Oxygen: Breath of Life or Kiss of Death*
Everything is poisonous, nothing is poisonous; it is all a matter of dose. —Claude Bernard
(1813–1878)
Jesús Villar, MD, PhD, FCCM
CIBER de Enfermedades Respiratorias
Instituto de Salud Carlos III
Madrid, Spain; and
Multidisciplinary Organ Dysfunction Evaluation Research
Network
Research Unit
Hospital Universitario Dr. Negrín
Las Palmas de Gran Canaria, Spain
Robert M. Kacmarek, PhD, RRT, FCCM
Department of Respiratory Care
Massachusetts General Hospital; and
Department of Anesthesiology
Harvard University
Boston, MA
Life today depends heavily on oxygen. Oxygen is routinely
administered to almost all critically ill patients. The first
study of long-term oxygen therapy was published in 1968
(1); however, Haldane (2) (1860–1936) was the first to bring
oxygen therapy to a rational and scientific basis. In 1917, he
published an article, where he stressed the importance of
knowing the percentage of oxygen that is being breathed.
Although oxygen therapy can be lifesaving, it is not without
serious side effects (3). Too little oxygen is problematic but
so is too much. In clinical practice, oxygen therapy is often
provided liberally and may result in hyperoxemia or in the
delivery of supplemental oxygen during nonhypoxemic con-
ditions. The liberal use of oxygen may provide a margin of
safety against hypoxia, but this has to be balanced against
an increasing recognition of the potential harm of hyperoxia
and hyperoxemia.
Prior to the extensive use of pulse oximetry, hypoxemia and
hyperoxemia could not be easily detected clinically and oxy-
gen was used liberally in any potentially hypoxemic patient.
However, in today’s ICUs, there is no reason to administer
oxygen to patients with a Pao2 greater than 100 mm Hg or a
*See also p. 187.
Key Words: hyperoxemia; hyperoxia; mechanical ventilation; outcome
Supported, in part, by Instituto de Salud Carlos III (CB06/06/1088,
PI13/0119) and Asociación Científica Pulmón y Ventilación Mecánica.
Dr. Villar has received a research grant from Maquet. Dr. Kacmarek has
received research grants from Venner Medical and Covidien and is a con-
sultant for Covidien and Orange Med. His institution received funding from
Covidien and from Venner Medica.
Copyright © 2017 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000002113
368 www.ccmjournal.org February 2017 • Volume 45 • Number 2
Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
pulse oximeter oxygen saturation (Spo2) greater than 97%.
Oxygen therapy can be deleterious: it triggers formation
of reactive oxygen species (4), induces hemodynamic and
inflammatory changes (3, 5), contributes to tissue injury,
and influences the progression or development of multiple
system organ dysfunction (6). Hyperoxemia is associated
with increased risk of death compared with normoxemia or
hypoxemia following cardiopulmonary resuscitation (7). In
a recent randomized controlled trial (RCT) in patients with
acute myocardial infarction, routine oxygen administration
was not associated with a reduction of symptoms; instead,
oxygen supplementation was accompanied by a significant
increase in biomarkers of myocardial damage and a larger
infarct size (8). Furthermore, hyperoxia and hyperoxemia
may promote lung injury during mechanical ventilation and
have been linked to poor outcome in various subgroups (9).
Despite these findings, no large RCTs have investigated the
effects of different oxygenation targets in patients with acute
respiratory failure managed with mechanical ventilation and
supplemental oxygen.
Current guidelines recommend Pao2 levels (independent
of the applied Fio2) of approximately 60–90 mm Hg and arte-
rial oxygen saturation (Sao2) of 90–97%, but these target
ranges are based on expert consensus more than on evidence
from clinical studies. As a result, attitudes regarding the man-
agement of oxygen therapy vary considerably, and clinicians
often consider hyperoxemia acceptable as long as the Fio2 is
low. Evidence clearly indicates that hypoxemia, defined as a
Sao2 less than 90% or a Pao2 less than 60 mm Hg, may pre-
dispose patients to cardiac arrest and death (10). However,
we do not know whether there is a safe upper limit for Pao2,
once a critically ill patient is resuscitated or during disease
recovery.
Panwar et al (11) performed a pilot RCT in 103 critically
ill patients mechanically ventilated for more than or equal to
24 hours to determine whether a conservative oxygenation
strategy (target Spo2, 88–92%) was a feasible alternative to a
liberal oxygenation strategy (target Spo2, ≥ 96%) and found
that there was no evidence of any harm associated with a con-
servative target, as assessed by organ dysfunction and mortal-
ity. This pilot study was intended to inform the design of any
subsequent larger RCTs on the use of conservative versus lib-
eral oxygen therapy in mechanically ventilated patients.
In this issue of Critical Care Medicine, Helmerhorst et al (12)
reported the results of a retrospective analysis of Pao2 values
in a heterogeneous population of more than 14,000 patients
(almost 12,000 of these patients were mechanically venti-
lated) admitted to three large ICUs during a 3-year period. By
using several existing and new cut-points for Pao2 at several

time-points (on ICU admission, the highest, the median, and
the average Pao2 value during the first 24 hr, and during the
total ICU stay), they examined the association of different out-
comes measures (including hospital mortality and ventilator-
free days) with three categories of arterial oxygenation based
on the values of Pao2, independent of applied Fio2 levels. They
termed these categories “normoxia” (Pao2, 60–120 mm Hg),
“mild hyperoxia” (Pao₂, > 120–200 mm Hg), and “severe hyper-
oxia” (Pao₂, > 200 mm Hg). A Pao2 greater than 200 mm Hg was
associated with unfavorable hospital outcome (hospital mor-
tality, ICU mortality, and ventilator-free days). In this analysis,
metrics of central tendency (mean and median) were found
to have the strongest relationship with outcome. This associa-
tion was found both within and beyond the first 24 hours of
ICU admission and was consistent for large subgroups. Their
analysis also showed that time spent with supranormal levels
of Pao2 resulted in a linear and positive relationship with hos-
pital mortality. As a result of the retrospective nature of this
observational study, these findings should be interpreted with
caution. In the subsets of patients with cardiac arrest, stroke,
or sepsis, no significant effects of hyperoxemia were found.
It is plausible that the sample size and the associated chronic
comorbidities of the different studied subsets could explain
these contradictory results but they still raise concerns. In
a study with an almost 14-fold greater number of patients
(n = 195,176), there was no apparent adverse effect of hyperox-
emia once adjustments for comorbidities were performed using
a modified Acute Physiology and Chronic Health Evaluation III
score in which oxygen-derived variables were removed (13).
However, despite these limitations, as stated by the authors,
this study adds an important piece to the complex puzzle of the
effects of hyperoxia and hyperoxemia and provides a basis for
new guidelines for targeting Pao2 levels in the management of
critically ill patients.
In summary, the use of supplemental oxygen in the man-
agement of critically ill patients should be carefully adjusted
to achieve a proper balance between beneficial and poten-
tially detrimental effects. We urgently need to address whether
hyperoxemia is a marker for poor outcome and what exposure
is sufficient to cause harm. Long-term effects of oxygen therapy
still need to be assessed prospectively in homogeneous cohorts
in RCTs. However, although we wait for more evidence to
Critical Care Medicine www.ccmjournal.org 369
Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Editorials
provide tailored Pao2 targets for critically ill patients, it is time
to revise our practice of the liberal use of oxygen and supra-
normal levels of Pao2. If these results are validated, instead of
being the breath of life (14), hyperoxemia in defined cohorts
maybe the kiss of death!
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