Iscoe S, Beasley R, Fisher JA. Supplementary oxygen for nonhypoxemic patients: O2 much of a good thing? Crit Care. 15:305

Abstract

Supplementary oxygen is routinely administered to patients, even those with adequate oxygen saturations, in the belief that it increases oxygen delivery. But oxygen delivery depends not just on arterial oxygen content but also on perfusion. It is not widely recognized that hyperoxia causes vasoconstriction, either directly or through hyperoxia-induced hypocapnia. If perfusion decreases more than arterial oxygen content increases during hyperoxia, then regional oxygen delivery decreases. This mechanism, and not (just) that attributed to reactive oxygen species, is likely to contribute to the worse outcomes in patients given high-concentration oxygen in the treatment of myocardial infarction, in postcardiac arrest, in stroke, in neonatal resuscitation and in the critically ill. The mechanism may also contribute to the increased risk of mortality in acute exacerbations of chronic obstructive pulmonary disease, in which worsening respiratory failure plays a predominant role. To avoid these effects, hyperoxia and hypocapnia should be avoided, with oxygen administered only to patients with evidence of hypoxemia and at a dose that relieves hypoxemia without causing hyperoxia.

Full text

… the aim of oxygen therapy should be to increase the
delivery of oxygen rather than to reach any arbitrary
concentration in the arterial blood.
EJM Campbell [1]
Is administration of oxygen, the most widely prescribed
drug in the formulary, free of risks to nonhypoxemic
patients with regional ischemia? Hyperoxia marginally
increases the arterial blood oxygen content (CaO2),
theoretically increasing tissue oxygen delivery (DO2)
assuming no reduction in tissue blood fl ow. However,
oxygen causes constriction of the coronary, cerebral,
renal and other key vasculatures – and if regional per-
fusion decreases concomitantly with blood hyperoxyge-
nation, one would have a seemingly paradoxical situation
in which the administration of oxygen may place tissues
at increased risk of hypoxic stress. Any tissue damage in
the course of oxygen administration would plausibly be
attributed to the underlying disease process. Ascribing
hypoxic damage to oxygen administration is counter-
intuitive and is diffi cult to accept without a receptive
mindset. Considering the ubiquity of oxygen therapy, the
continued low threshold for its administration, and the
widespread belief that its use is justifi ed and safe [2,3], we
believe it is important to revisit the arguments made to
justify the status quo.
Owing to the vasoconstrictor eff ects on the coronary,
cerebral, renal and other key vasculatures, there are many
scenarios in which administration of oxygen decreases
the perfusion to vital organs to a greater extent than the
small increase in CaO2, thereby actually reducing DO2.
 e calculated CaO2 increases with normobaric
hyperoxia (assuming all hemoglobin is already saturated)
by only 0.03 ml/l per mmHg. With increases in alveolar
PaO2 from 100 to 600 mmHg, CaO2 increases by 15 ml/l,
or about ~7.5% assuming a hemoglobin concentration of
150 g/l.
In healthy adults, hyperoxia decreases cerebral blood
fl ow by 11 to 33% [4,5]. Administration of high oxygen
concentrations is therefore likely to decrease brain DO2.
Despite this known eff ect of hyperoxia on cerebral blood
fl ow, and the published recommendations [6], patients
with stroke – even those with satisfactory arterial satura-
tions – are routinely administered oxygen [4]. Does this
matter? Possibly. Although Singhal and colleagues repor-
ted transient improvement in patients with ische mic
strokes [7], survival at 7 months for patients with mild or
moderate strokes is signifi cantly greater in those
administered air than in those given 100% oxygen for the
fi rst 24 hours after the event [8].
Hyperoxia-induced decreases in regional DO2 are not
confi ned to the brain. Normobaric hyperoxia reduces
Abstract
Supplementary oxygen is routinely administered to
patients, even those with adequate oxygen saturations,
in the belief that it increases oxygen delivery. But
oxygen delivery depends not just on arterial oxygen
content but also on perfusion. It is not widely
recognized that hyperoxia causes vasoconstriction,
either directly or through hyperoxia-induced
hypocapnia. If perfusion decreases more than arterial
oxygen content increases during hyperoxia, then
regional oxygen delivery decreases. This mechanism,
and not (just) that attributed to reactive oxygen
species, is likely to contribute to the worse outcomes
in patients given high-concentration oxygen in the
treatment of myocardial infarction, in postcardiac
arrest, in stroke, in neonatal resuscitation and in the
critically ill. The mechanism may also contribute to
the increased risk of mortality in acute exacerbations
of chronic obstructive pulmonary disease, in which
worsening respiratory failure plays a predominant
role. To avoid these e ects, hyperoxia and hypocapnia
should be avoided, with oxygen administered only to
patients with evidence of hypoxemia and at a dose
that relieves hypoxemia without causing hyperoxia.
© 2010 BioMed Central Ltd
Supplementary oxygen for nonhypoxemic
patients: O2 much of a good thing?
Steve Iscoe
1
*, Richard Beasley
2
and Joseph A Fisher
3
VIEWPOINT
*Correspondence: iscoes@queensu.ca
1
Department of Physiology, Queen’s University, Kingston, Ontario, Canada K7L 3N6
Full list of author information is available at the end of the article
Iscoe et al. Critical Care 2011, 15:305
http://ccforum.com/content/15/3/305
© 2011 BioMed Central Ltd

coronary blood fl ow by 8 to 29% in normal subjects and
in patients with coronary artery disease or chronic heart
failure [9].  e reduction in coronary artery fl ow is
associated with a reduction in myocardial DO2 and oxy-
gen consumption [10].  ese eff ects may explain disturb-
ing fi ndings in patients with coronary artery disease. As
early as 1950 Russek and colleagues reported that supple-
mental oxygen failed to reduce electrocardio graphic
signs of ischemia or reduce anginal pain in patients with
myocardial infarction [11]. In 1969 Bourassa and
colleagues proposed that hyperoxia-induced decreases in
coronary blood fl ow provoke myocardial ischemia in
patients with severe coronary artery disease [12].  en in
1976, in a double-blind randomized controlled trial,
Rawles and Kenmure reported greater serum aspartate
aminotransferase levels, indicating increased infarct size,
in patients with acute myocardial infarction receiving
high-fl ow oxygen compared with room air [13].  ey also
observed a nonsignifi cant tripling of the death rate in
those patients.
Given these concerns, the Emergency Oxygen Guide-
line Group of the British  oracic Society called for ‘large
randomised trials of oxygen therapy for non-hypoxaemic
patients with acute cardiac and cerebral ischaemia’ [14].
Conti, in a recent editorial [15], reminded readers that
that there is only level C evidence for the administration
of supplemental oxygen to patients with uncomplicated
ST elevation in myocardial infarction during the fi rst
6 hours [16]. Based on currently available evidence, the
UK National Institute for Health and Clinical Excellence
guidelines have recently emphasized that ‘supplementary
oxygen should not be routinely administered to patients
with acute chest pain of suspected cardiac origin, but
that oxygen saturation levels should be monitored and
used to guide its administration’ [17]. Similar cautions
have been expressed about the use of oxygen for the
treatment of traumatic brain injury [18].
 e mechanisms by which hyperoxia causes systemic
vasoconstriction remain uncertain. Recent work focuses
on the inhibition of vasodilators (prostaglandins, nitric
oxide) by reactive oxygen species generated as a result of
the hyperoxia [19-23]. Other work suggests that reactive
oxygen species activate brainstem respiratory neurons
[24], but this suggestion needs to be established as occur-
ring under normobaric conditions.  e role of hyperoxia-
induced hypocapnia (that is, the reverse Haldane eff ect)
remains contentious [3,25]. Regardless of the underlying
mechanism(s), the importance of considering the eff ects
of both PaO2 and PaCO2 on vascular tone is evident in a
study in which both hyperoxia and hypocapnia
independently increased cerebrovascular resistance and
reduced cerebral blood fl ow [5]. Indeed, in some situa-
tions, the vasoconstrictive eff ects of hyperoxia may be
predominantly due to the concomitant hypocapnia
[25,26]. Positron emission tomography provides similar
results: the reduction of cerebral blood fl ow and the
increase in oxygen extraction during inhalation of 100%
oxygen is completely reversed when subjects breathe
carbogen (5% carbon dioxide, 95% oxygen) [27].  ese
observations emphasize the importance of independent
control of arterial PCO2 and PO2 – possibly using
dynamic forcing of alveolar gases (for example [28]) or
sequential gas delivery (for example [29]) – when studying
the independent eff ects of PO2 and PCO2 on regional
perfusions.  ese observations also suggest that adding
carbon dioxide to oxygen may off set the vasoconstriction
due to hyperoxia or hypoxia-induced hypocapnia.
 ere are other clinical situations in which the routine
administration of high-concentration oxygen may lead to
worse outcomes, although primarily through mecha nisms
other than changes in regional perfusion. Austin and
colleagues recently reported in a randomized controlled
trial that patients with acute exacerbations of chronic
obstruc tive pulmonary disease have a twofold to fourfold
increased mortality when treated with high-fl ow oxygen
compared with oxygen titrated to result in an arterial
oxygen saturation between 88 and 92% [30]. Although
several mechanisms may account for these fi ndings [31],
worsening respiratory failure is probably the predomi-
nant mechanism. Of the patients whose arterial blood
gases were measured within 30 minutes of presentation
to hospital, those who received high-concentration
oxygen were more likely to have hypercapnia (mean
diff erence PaCO2 34 mmHg) or respiratory acidosis
(mean diff erence pH 0.12).
Adverse outcomes with hyperoxia have also been
reported in critically ill patients admitted to the intensive
care unit; a high PaO2 in the fi rst 24 hours after admission
is independently associated with in-hospital mortality
[32]. In this study a U-shaped curve of mortality with
PaO2 was observed, illustrating the risks of both hypoxia
and hyperoxia. Kilgannon and colleagues recently repor-
ted that patients administered high-concentration oxygen
resulting in hyperoxia (PaO2 >300 mmHg) following
cardiac arrest have increased in-hospital mortality, a
fi nd ing they attributed to increased oxidative stress asso-
ciated with hyperoxia [33]. However, because a subse-
quent study was unable to replicate these fi ndings [34],
randomized controlled trials will be required to resolve
the clinical uncertainty.
Neonatal resuscitation is the clinical situation in which
administration of 100% oxygen has most clearly been
demonstrated to increase the risk of death [35,36].  is
has resulted in a radical change in practice whereby room
air rather than oxygen is now the recommended resus ci-
tation regime [36].
Considering the ubiquity of the administration of
supplemental oxygen, there are surprisingly few
Iscoe et al. Critical Care 2011, 15:305
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Page 2 of 4

random ized clinical trials that demonstrate its benefi cial
role when hypoxemia is absent.  is may refl ect the fact
that its usage is so embedded in clinical practice that it is
accepted as safe [2]. Nevertheless, there are some
situations in which supplemental oxygen administration
is useful: treatment of cluster headache [37], reducing the
oxidative stress associated with colon surgery [38], and
the prevention of desaturation during endoscopy [39,40].
Supplemental oxygen adminis tration can, however, have
the unintended side eff ect of delaying recognition by
oximetry of hypo venti lation [41,42]. Until recently many
studies had indicated that supple mentary oxygen reduced
postoperative nausea and vomit ing, but the current
status is ambiguous (for example [43-46]). Similarly,
oxygen was thought to reduce postsurgical infections –
but more recent studies (see [47] for a partial summary)
have cast doubt on the original fi ndings. More over,
ventilation with high inspired oxygen concen trations
during surgery leads to subsequent impairment of
pulmonary gas exchange [48-50] that may be of clinical
signifi cance [50]. Traumatic injury and compartment
syndrome may appear to be obvious applications for
supplementary oxygen – an increased PO2 would help
overcome the reductions in perfusion – but hyperbaric
rather than normobaric oxygen is the treatment of choice
[51-53]. Oxygen is used for the treatment of carbon
monoxide poisoning [54], but this is probably less
eff ective than it should be if the accompanying hypo-
capnia is not prevented [26]. In the case of breathlessness,
which has long been treated with supplementary oxygen,
a recent randomized double-blind controlled trial estab-
lished that nasal oxygen was no better than air in reliev-
ing breathlessness and improving quality of life in pallia-
tive care patients with refractory breathlessness [55].
In conclusion, NASA managers demanded in 1986 that
their counterparts at Martin- iokol prove that it was
not safe to launch the Space Shuttle Challenger despite
concerns expressed by engineers about the integrity at
low temperatures of the O-rings joining the segments of
the solid rocket boosters [56].  e correct question
would have been: can you prove that it is safe? In the case
of supplementary oxygen, failure to ask the right question
reinforces complacency about its use in patients who may
have regional hypoxia or ischemia but are not hypoxemic.
Abbreviations
CaO2, arterial blood oxygen content; DO2, oxygen delivery; PaCO2, arterial
partial pressure of carbon dioxide; PaO2, arterial partial pressure of oxygen;
PCO2, partial pressure of carbon dioxide; PO2, partial pressure of oxygen.
Competing interests
SI and JAF have participated in the development of devices suitable for
increasing the e ciency of oxygen delivery. The protection of the related
intellectual property and distribution of income from sales (if any) follow the
guidelines set by the University Health Network.
Author details
1Department of Physiology, Queen’s University, Kingston, Ontario, Canada
K7L 3N6. 2Medical Research Institute of New Zealand, Level 7, CSB Building,
Wellington Hospital, Private Bag 7902, Wellington 6242, New Zealand.
3Department of Anesthesiology, Toronto General Hospital, 3EN 200 Elizabeth
Street, Toronto, Ontario, Canada M5G 2C4.
Published: 30 June 2011
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doi:10.1186/cc10229
Cite this article as: Iscoe S, et al.: Supplementary oxygen for nonhypoxemic
patients: O
2
much of a good thing? Critical Care 2011, 15:305.
Iscoe et al. Critical Care 2011, 15:305
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