reported by Girardis and
colleagues17 in JAMA. The authors compared controlled nor-
moxia (targeting a PaO2 of 70-100 mm Hg or an oxygen satu-
ration by pulse oximetry [SpO2] of 94%-98%) vs usual care,
which consisted of administering supplemental oxygen at a
fraction of inspired oxygen (FiO2) of 0.4 or higher as needed,
targeting a SpO2 of 97% to 100% with a PaO2 up to 150 mm Hg.
The investigators enrolled patients who were considered likely
to remain in the ICU for at least 72 hours and excluded those
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with exacerbations of chronic obstructive pulmonary disease
or with moderate-severe ARDS because of differences in stan-
dard oxygen administration for these patients. The primary out-
come was predefined as all-cause ICU mortality in the subset
of patients who remained in the ICU for at least 72 hours after
randomization.
The study was stopped early after 480 of a planned 660
patients had been enrolled, partially related to slow recruit-
ment following ICU bed reductions after an earthquake had
damaged the hospital, but also following positive results
from an unplanned interim analysis. These investigators found
striking results favoring the conservative oxygen group. In the
modified intent-to-treat population, there were 25 deaths
(11.6%) among 216 patients in the conservative oxygen therapy
group and 44 deaths (20.2%) among 218 patients in the con-
ventional oxygen therapy group, an absolute risk reduction of
8.6% (P = .01) for the primary outcome of ICU mortality. The
authors found similar results for a secondary outcome of hos-
pital mortality.
These thought-provoking results require close scrutiny
on several points. It is likely that to some extent, this trial has
overestimated the true treatment effect of conservative oxy-
gen therapy for a number of reasons. First, there were base-
line imbalances between groups at the time of randomiza-
tion, including age, severity of illness, and organ failures,
which favored the conservative oxygen group. Second, the
study was stopped early after a positive finding based on an
unplanned interim analysis, which is known to increase the
likelihood of effect overestimation.18,19 Third, although the
overall number of patients recruited was moderate at close to
500, the number of outcome events was actually quite small,
particularly in the conservative oxygen group, with only 25
deaths. Even though the P value was significant, the study
was still underpowered, which increases the likelihood of a
false-positive result.20,21
The investigators designed their primary analysis using
what they describe as a modified intent-to-treat (ITT) ap-
proach: analyzing patients according to the group to which they
were randomly assigned but excluding patients who did not
remain in the ICU for at least 72 hours. It should be very clear
that this modified ITT analysis is not equivalent to an ITT analy-
sis. This modified ITT analysis excludes patients based on
events after randomization and is extremely problematic be-
cause the intervention may influence who is included in the
primary analysis, and this typically leads to larger effect sizes.22
For example, if conservative oxygen therapy had resulted in
the early death of a number of patients, this would have been
(Reprinted) JAMA Published online October 5, 2016 E1
 Opinion Editorial

overlooked in this analysis plan because those patients were
excluded. This is in contrast to cases of acceptable postran-
domization exclusion, which generally involve variables that
were present but unknown at the time of randomization.23
In this particular case clinicians can be reassured because
the results of the true ITT analysis (presented in the online
supplementary material) were almost identical to their pri-
mary analysis plan, with an absolute risk reduction for ICU mo-
rality of 8.7% (P = .009).
This trial by Girardis and colleagues contrasts with a
recently published RCT from the ANZICS clinical trials group
that demonstrated the feasibility and safety of conservative
oxygen administration in a pilot trial of 103 adults.24 This
pilot trial did not, however, show any trend toward improved
outcomes with lower oxygen targets. Differences in oxygen-
ation between groups was comparable between these trials,
but the target and actual PaO2 levels were higher in both con-
servative and conventional treatment groups in the study by
Girardis et al (87 vs 102 mm Hg) relative to their correspond-
ing levels in the ANZICS pilot study (70 vs 92 mm Hg). It is
possible that some of the difference in outcomes between
these trials was because even in the liberal oxygen arm of the
ANZICS trial, only 22% of time was spent with an SpO2 above
98%, so neither group was exposed to much hyperoxia.
Given these findings and the possible threats to the valid-
ity of the trial by Girardis et al,17 what is a clinician to do? It is
important to recognize that this study is not a trial of permis-
sive hypoxemia, which has been proposed but is as yet a
completely unproven therapeutic strategy. This trial involved
targeting relative normoxia, avoiding both significant desatu-
rations and exposure to supraphysiological PaO2. Until the
results of further trials addressing this issue are available,
there appears to be little downside in the careful titration and
monitoring of supplemental oxygen in the ICU to achieve
physiologically normal levels of PaO2 while avoiding poten-
tially dangerous hyperoxia.

ARTICLE INFORMATION
Author Affiliations: Interdepartmental Division of
Critical Care Medicine and Departments of
Medicine and Physiology, University of Toronto,
Toronto, Canada; Institute of Health Policy,
Management, & Evaluation, University of Toronto,
Toronto, Canada; Division of Respirology,
Department of Medicine, University Health
Network and Mount Sinai Hospital, Toronto,
Canada; Toronto General Research Institute,
Toronto, Canada.
Corresponding Author: Niall D. Ferguson, MD,
MSc, Toronto General Hospital, 585 University Ave,
11-PMB-120, Toronto, ON M5G 2N2, Canada
(n.ferguson@utoronto.ca).
Published Online: October 5, 2016.
doi:10.1001/jama.2016.13800
Conflict of Interest Disclosures: The author has
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
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