Intensive Care Med

https://doi.org/10.1007/s00134-019-05619-9

EDITORIAL

What’s new in oxygen therapy?

Massimo Girardis1, Waleed Alhazzani2,3 and Bodil Steen Rasmussen4,5* 

© 2019 Springer-Verlag GmbH Germany, part of Springer Nature

Introduction oxygen therapy did not improve physical function (mRS

From ‘elixir of the life’ to the first cause of aging and score) in patients with stroke (proportional OR 1.02, 95%
death, the history of oxygen in modern science and medi- CI 0.93–1.12) [1]. Different thresholds for oxygen ther-
cine is a fascinating example of controversial hypotheses, apy ranged between 30% and 100% oxygen; therefore, a
uncertain findings and wrong theories. The debate con- threshold for benefit or harm could not be determined
tinues, especially in critically ill patients who frequently without an individual patient data meta-analysis.
receive oxygen supplementation for preventing or treat-
ing tissue hypoxia. In these patients, the appropriate oxy- Oxygen therapy in cardiac ischaemia and cardiac
gen dose (i.e. quantity and duration) remains unclear and arrest
may substantially vary in specific sub-populations. We The rationale for oxygen therapy in non-hypoxaemic
present a brief state-of-the-art update on oxygen ther- patients with cardiac ischaemia is to decrease the acute
apy in emergency, intensive care and non-intensive care ischaemic injury and the infarct area [3]. Although
settings. prominent international guidelines recommended using
Although the rationale for using oxygen therapy was oxygen in patients with cardiac ischaemia, the recom-
not well developed nor supported by convincing data, mendations were not supported by convincing evidence.
administering oxygen to non-hypoxaemic patients pre- Several studies showed that hyperoxaemia was associated
senting to the emergency department with acute medical with coronary vasoconstriction and reduced myocardial
emergencies was a common practice. This led researchers oxygen consumption [4]. Aiming to inform clinical prac-
to conduct several randomized controlled trials (RCTs) tice, a landmark RCT (DETO2X-AMI) randomized 6629
to determine the efficacy and safety of oxygen therapy in non-hypoxaemic patients with acute myocardial infarc-
this context. tion to receive either continuous supplemental oxygen or
no oxygen [5]. Oxygen therapy did not reduce mortality
Oxygen therapy in acute stroke or re-hospitalization. The main limitation of this trial is
There are six RCTs that examined the effect of oxygen imprecision as the sample size was not powered to firmly
therapy on mortality and physical function outcomes exclude harm. A recent systematic review identified six
[1]. The largest was the stroke oxygen study ­(SO2S) rand- RCTs (7778 patients) in a cardiac ischaemia population,
omized clinical trial [2] which randomized 8003 patients and a single RCT (17 patients) in cardiac arrest [1]. When
with acute ischaemic stroke to one of three arms: con- the effect on mortality was evaluated across all trials,
tinuous oxygen, nocturnal oxygen or no oxygen [2]. Oxy- oxygen therapy did not improve survival (RR 1.13, 95%
gen administration did not improve the modified Rankin CI 0.83–1.55); of note, the point estimate showed a 13%
scale (mRS) scores in patients with acute stroke [odds increase in mortality, and the CI could not exclude a 55%
ratio (OR) 0.97, 95% CI 0.89–1.05]. Similarly, when the increase in mortality.
total body of evidence was evaluated across six RCTs, Recent guidelines issued a strong recommendation
against using oxygen therapy in non-hypoxaemic patients
[peripheral oxygen saturation (­SpO2) ≥ 93%] with car-
*Correspondence: bodil.steen.rasmussen@rn.dk diac ischaemia or stroke. In addition, they issued a strong
4
Department of Anaesthesia and Intensive Care, Aalborg University recommendation for discontinuing oxygen when S ­ pO2
Hospital, Ålborg, Denmark
Full author information is available at the end of the article
≥ 96% [6].
Table 1  How conservative is the oxygenation targets in the ICU trials?
RCTs Status Number Inclusion criteria Oxygen target(s)
of patients in the conservative
recruited group

Girardis [9] Terminated after an unplanned 434 out of 660 Expected length of stay in the ICU SpO2 up to 98%
interim analysis of 72 h PaO2 70–100 mmHg
Asfar [10] Terminated after a planned interim 442 out of 800 Mechanical ventilation and septic SpO2 up to 97%
analysis shock
Panwar [11] Completed 103 Mechanical ventilation SpO2 up to 92%
ICU-ROX (ACTRN12615000957594) Completed but no results reported 1000 Mechanical ventilation SpO2 91–96%
yet
LOCO2 (NCT02713451) Active, not recruiting 205 out of 850 ARDS according to the Berlin PaO2 55–70 mmHg
definition SpO2 88–92%
HOT-ICU (NCT03174002) Recruiting 1504 out of 2928 FiO2 at least 0.50 or at least 10 L PaO2 60 mmHg
per minute in an open system
ICU-Conservative O2 trial Starts recruiting in May 2019 Expected 1000 Mechanical ventilation and SpO2 up to 98%
(EUDRACT 2018-002525-35) expected length of stay in the PaO2 70–100 mmHg
ICU of 72 h
ARDS acute respiratory distress syndrome, ICU intensive care unit, PaO2 partial pressure of arterial oxygen, SpO2 peripheral oxygen saturation

Non‑intensive care patients oxygen strategy compared with a liberal oxygen therapy
Oxygen supplementation is widely used in hypoxic [1]. Noteworthy, a single-centre RCT [9] provided 32%
patients admitted to general wards, frequently without of the weight in the mortality analysis in this recent sys-
targeted prescription [7]. Although the disease severity tematic review and meta-analysis [1], but stopped early
and the oxygen concentration used are lower, it is plausi- after a non-scheduled interim analysis. Adding to the
ble that inappropriate oxygen therapy may cause negative evidence, the HYPERS2S trial [10], a two-by-two facto-
effects similar to those observed in critically ill patients. rial multicentre RCT, found a higher risk of SAEs with
In addition, in general wards the monitoring of oxygen hyperoxaemia and was also terminated early. In contrast,
levels is commonly less precise than in patients admitted a pilot RCT showed no difference in mortality between
to intensive care unit (ICU). Therefore, the exposure to conservative versus liberal oxygenation targets for
hypoxia and hyperoxia may be even more frequent and mechanically ventilated patients [11]. Therefore, to what
uncontrolled. Unfortunately, few data are available on degree hyperoxaemia affects mortality in the ICU popu-
oxygen therapy in this setting, particularly on adverse lation remains uncertain.
effects related to possible exposure to hyperoxia. Inter- We await the results of several studies in the ICU. The
estingly, a recent retrospective single-centre cohort study largest multicentre RCT in mechanically ventilation
showed that early hyperoxaemia compared to normox- patients, the ICU-ROX trial (ACTRN12615000957594)
aemia was associated with larger in-hospital mortal- completed recruitment (1000 patients) in November
ity and late ICU transfer in patients admitted to general 2018, and the results are expected later in 2019. Addi-
wards. Moreover, as in critically ill patients, the total oxy- tionally, the LOCO2 trial (NCT02713451) stopped
gen exposure (area under the curve of P ­ aO2 levels) was recruiting and the results are expected soon. The HOT-
related to occurrence of new respiratory, hepatic and ICU trial (NCT03174002), which is focused on patients
renal dysfunctions [8]. with hypoxaemic respiratory failure, has randomized
over half of the planned 2928 patients and is still ongoing
(Table 1).
Oxygen therapy in ICU patients Undoubtedly, the overall body of evidence supports
Oxygen is the most common drug used in the ICU and conservative use of oxygen, but the question remains as
often administrated liberally to give a margin of safety to how conservative the oxygen therapeutic goals should
against life-threatening hypoxia. The life-saving proper- be. Table 1 provides an overview of how conservative the
ties of oxygen therapy in critically ill patients with hypox- oxygenation targets is in the ICU RCTs. Until the results
aemic respiratory failure seem to have overshadowed of ongoing trials are available, the optimal target of oxy-
the awareness of serious adverse events (SAEs) caused gen therapy in the ICU population is unknown.
by oxygen. Emerging evidence points towards a reduced
mortality in acutely ill adults treated with a conservative
Author details 4. Moradkhan R, Sinoway LI (2010) Revisiting the role of oxygen therapy in
1
 Department of Anaesthesia and Intensive Care, University Hospital cardiac patients. J Am Coll Cardiol 56:1013–1016
of Modena, Modena, Italy. 2 Division of Critical Care, Department of Medicine, 5. Hofmann R, James SK, Jernberg T, Lindahl B, Erlinge D, Witt N, Arefalk G,
McMaster University, Hamilton, Canada. 3 Health Research Methods, Evidence Frick M, Alfredsson J, Nilsson L, Ravn-Fischer A, Omerovic E, Kellerth T,
and Impact, McMaster University, Hamilton, Canada. 4 Department of Anaes- Sparv D, Ekelund U, Linder R, Ekstrom M, Lauermann J, Haaga U, Pernow
thesia and Intensive Care, Aalborg University Hospital, Ålborg, Denmark. J, Ostlund O, Herlitz J, Svensson L, DETO2X–SWEDEHEART Investigators
5
 Clinical Institute, Aalborg University, Ålborg, Denmark. (2017) Oxygen therapy in suspected acute myocardial infarction. N Engl J
Med 377:1240–1249
Compliance with ethical standards 6. Siemieniuk RAC, Chu DK, Kim LH, Guell-Rous MR, Alhazzani W, Soccal PM,
Karanicolas PJ, Farhoumand PD, Siemieniuk JLK, Satia I, Irusen EM, Refaat
Conflicts of interest MM, Mikita JS, Smith M, Cohen DN, Vandvik PO, Agoritsas T, Lytvyn L,
Dr. Girardis was the principal investigator of a completed trial [9] and a Guyatt GH (2018) Oxygen therapy for acutely ill medical patients: a clini-
principal investigator of a coming trial (EUDRACT 2018-002525-35) evaluating cal practice guideline. BMJ 363:k4169
oxygen saturation targets for critical ill patients. Dr. Rasmussen is a principal 7. O’Driscoll R (2016) British Thoracic Society: emergency oxygen audit
investigator of an ongoing trial (NCT03174002) evaluating oxygen saturation report. National audit period 15 August–1 November 2015. https​://www.
targets for critically ill patients. Dr. Alhazzani co-authored a systematic review brit-thora​cic.org.uk/docum​ent-libra​r y/quali​ty-impro​vemen​t/audit​-repor​
and a guideline on oxygen therapy for acutely ill patients. ts/emerg​ency-oxyge​n-2015/. Accessed 5 Mar 2019.
8. Jeong JH, Kim DH, Kim TY, Kang C, Lee SH, Lee SB, Kim SC, Park YJ
(2018) Harmful effects of early hyperoxaemia in patients admitted to
general wards: an observational cohort study in South Korea. BMJ Open
Publisher’s Note 8:e021758
Springer Nature remains neutral with regard to jurisdictional claims in pub- 9. Girardis M, Busani S, Damiani E, Donati A, Rinaldi L, Marudi A, Morelli
lished maps and institutional affiliations. A, Antonelli M, Singer M (2016) Effect of conservative vs conventional
oxygen therapy on mortality among patients in an intensive care unit:
Received: 15 March 2019 Accepted: 9 April 2019 the oxygen-ICU randomized clinical trial. JAMA 316:1583–1589
10. Asfar P, Schortgen F, Boisrame-Helms J, Charpentier J, Guerot E, Megar-
bane B, Grimaldi D, Grelon F, Anguel N, Lasocki S, Henry-Lagarrigue M,
Gonzalez F, Legay F, Guitton C, Schenck M, Doise JM, Devaquet J, Van Der
Linden T, Chatellier D, Rigaud JP, Dellamonica J, Tamion F, Meziani F, Mer-
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