Correspondence
Oxygen Therapy in the ICU
To the Editor: Mackle et al. (March 12 issue)1
report that ICU-ROX (Intensive Care Unit Ran-
domized Trial Comparing Two Approaches to
Oxygen Therapy) showed that in patients under-
going mechanical ventilation, there was no signifi-
cant difference in ventilator-free days between
those who received conservative oxygen supple-
mentation to avoid systemic hyperoxemia and
those who received usual oxygen therapy. Although
patients who had received invasive mechanical
ventilation or noninvasive ventilation for 2 hours
or more before enrollment were excluded, there
was no mention or documentation of the fraction
of inspired oxygen (Fio2) received before the trial
interventions. This may be a considerable omis-
sion and possible confounder, since even short
durations of hyperoxemia can affect outcomes.2,3
In addition, the authors chose to decrease the
Fio2 in the conservative-oxygen group when the
oxygen saturation, as measured by pulse oximetry
(Spo2), reached 97%. Pulse oximeters have an
absolute accuracy of approximately 3%,4 which
means that some patients in the conservative-
oxygen group could have had an oxygen satura-
tion of up to 100% and, accordingly, a partial
pressure of arterial oxygen (Pao2) higher than
150 mm Hg. The choice of an upper limit of 95%
instead would have yielded a Pao2 of 85 to 115
mm Hg, which would have avoided any potential
hyperoxemia. These possible confounders may
vitiate the clinical implications of this trial.
Tyler J. Albert, M.D.
Erik R. Swenson, M.D.
University of Washington
Seattle, WA
tyler​.­albert@​­va​.­gov
No potential conflict of interest relevant to this letter was
reported.
1. The ICU-ROX Investigators and the Australian and New Zea-
land Intensive Care Society Clinical Trials Group. Conservative
oxygen therapy during mechanical ventilation in the ICU. N Engl
J Med 2020;​382:​989-98.
2. Austin MA, Wills KE, Blizzard L, Walters EH, Wood-Baker
R. Effect of high flow oxygen on mortality in chronic obstructive
pulmonary disease patients in prehospital setting: randomised
controlled trial. BMJ 2010;​341:​c5462.
3. Page D, Ablordeppey E, Wessman BT, et al. Emergency de-
partment hyperoxia is associated with increased mortality in
mechanically ventilated patients: a cohort study. Crit Care 2018;​
22:​9.
4. Luks AM, Swenson ER. Pulse oximetry at high altitude. High
Alt Med Biol 2011;​12:​109-19.
DOI: 10.1056/NEJMc2009489
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To the Editor: In the LOCO2 (Liberal Oxygen-
ation versus Conservative Oxygenation in Acute
Respiratory Distress Syndrome) trial conducted by
Barrot et al. (March 12 issue)1 comparing liberal
oxygen therapy with conservative oxygen therapy
in patients with acute respiratory distress syn-
drome (ARDS), there was a signal of increased
mortality in the conservative-oxygen group. This
signal was part of the reason why the trial was
stopped prematurely. We think the higher inci-
dence of prone positioning during ventilation in
the liberal-oxygen group than in the conservative-
oxygen group (in 51.0% vs. 34.3% of the patients)
should be considered as a reason for the differ-
ence in mortality between the two groups. Since
we learned from the PROSEVA (Proning Severe
ARDS Patients) trial2 that prone ventilation may
lead to survival benefits in patients with ARDS, it
is reasonable to assume that the between-group
difference of 16.7 percentage points in the use of
prone positioning in the current trial may have
confounded the trial results. Can the authors
provide an analysis controlling for the use of
prone positioning?
Jonathan C.H. Cheung, M.B., Ch.B.
Philip K.N. Lam, M.B., B.S.
North District Hospital
Hong Kong, China
jonathanchunheicheung@​­gmail​.­com
No potential conflict of interest relevant to this letter was
reported.
1. Barrot L, Asfar P, Mauny F, et al. Liberal or conservative oxy-
gen therapy for acute respiratory distress syndrome. N Engl J
Med 2020;​382:​999-1008.
2. Guérin C, Reignier J, Richard J-C, et al. Prone positioning in
severe acute respiratory distress syndrome. N Engl J Med 2013;​
368:​2159-68.
DOI: 10.1056/NEJMc2009489
To the Editor: The trial conducted by Barrot
et al. involving patients with ARDS shows higher
mortality at 28 and 90 days among patients who
received mechanical ventilation with a conserva-
tive oxygen strategy than among those who re-
ceived mechanical ventilation with a liberal oxy-
gen strategy. The risk of cardiac dysfunction in
the form of acute cor pulmonale is 23% higher
among patients with ARDS than among those
without this condition.1 Since oxygen delivery de-
pends on oxygen content and cardiac output, the
2577
 The n e w e ng l a n d j o u r na l of m e dic i n e

latter should have been assessed and compared Paul Young, M.D., Ph.D.
in the two groups.2 Do the investigators have Diane Mackle, M.N.
measures of cardiac output to resolve these issues? Medical Research Institute of New Zealand
Wellington, New Zealand
Saurabh K. Das, M.D.
Artemis Hospital Rinaldo Bellomo, M.D.
Gurugram, India
dassk1729@​­gmail​.­com
Nang S. Choupoo, M.D.
Dr. Ram Manohar Lohia Hospital
New Delhi, India
Sumit Ray, M.D.
Artemis Hospital
Gurugram, India
No potential conflict of interest relevant to this letter was
reported.
1. Das SK, Choupoo NS, Saikia P, Lahkar A. Incidence propor-
tion of acute cor pulmonale in patients with acute respiratory
distress syndrome subjected to lung protective ventilation: a sys-
tematic review and meta-analysis. Indian J Crit Care Med 2017;​
21:​364-75.
2. Dunn J-OC, Mythen MG, Grocott MP. Physiology of oxygen
transport. BJA Education 2016;​16:​341-8.
DOI: 10.1056/NEJMc2009489
Dr. Young and colleagues reply: With regard
to the comments by Albert and Swenson: we ac-
knowledge that patients in the ICU-ROX may have
been exposed to hyperoxemia before randomiza-
tion. However, at randomization, the median Pao2
was 110 mm Hg (interquartile range, 83 to 177)
in the conservative-oxygen group, as compared
with 112 mm Hg (interquartile range, 82 to 167)
in the usual-oxygen group, and the mean (±SD)
FiO2 levels were 0.61±0.24 and 0.63±0.23, respec-
tively. Given that both the Pao2 and Fio2 levels
were similar in the two groups at baseline, we
consider it unlikely that between-group differ-
ences in exposure to oxygen before randomiza-
tion resulted in bias.
In our trial, conservative oxygen therapy had
two components. The first was to treat an oxy-
gen saturation of 97% or higher as an urgent
prompt to reduce the Fio2, and the second was to
use the lowest Fio2 possible to achieve an oxygen
saturation that was higher than the prescribed
lower limit. In many patients assigned to conser-
vative oxygen therapy, this approach resulted in
a reduction of the Fio2 to 0.21. We recorded the
Pao2 daily while patients were receiving ventila-
tion in the ICU. Among patients assigned to con-
servative oxygen therapy, the daily time-weight-
ed mean Pao2 was 80 to 90 mm Hg. We did not
observe Pao2 values higher than 150 mm Hg in
patients assigned to conservative oxygen therapy.
Austin Hospital
Heidelberg, VIC, Australia
paul​.­young@​­ccdhb​.­org​.­nz
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
DOI: 10.1056/NEJMc2009489
Dr. Capellier and colleagues reply: In re-
sponse to Cheung and Lam: in the LOCO2 trial,
prone positioning was recommended when the
ratio of Pao2 to Fio2 was less than 150 mm Hg.
Over time, the number of patients with a ratio of
Pao2 to Fio2 of more than 150 mm Hg was higher
in the conservative-oxygen group than in the
liberal-oxygen group. There are several mecha-
nisms that plausibly explain this difference be-
tween the two groups, and together these mech-
anisms could explain the lower incidence of prone
positioning in the conservative-oxygen group. In
a recent trial of personalized mechanical ventila-
tion,1 approximately 90% of the patients in the
intervention group and 25% of the patients in the
control group had prone positioning without any
difference in mortality. Prone positioning was
used in approximately 15% of the patients in the
Reevaluation of Systemic Early Neuromuscular
Blockade (ROSE) trial from the Prevention and
Early Treatment of Acute Lung Injury (PETAL)
Clinical Trials Network of the National Heart,
Lung, and Blood Institute2; this incidence was
lower than that in our control group. As suggested
by Cheung and Lam, we performed an additional
analysis with adjustment for the use of prone po-
sitioning. The probability of survival remained
lower in the conservative-oxygen group than in
the liberal-oxygen group after adjustment (ad-
justed hazard ratio, 1.70; 95% confidence inter-
val [CI], 1.05 to 2.73; P = 0.03). The univariate
hazard ratio for survival with prone positioning
was not significant (hazard ratio, 0.83; 95% CI,
0.50 to 1.36; P = 0.45).
Das and colleagues note the relationship be-
tween oxygen delivery and cardiac function in
patients with ARDS. In our trial, there was no
monitoring of cardiac output per se. We agree
that right heart failure is commonly described in
such patients,3 and it has been associated with
high partial pressure of arterial carbon dioxide

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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
 Correspondence
(Paco2) and elevated ventilator driving pressure
(defined as the difference between plateau pres-
sure and positive end-expiratory pressure [PEEP]).
The Paco2 and pH did not differ in the two
groups during the 7-day intervention. The PEEP
was slightly higher in the liberal-oxygen group,
but both the plateau and driving pressures were
similar in the two groups. We calculated a sur-
rogate of oxygen transport for the 7-day inter-
vention period comprising the hemoglobin level,
arterial oxygen saturation, and heart rate, and it
did not differ in the two groups. Furthermore,
we did not observe any signal of an increased
lactate level or increased Sequential Organ Fail-
ure Assessment score during follow-up. Several
studies that have investigated the relationship be-
tween oxygen delivery and oxygen consumption
in critically ill patients or patients with sepsis4
have not shown differences in outcomes. Oxy-
gen delivery has to decrease to a level below 25%
to reach the anaerobic threshold.5 Our findings
do not provide any evidence that the hypothesis
of acute cor pulmonale and low cardiac output
could explain our results.
Gilles Capellier, M.D., Ph.D.
Loic Barrot, M.D.
Marc Puyraveau, M.Sc.
University Hospital Jean Minjoz
Besançon, France
gilles​.­capellier@​­univ-fcomte​.­fr
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
1. Constantin J-M, Jabaudon M, Lefrant J-Y, et al. Personalised
mechanical ventilation tailored to lung morphology versus low
positive end-expiratory pressure for patients with acute respira-
tory distress syndrome in France (the LIVE study): a multicentre,
single-blind, randomised controlled trial. Lancet Respir Med
2019;​7:​870-80.
2. The National Heart, Lung, and Blood Institute PETAL Clini-
cal Trials Network. Early neuromuscular blockade in the acute
respiratory distress syndrome. N Engl J Med 2019;​380:​1997-2008.
3. Mekontso Dessap A, Boissier F, Charron C, et al. Acute cor
pulmonale during protective ventilation for acute respiratory
distress syndrome: prevalence, predictors, and clinical impact.
Intensive Care Med 2016;​42:​862-70.
4. Heyland DK, Cook DJ, King D, Kernerman P, Brun-Buisson C.
Maximizing oxygen delivery in critically ill patients: a methodo-
logic appraisal of the evidence. Crit Care Med 1996;​24:​517-24.
5. Ronco JJ, Fenwick JC, Tweeddale MG, et al. Identification of
Fall Prevention in Community-Dwelling Older Adults
To the Editor: Ganz and Latham (Feb. 20 is-
sue)1 review strategies and evidence regarding
fall prevention in older adults and make recom-
mendations for practice. The case vignette de-
n engl j med 382;26  nejm.org  June 25, 2020
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
the critical oxygen delivery for anaerobic metabolism in criti-
cally ill septic and nonseptic humans. JAMA 1993;​270:​1724-30.
DOI: 10.1056/NEJMc2009489
The editorialist replies: Cheung and Lam sug-
gest that the use of the prone position could have
confounded the results of the trial conducted by
Barrot et al. Although the prone position can in-
deed affect both oxygenation and survival, it was
probably a postrandomization event, possibly mo-
tivated by the patients’ clinical progress. The sta-
tistical and clinical interpretation of any analyses
that adjust for postrandomization events is diffi-
cult in any situation and probably quite problem-
atic in this trial in which the overall sample size
was small and the prone position was one of many
actions initiated by the bedside clinical team.
Das et al. speculate that in the LOCO2 trial,
acute cor pulmonale could have been one mech-
anism by which the group of patients who were
randomly assigned to lower oxygen titration tar-
gets may have incurred a worse outcome than
those assigned to higher oxygen titration targets.
It is certainly one of several possible explanations,
assuming the difference was not simply due to
chance alone.
Albert and Swenson raise issues regarding the
potential role of prerandomization oxygenation
strategies and the accuracy of pulse oximetry in
ICU-ROX. Although prerandomization oxygenation
may be important, the distributions should be
balanced in the two groups and therefore should
not confound interpretation in the traditional
sense. As I mentioned in my editorial,1 the lim-
ited accuracy of pulse oximetry can complicate
the delivery and interpretation of alternative oxy-
genation strategies.
Derek C. Angus, M.D., M.P.H.
University of Pittsburgh School of Medicine
Pittsburgh, PA
Since publication of his editorial, the author reports no fur-
ther potential conflict of interest.
1. Angus DC. Oxygen therapy for the critically ill. N Engl J Med
2020;​382:​1054-6.
DOI: 10.1056/NEJMc2009489
scribes a woman who has fallen after tripping on
uneven pavement, an event that reflects a com-
mon cause of fall-related injuries.2 Prevention of
a fall after a trip requires either the perception
2579