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Review

Oxygen therapy in acute

exacerbations of chronic
obstructive pulmonary
disease
Expert Rev. Respir. Med. 9(3), 287293 (2015)

Janine Pilcher*13,
Mark Weatherall2,4,
Kyle Perrin1,2,4 and
Richard Beasley14
1
Medical Research Institute of
New Zealand, Private Bag 7902,
Wellington 6242, New Zealand
2
Capital and Coast District Health
Board, Wellington, New Zealand
3
Victoria University of Wellington,
Wellington, New Zealand
4
University of Otago Wellington,
Wellington, New Zealand
*Author for correspondence:
Tel.: +64 4805 0147
Fax: +64 4389 5707
Janine.Pilcher@mrinz.ac.nz

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During the last decade, there have been major advances in knowledge of the effects of
oxygen therapy in patients with acute exacerbations of chronic obstructive pulmonary disease.
This includes a randomised controlled trial of oxygen therapy in the pre-hospital setting, which
showed that high concentration oxygen therapy leads to a 2.4-fold increased risk of mortality
compared with titrated oxygen therapy to maintain oxygen saturations (SpO2) within a target
range of 8892%. Professional guidelines now recommend the use of supplementary oxygen
in acute exacerbations of chronic obstructive pulmonary disease only if the SpO2 is less than
88%, with titration to achieve an SpO2 of 8892%, and the delivery of bronchodilators by
air-driven nebulisation or metered dose inhaler with a spacer. The aim of this review is to
provide an overview of the evidence base that underpins these recommendations. We suggest
that their implementation will require important changes to current clinical practice in which
there is an entrenched culture of the use of high concentration oxygen therapy.
KEYWORDS: chronic obstructive pulmonary disease . exacerbation . oxygen . review

Concerns that high concentration oxygen therapy may harm patients with chronic obstructive pulmonary disease (COPD) were expressed
over 50 years ago [1,2]. Murphy et al. published
a comprehensive review of the relevant literature to 2000 and concluded that administration of high concentration oxygen can cause
hypercapnia in patients with COPD (BOX 1) [3].
Although low concentration oxygen therapy
may not adequately relieve hypoxaemia, and
cause harm in this way, the review found insufficient evidence to determine the relative risk
of death for high concentration oxygen therapy
compared with low concentration therapy in
COPD. This review highlights the key points
made by Murphy et al. and explores the
subsequent evidence available that now guides
oxygen treatment in COPD. Following
Murphy et al. review, evidence about increased
mortality in patients with exacerbations of
COPD treated with high concentration oxygen
has changed from Level 3, based on nonexperimental cohort studies at moderate risk of
bias, to Level 1b, based on a randomised controlled trial at low risk of bias [4]. The mortality
10.1586/17476348.2015.1016503

risk of high concentration oxygen administration compared with titrated oxygen therapy,
with a target oxygen saturation (SpO2) range
of 8892%, is quantified and firmly
established.
Evidence to guide oxygen therapy to
2000

In 2000, when Murphy et al. reviewed the literature, the role of oxygen therapy in COPD was
described as an area of confusion and controversy [3]. The risks of hypoxaemia were recognised by physicians, but there was uncertainty
about the appropriate fraction of inspired oxygen (FiO2) required for both relieving hypoxaemia and avoiding clinically relevant hypercapnia.
The key clinical questions considered in the
review are described below:
What are the perceived dangers of
hypoxaemia & at what partial pressure of
oxygen does it become dangerous?

Profound hypoxaemia causes irreversible damage to tissues, vital organ dysfunction, and
death, but the exact relationship between

2015 Informa UK Ltd

ISSN 1747-6348

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Review

Pilcher, Weatherall, Perrin & Beasley

Box 1. Key learning points from the Murphy et al.

literature review to year 2000 [3].
.

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The exact levels of hypoxaemia and hypercapnia that cause

clinical harm are unknown, but are likely to be partial pressure of oxygen <50 mmHg and partial pressure of carbon
dioxide (PaCO2) >80 mmHg
Patients presenting with an acute exacerbation of chronic
obstructive pulmonary disease (COPD) rarely have a PaCO2
>80 mmHg breathing room air
In patients with COPD, exposure to high concentration
oxygen therapy causes increased PaCO2, and
a higher fraction of inspired oxygen (FiO2) level is positively
associated with the magnitude of increase in PaCO2
low therapeutic FiO2 is capable of increasing PaCO2
in patients with oxygen-induced hypercapnia PaCO2 levels
decrease with a decrease in FiO2
In patients with COPD, it is difficult to predict
the FiO2 required to relieve hypoxaemia
whether an increase in PaCO2 in response to oxygen
therapy will occur
the magnitude of any change in PaCO2 following oxygen
therapy
There had been no randomised controlled trials to investigate
the effects of differing concentrations of oxygen on clinical
outcomes in patients with acute exacerbations of COPD

hypoxaemia and the risk of irreversible damage was not clear.

An arterial partial pressure of oxygen (PaO2) >50 mmHg was
proposed as a safe level of oxygenation that prevents immediate death from hypoxaemia, so oxygen therapy should provide
a PaO2 of at least this level [57]. The minimum target for
PaO2 may vary from patient to patient, but it was known that
loss of consciousness occurs when PaO2 is about
30 mmHg [8,9]. The relevance of this evidence to patients with
stable COPD, in whom a PaO2 may fall to <50 mmHg while
exercising without symptoms, was not clear [10].
How much oxygen is required to relieve hypoxaemia?

Clinical studies confirmed theoretical predictions that small

increases in FiO2 produce considerable relief from hypoxaemia [5,1118]. However, patients with an acute exacerbation of
COPD have a variable response to increases in FiO2 [5,11,1315].
Some patients with an acute exacerbation of COPD do not
increase their PaO2 beyond 50 mmHg after administration of
oxygen with FiO2 of up to 35% [11]. This means that routine
administration of fixed low concentration oxygen therapy, such
as an FiO2 of 24, 28 or 35%, is not a universally satisfactory therapeutic approach because it does not guarantee relief of marked
hypoxaemia, to achieve PaO2 >50 mmHg, in all patients [11].
What are the perceived dangers of carbon dioxide
retention & at what partial pressure of carbon dioxide
does it become dangerous?

Profound hypercapnia may cause depression of neurological and

cardiorespiratory function [1923]. In COPD patients treated with
288

oxygen, and who develop hypercapnia, the adverse clinical effects

may last for hours to days [2]. Both the arterial partial pressure of
carbon dioxide (PaCO2) and pH are important. PaCO2
>80 mmHg puts COPD patients at significant risk of reduced
level of consciousness and poor clinical outcomes. The pH is
likely to be a more important indicator of severity and prognosis [5,24]. For example, a pH <7.3 was associated with an
increased risk of intensive care unit admission [24] and a pH
>7.25 was associated with survival in exacerbations of COPD [5].
Does oxygen therapy cause CO2 retention in patients with
COPD or does CO2 retention result from progressive
respiratory failure?

Clinical studies identified that while severe exacerbations of

COPD may present with CO2 retention, the administration of
oxygen may lead to further and progressive increase in PaCO2 in
some patients [18]. Importantly, a PaCO2 >80 mmHg, the level
of clinical concern, almost always occurs in the setting of oxygen
therapy and rarely occurs while breathing room air [25,26]. The
increase of PaCO2 with oxygen therapy varies between patients
and although patients with a history of an episode of hypercapnia
during a previous COPD exacerbation, or greater degree of
hypoxaemia and higher PaCO2 levels at the acute presentation,
may be at greater risk of CO2 narcosis with oxygen therapy, it
was not possible to predict with clinical certainty which patients
were likely to respond to oxygen treatment in this way [16,27,28].
Does low concentration oxygen therapy cause less carbon
dioxide retention than high concentration oxygen?

The available evidence was that high concentration oxygen

therapy was more likely to cause an increase in PaCO2 than
low concentration oxygen, and that the raised PaCO2 could be
reduced by lowering the inspired oxygen concentration [1,18,29].
However, even low concentrations (FiO2 2428%) could
increase PaCO2 [6,12,14,27,29,30]. An important negative association
between pH and PaO2 indicated that the more oxygenated the
COPD patients became, the greater the magnitude of the subsequent respiratory acidosis [24]. The implication of these findings is that there is no lower level of therapeutic FiO2 at which
the physiological response of an increase in PaCO2 does not
occur. In turn, this implies that titration of oxygen therapy to
relieve hypoxaemia, while avoiding unnecessarily high PaO2,
might be preferred to the routine administration of fixed low
FiO2 in treatment of COPD.
Recommendation

The final conclusion of Murphy et al. [3] was that robust randomised controlled trials were needed to investigate the effects
of different concentrations of, and strategies for, oxygen delivery on clinical outcomes in patients with acute exacerbations
of COPD.
Evidence to guide oxygen therapy after 2000

Despite this call to action in 2000, it was not until 2010 that
the first high-quality randomised controlled trial of high
Expert Rev. Respir. Med. 9(3), (2015)

Oxygen therapy in acute exacerbations of COPD

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concentration oxygen therapy in acute exacerbations of COPD

was published (BOX 2) [4]. This controlled trial randomised
ambulances responding to patients with likely acute exacerbations of COPD to use either high concentration oxygen therapy, 810 l/min by a simple face mask, and oxygen-driven
bronchodilator nebuliser delivery or titrated oxygen therapy,
oxygen delivered by nasal cannulae, only if required, to achieve
an SpO2 of 8892%, and air-driven nebuliser bronchodilator
delivery.
Reduction in mortality with titrated oxygen therapy

The study by Austin et al. [4] reported that mortality was 9%

when high concentration oxygen was given, compared with 4%
when titrated oxygen was given, a 2.4-fold increased risk of
death in the high concentration group (TABLE 1). In the subgroup
of patients with COPD, later confirmed on lung function testing, the risk of death with high concentration oxygen was even
higher, about a 4.5-fold risk, albeit with wide CIs. The point
estimates indicate number needed to harm, in this case death,
of only 14, for patients given high concentration oxygen compared to titrated oxygen therapy.
Physiological effects

The physiological effects of FiO2 on PaCO2 are also reported

in the study of Austin et al. [4]. In patients who had arterial
blood gas measurements within 30 min of presentation to hospital, the group that had a confirmed diagnosis of COPD and
received the titrated oxygen regimen were significantly less
likely to have hypercapnia, mean difference in PaCO2
34 mmHg, or respiratory acidosis, mean difference in pH
0.12, compared to those allocated to the high concentration
oxygen therapy regimen. These physiological effects are likely
to have been the main cause for the increased risk of death,
but other mechanisms may have been important. For example,
profound rebound hypoxaemia can occur if high concentration
oxygen therapy is abruptly stopped either inadvertently or
deliberately in response to identifying hypercapnia [17,29,31,32].
Rebound hypoxaemia is partly due to PaO2 falling more
quickly than PaCO2 when oxygen therapy is stopped. This can
lead to PaO2 falling to a lower level than if oxygen had not
been given at all.

Review

Box 2. Key learning points from Austin et al.

randomised controlled trial [4].
.

Pre-hospital titrated oxygen therapy to achieve an oxygen

saturation of 8892% reduces the risk of mortality in
patients with an acute exacerbation of chronic obstructive
pulmonary disease compared to high concentration
oxygen therapy
The magnitude of the mortality risk reduction with titrated
oxygen therapy is large, relative risk of death 0.22, numbers
needed to treat to prevent one death 14
Even in the clinical trial setting, most trained staff delivered
high concentration oxygen at some time to patients randomised to the titration regimen. This shows the difficulty in
changing established clinical practice
Titrated oxygen therapy delivers oxygen by nasal cannulae,
only if required, to achieve oxygen saturation of 8892%,
and air-driven nebulisers to administer bronchodilator
therapy

Other potential mechanisms for the increased risk of death

observed in the study by Austin et al. [4] are that hyperoxaemia
causes reduced coronary artery blood flow or increased myocardial reperfusion injury, which are relevant to patients with
myocardial ischemia complicating their COPD exacerbation [3335]. When cardiac troponin concentration was measured, it was found to be raised in a quarter of patients with
an acute exacerbation of COPD [36]. Elevated levels are associated with the degree of hypercapnia and acidosis [36], and are
also associated with an increased risk of mortality [37].
The 8892% SpO2 target range

Austin et al. [4] used a target range for the titrated oxygen
group of 8892% and this represents the current evidencebased target in the situation of an acute exacerbation of
COPD. However, further research is needed to determine if
even this range is, in fact, optimal. Non-experimental evidence
suggests that the upper SpO2 limit should probably not be
above 95%, as a higher level was associated with a greater risk
of acidosis in hypercapnic patients in one study [38], and longer
hospital stays, higher rates of non-invasive ventilation, and
increased admission to a high dependency unit in another

Table 1. Mortality in patients with an acute exacerbation of COPD, randomised to high concentration
oxygen versus titrated oxygen therapy in the pre-hospital setting [4].
All patients

Confirmed COPD

High concentration group

Titrated group

Treatment effect (relative risk [95% CI])

p-value

21/226 (9%)

7/179 (4%)

0.42 (0.200.89)

0.02

11/117 (9%)

2/97 (2%)

0.22 (0.050.91)

0.04

Extract from a Table published by Austin et al., 2010 [4] and reproduced with permission from BMJ.

High concentration oxygen: High flow oxygen treatment (810 l/min) administered via a non-rebreather face mask and bronchodilators delivered by nebulisation with
oxygen flows of 68 l/min.

Titrated oxygen: Oxygen treatment delivered by nasal cannulae to achieve oxygen saturation between 88 and 92%, with concurrent bronchodilator treatment
administered by nebuliser driven by compressed air, delivered via a face mask over the nasal cannulae.

Confirmed COPD: A subgroup with a definite diagnosis of COPD, as defined by national guidelines, based on a retrospective review of medical records, including lung
function data in the 5 years prior to study entry.
COPD: Chronic obstructive pulmonary disease.

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Review

Pilcher, Weatherall, Perrin & Beasley

study [39]. A U-shaped curve of risk with PaO2 has been

reported. In a non-experimental study of patients admitted to
hospital with acute exacerbation of COPD, hypoxaemia,
defined as a PaO2 <60 mmHg, and hyperoxaemia, defined as a
PaO2 >100 mmHg, were both associated with an increased risk
of serious adverse clinical outcomes (respiratory failure, assisted
ventilation or death) when compared with normoxaemia, PaO2
60100 mmHg, the risks were 2.2 (95% CI: 1.14.2) for
hypoxaemia and 9.2 (95% CI: 4.120.6) for hyperoxaemia,
respectively [40]. The risk of adverse clinical outcomes within
the normoxic range, for example, SpO2 8890% compared to
9095%, needs further study.
Bronchodilator nebuliser therapy

The titrated oxygen regimen in the study by Austin et al. [4]

used both titrated supplemental oxygen therapy by nasal cannulae to the SpO2 target and air-driven nebulisers to deliver bronchodilator medication. This element of titrated oxygen delivery
avoided exposure to high concentration oxygen via oxygendriven nebulisers. The importance of this therapeutic approach
is also seen in clinical trials in patients with acute exacerbations [41,42] and stable COPD [43], where air-driven nebuliser use
prevented the increase in PaCO2 that occurs with oxygen-driven
nebulisers in patients with or without baseline CO2 retention.
A recent audit of an educational programme within an
ambulance service that used oxygen-driven nebulisers illustrates
the importance of air-driven compared to oxygen-driven nebulisers [44]. This audit found that over half the patients with
COPD who were otherwise not treated with supplementary
high concentration oxygen therapy were still exposed to high
concentrations of oxygen through the use of oxygen-driven
nebulisers as part of pre-hospital management. In about half of
the patients who were administered oxygen only through
oxygen-driven nebulisers, the last SpO2 documented prior to
hospital arrival was 97%, a similar proportion to those receiving deliberate supplementary high concentration oxygen therapy. Case reports of treatment of patients with an acute
exacerbation of COPD also show that marked increases in
PaCO2 are directly related to bronchodilator nebulisation
driven by high flow oxygen, which result in stupor, seizures
and death [4547]. This evidence indicates that titrated oxygen
regimens should include the use of air-driven nebulisers or
alternative methods for the delivery of bronchodilators such as
metered-dose inhalers with spacers. In acute exacerbations of
COPD, spacer use provides equivalent bronchodilator efficacy
to nebuliser delivered medication [48].
Difficulty with diagnosis of acute exacerbations of COPD

A definite diagnosis of acute exacerbation of COPD can be difficult in the acute pre-hospital setting [49,50]. The main difficulty is distinguishing this from acute severe asthma [49]. It is
therefore relevant to consider the effect of high concentration
oxygen therapy on PaCO2 in this clinical situation. A number
of trials show that high concentration oxygen therapy increases
the risk of hypercapnia in severe asthma [5153]. In one study,
290

high concentration oxygen therapy, delivered at 8 l/min by a

simple face mask, was compared to titrated oxygen therapy,
aiming to achieve an SpO2 target of 9395% [53]. It was found
that all cases of hypercapnia occurred in patients who received
high concentration oxygen. This finding raises the possibility
that most cases of hypercapnic respiratory failure in acute severe
asthma are caused by excessive oxygen therapy. It also suggests
that in clinical practice it may be preferable to assume a diagnosis of an acute exacerbation of COPD rather than asthma
when there is diagnostic uncertainty. Then titrated oxygen therapy can be used to achieve an SpO2 in the 8892% target
range. This approach is supported by the findings of
Austin et al. [4], because the lower risk of death in the titrated
group was regardless of whether patients had COPD confirmed
later (TABLE 1).
Other respiratory conditions

In addition to asthma, there are a number of other acute and

chronic respiratory conditions in which high concentration oxygen therapy may cause an increase in PaCO2. These include
community-acquired pneumonia [54], obesityhypoventilation
syndrome [55] and acute lung injury [56]. This effect likely represents a common physiological response across these different
respiratory conditions consistent with recognised potential
mechanisms such as reduction in hypoxic respiratory drive and
blunted ventilatory response to elevated carbon dioxide levels,
increased physiological dead space due to worsening of ventilationperfusion mismatch secondary to a release of hypoxic pulmonary vasoconstriction, absorption atelectasis, and the
Haldane effect [5759].
Changing clinical practice

Another key finding from Austin et al. study [4] is that more than
half of the patients with confirmed COPD who were assigned to
the titrated oxygen regimen received high concentration oxygen
at some time during their pre-hospital ambulance transfer. This
major protocol violation occurred despite an extensive training
programme of ambulance paramedics prior to the study and
ongoing supervision within the context of a randomised controlled trial. This is likely due to an entrenched culture of health
professionals to administer high concentration oxygen to breathless patients with exacerbations of COPD even when this is not
recommended by evidence-based guidelines. This culture is not
limited to ambulance paramedics and also occurs with hospitalbased medical and nursing staff [3840,49,50,60,61]. It will require
major integrated educational and management initiatives to
change the practice, so that those who administer oxygen recognise that oxygen is a drug that is prescribed for defined indications, in which its benefits outweigh its risks, that prescriptions
specify the dose and method of delivery to achieve a specified
SpO2 target to avoid both hypoxaemia and hyperoxaemia, and
that the patients response to oxygen therapy is monitored.
A greater insight into the beneficial physiological characteristics
of the oxyhaemoglobin dissociation curve is also required to
underpin the rationale for this approach to oxygen therapy [62].
Expert Rev. Respir. Med. 9(3), (2015)

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Oxygen therapy in acute exacerbations of COPD

The extent of this entrenched practice is illustrated in the

national UK audit of clinical care of COPD admissions undertaken in 2008 [38]. In a study of 9716 patients from 232 hospital
units, 30% had received >35% oxygen in the ambulance prior
to admission, and 35% of these patients were still receiving this
when admission arterial blood gases were taken. In a significant
proportion, this oxygen therapy was clearly inappropriate, as
illustrated by the observation that 25% of all patients who had
an arterial blood gas measurement had a PaO2 85 mmHg
(11.3 kPa), well in excess of the upper SpO2 target of 92%.
The clinical significance of this excessive oxygen therapy is suggested by the observation that 25% of patients acidotic on
admission had a PaO2 111 mmHg (14.8 kPa). These findings reflect practice after the 2004 publication of the NICE
guidelines recommending that the aim of oxygen therapy is to
maintain adequate levels of oxygenation without precipitating
respiratory acidosis or worsening hypercapnia [63].
Another possible approach to reduce the risk of high dose
oxygen administration in patients with an acute exacerbation of
COPD is to provide patients with severe COPD with an alert
card and Venturi mask to show to paramedics in the setting of
an acute exacerbation, reinforcing appropriate use of oxygen in
this situation [64,65].
Appropriate use of oxygen therapy requires a sea-change in
both the hearts and minds of health professionals who administer this potentially life-saving but also life-threatening therapy [57,66]. The Level 1b evidence provided by the study of
Austin et al. [4] of a reduced risk of mortality with titrated oxygen therapy to achieve an SpO2 of 8892% provides the basis
for the guideline recommendations [58]. Failure to follow this
therapeutic approach will increase the risk of harm to vulnerable patients and represents poor clinical practice [66].

Review

Expert commentary

A randomised controlled trial at low risk of bias provides Level

1b evidence that acute exacerbations of COPD should be
treated with titrated oxygen therapy to achieve an SpO2 target
of 8892%. This requires administration of supplementary
oxygen only if the SpO2 is <88% and administration of bronchodilators by air-driven nebuliser or metered-dose inhaler with
spacer. In the case of uncertainty between the diagnosis of an
acute exacerbation of COPD or acute severe asthma, the
patient should be treated as having COPD in respect to
oxygen therapy.
Five-year view

Future research into the optimal target saturation range in

patients with COPD and other respiratory diseases is needed to
further improve clinical outcomes. However, current high-grade
evidence for the titration of oxygen therapy to an SpO2 target
of 8892% provides the evidence on which to base current
practice. Clinical champions in health organisations are needed
to provide leadership and oversight to ensure that all health
practitioners within their service practice evidence-based medicine with the use of oxygen therapy in acute exacerbations of
COPD [58,67].
Financial & competing interests disclosure

The Medical Research Institute of New Zealand has received research

funding from Fisher & Paykel Healthcare (<$NZ 50,000). J Pilcher is a
Health Research Council of New Zealand Clinical Training Fellow. The
authors have no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed.

Key issues
.

There is Level 1b evidence that acute exacerbations of chronic obstructive pulmonary disease (COPD) should be treated with titrated
oxygen therapy to achieve an oxygen saturation target of 8892%, thereby avoiding the potential risks of both hypoxaemia
and hyperoxaemia.

In acute exacerbations of COPD, there is a 2.4-fold increase in the risk of death if patients receive high concentration oxygen therapy,
compared with titrated oxygen therapy.

The increased mortality is likely due to increased partial pressure of carbon dioxide; however, other mechanisms may include hyperoxaemia
causing reduced coronary blood flow or myocardial reperfusion injury, or rebound hypoxia if oxygen therapy is abruptly stopped.

Further research is needed to determine if the 8892% target saturation range for oxygen therapy is optimal (e.g., compared with
8590% or 9095% ranges).

Exposure to high concentration oxygen therapy is avoided by delivering bronchodilators by air-driven nebuliser or metered-dose inhaler
with a spacer rather than an oxygen-driven nebuliser.

If there is diagnostic uncertainty with acute severe asthma, it is preferable to administer oxygen therapy as if the patient is having an
acute exacerbation of COPD and therefore may be at risk of oxygen-induced hypercapnia.

High concentration oxygen therapy may also lead to an increase in partial pressure of carbon dioxide in a number of other acute and
chronic respiratory disorders, including severe asthma, community-acquired pneumonia, obesityhypoventilation syndrome, and acute
lung injury.

Appropriate use of oxygen therapy requires a practice change by health professionals who administer this potentially life-saving but also
life-threatening therapy.

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Pilcher, Weatherall, Perrin & Beasley

References

12.

Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 06/06/15
For personal use only.

Papers of special note have been highlighted as:

. of interest
.. of considerable interest
1.

Donald KW. Neurological effects of oxygen.

Lancet 1949;254:1056-7

2.

Westlake EK, Simpson T, Kaye M. Carbon

dioxide narcosis in emphysema. Q J Med
1955;24:155-73

3.

Murphy R, Driscoll P, ODriscoll R.

Emergency oxygen therapy for the COPD
patient. Emerg Med J 2001;18:333-9

..

A literature review of the evidence of the

effects of oxygen therapy in chronic
obstructive pulmonary disease up to
2000.

4.

..

Austin MA, Wills KE, Blizzard L, et al.

Effect of high flow oxygen on mortality in
chronic obstructive pulmonary disease
patients in prehospital setting: randomised
controlled trial. BMJ 2010;341:c5462
A randomised controlled trial
demonstrating increased mortality
following high concentration oxygen
therapy compared with titrated oxygen
therapy in patients with an acute
exacerbation of chronic obstructive
pulmonary disease.

5.

Hutchison DC, Flenley DC, Donald KW.

Controlled oxygen therapy in respiratory
failure. BMJ 1964;2:1159-66

6.

Smith JP, Stone RW, Muschenheim C.

Acute respiratory failure in chronic lung
disease. Observations on controlled oxygen
therapy. Am Rev Respir Dis 1968;97:
791-803

7.

8.

9.

10.

11.

Jeffrey AA, Warren PM, Flenley DC. Acute

hypercapnic respiratory failure in patients
with chronic obstructive lung disease: risk
factors and use of guidelines for
management. Thorax 1992;47:34-40

13.

Christensen CC, Ryg M, Refvem OK, et al.

Development of severe hypoxaemia in
chronic obstructive pulmonary disease
patients at 2,438 m (8,000 ft) altitude. Eur
Respir J 2000;15:635-9
Mithoefer JC, Karetzky MS, Mead GD.
Oxygen therapy in respiratory failure. N
Engl J Med 1967;277:947-9

292

King TK, Ali N, Briscoe WA. Treatment of

hypoxia with 24 percent oxygen. A new
approach to the interpretation of data
collected in a pulmonary intensive care unit.
Am Rev Respir Dis 1973;108:19-29

implications for the provision of

non-invasive ventilation and oxygen
administration. Thorax 2000;55:550-4
25.

Lal S. Blood gases in respiratory failure.

State on admission to hospital and
management. Lancet 1965;1:339-41

26.

McNicol MW, Campbell EJ. Severity of

respiratory failure. Arterial blood-gases in
untreated patients. Lancet 1965;1:336-8

27.

Bone RC, Pierce AK, Johnson RL Jr.

Controlled oxygen administration in acute
respiratory failure in chronic obstructive
pulmonary disease: a reappraisal. Am J Med
1978;65:896-902

28.

Lopez-Majano V, Dutton RE. Regulation of

respiration during oxygen breathing in
chronic obstructive lung disease. Am Rev
Respir Dis 1973;108:232-40

29.

Massaro DJ, Katz S, Luchsinger PC. Effect

of various modes of oxygen administration
on the arterial gas values in patients with
respiratory acidosis. Br Med J 1962;2:627-9

30.

DeGaute JP, Domenighetti G, Naeije R,

et al. Oxygen delivery in acute exacerbation
of chronic obstructive pulmonary disease.
Effects of controlled oxygen therapy. Am
Rev Respir Dis 1981;124:26-30

31.

Rudolf M, Turner JA, Harrison BD, et al.

Changes in arterial blood gases during and
after a period of oxygen breathing in
patients with chronic hypercapnic
respiratory failure and in patients with
asthma. Clin Sci (Lond) 1979;57:389-96

14.

Warrell DA, Edwards RH, Godfrey S, et al.

Effect of controlled oxygen therapy on
arterial blood gases in acute respiratory
failure. Br Med J 1970;1:452-5

15.

Agusti AG, Carrera M, Barbe F, et al.

Oxygen therapy during exacerbations of
chronic obstructive pulmonary disease. Eur
Respir J 1999;14:934-9

16.

Campbell EJ. The J. Burns Amberson

Lecture. The management of acute
respiratory failure in chronic bronchitis and
emphysema. Am Rev Respir Dis 1967;96:
626-39

17.

Campbell EJ. Respiratory failure: the

relation between oxygen concentrations of
inspired air and arterial blood. Lancet
1960;2:10-11

18.

Campbell EJ. A method of controlled

oxygen administration which reduces the
risk of carbon-dioxide retention. Lancet
1960;2:12-14

19.

Sieker HO, Hickam JB. Carbon dioxide

intoxication: the clinical syndrome, its
etiology and management with particular
reference to the use of mechanical
respirators. Medicine (Baltimore) 1956;35:
389-423

32.

Lange K, Graig F, Tchertkoff V, et al. The

effects of experimental acidosis on the
dynamics of circulation. Am J Med Sci
1951;222:61-5

Kane B, Turkington PM, Howard LS, et al.

Rebound hypoxaemia after administration
of oxygen in an acute exacerbation of
chronic obstructive pulmonary disease. BMJ
2011;342:d1557

An overview of the risks and mechanisms

associated with rebound hypoxaemia.

Dripps RD, Comroe JH Jr. The respiratory

and circulatory response of normal man to
inhalation of 7.6 and 10.4 per cent
CO2 with a comparison of the maximal
ventilation produced by severe muscular
exercise, inhalation of CO2 and maximal
voluntary hyperventilation. Am J Physiol
1947;149:43-51

33.

Beasley R, Aldington S, Weatherall M, et al.

Oxygen therapy in myocardial infarction:
an historical perspective. J R Soc Med
2007;100:130-3

34.

Thomson AJ, Webb DJ, Maxwell SR, et al.

Oxygen therapy in acute medical care. BMJ
2002;324:1406-7

35.

Sjoberg F, Singer M. The medical use of

oxygen: a time for critical reappraisal.
J Intern Med 2013;274:505-28

36.

Harvey MG, Hancox RJ. Elevation of

cardiac troponins in exacerbation of chronic
obstructive pulmonary disease. Emerg Med
Australas 2004;16:212-15

37.

Martins CS, Rodrigues MJ, Miranda VP,

et al. Prognostic value of cardiac troponin I
in patients with COPD acute exacerbation.
Neth J Med 2009;67:341-9

20.

21.

Harboe M. Lactic acid content in human

venous blood during hypoxia at high
altitude. Acta Physiol Scand 1957;40:
248-53
Hoffman CE, Clark RT Jr, Brown EB Jr.
Blood oxygen saturations and duration of
consciousness in anoxia at high altitudes.
Am J Physiol 1946;145:685-92

Schiff MM, Massaro D. Effect of oxygen

administration by a Venturi apparatus on
arterial blood gas values in patients with
respiratory failure. N Engl J Med 1967;277:
950-3

22.

23.

24.

Leake CD, Guedel AE, Botsford ME. The

stimulating effect of carbon dioxide
inhalations in dementia praecox catatonia.
Cal West Med 1929;31:20-3
Seevers M. The narcotic properties of
carbon dioxide. N Y State J Med 1944;44:
597-602
Plant PK, Owen JL, Elliott MW. One year
period prevalence study of respiratory
acidosis in acute exacerbations of COPD:

Expert Rev. Respir. Med. 9(3), (2015)

Oxygen therapy in acute exacerbations of COPD

38.

Roberts CM, Stone RA, Buckingham RJ,

et al. Acidosis, non-invasive ventilation and
mortality in hospitalised COPD
exacerbations. Thorax 2011;66:43-8

39.

Joosten SA, Koh MS, Bu X, et al. The

effects of oxygen therapy in patients
presenting to an emergency department
with exacerbation of chronic obstructive
pulmonary disease. Med J Aust 2007;186:
235-8

Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 06/06/15
For personal use only.

40.

41.

42.

43.

44.

45.

46.

47.

Cameron L, Pilcher J, Weatherall M, et al.

The risk of serious adverse outcomes
associated with hypoxaemia and
hyperoxaemia in acute exacerbations of
COPD. Postgrad Med J 2012;88:684-9
Gunawardena KA, Patel B, Campbell IA,
et al. Oxygen as a driving gas for nebulisers:
safe or dangerous? Br Med J (Clin Res Ed)
1984;288:272-4
ODonnell D, Kelly CP, Cotter P, et al.
Use of oxygen driven nebulizer delivery
systems for beta-2 agonists in chronic
bronchitis. Ir J Med Sci 1985;154:198-200
Edwards L, Perrin K, Williams M, et al.
Randomised controlled crossover trial of the
effect on PtCO2 of oxygen-driven versus
air-driven nebulisers in severe chronic
obstructive pulmonary disease. Emerg Med
J 2012;29:894-8
A randomised controlled trial
demonstrating increased partial pressure
of carbon dioxide following
oxygen-driven bronchodilator nebuliser
delivery, compared with air-driven
nebuliser delivery.
Pilcher J, Cameron L, Braithwaite I, et al.
Comparative audit of oxygen use in the
prehospital setting, in acute COPD
exacerbation, over 5 years. Emerg Med J
2013. [Epub ahead of print]

48.

49.

50.

51.

52.

ODriscoll BR, Howard LS, Davison AG.

BTS guideline for emergency oxygen use in
adult patients. Thorax 2008;63:vi1-68

..

British Thoracic Society Guidelines on

emergency oxygen therapy in adults.

59.

West J. Respiratory physiology.

The essentials. 9th edition. Lippincott
Williams & Wilkins, Philadelphia: 2012

60.

Wijesinghe M, Perrin K, Healy B, et al.

Pre-hospital oxygen therapy in acute
exacerbations of chronic obstructive
pulmonary disease. Intern Med J 2011;41:
618-22

61.

Considine J, Botti M, Thomas S.

Descriptive analysis of emergency
department oxygen use in acute exacerbation
of chronic obstructive pulmonary disease.
Intern Med J 2008;42:e38-47

62.

Beasley R, McNaughton A, Robinson G.

New look at the oxyhaemoglobin
dissociation curve. Lancet 2006;367(9517):
1124-6

New look at the oxygenhaemoglobin

dissociation curve.

63.

National Institute for Clinical Excellence

(NICE). Chronic obstructive pulmonary
disease. National clinical guideline on
management of chronic obstructive
pulmonary disease in adults in primary and
secondary care. Thorax 2004;59(Suppl 1):
1-232

64.

Gooptu B, Ward L, Ansari SO, et al.

Oxygen alert cards and controlled oxygen:
preventing emergency admissions at risk of
hypercapnic acidosis receiving high inspired
oxygen concentrations in ambulances and
A&E departments. Emerg Med J 2006;23:
636-8

65.

Santos C, Ferrer M, Roca J, et al.

Pulmonary gas exchange response to oxygen
breathing in acute lung injury. Am J Respir
Crit Care Med 2000;161:26-31

Durrington HJ, Flubacher M, Ramsay CF,

et al. Initial oxygen management in patients
with an exacerbation of chronic obstructive
pulmonary disease. QJM 2005;98:499-504

66.

New A. Oxygen: kill or cure? Prehospital

hyperoxia in the COPD patient. Emerg
Med J 2006;23:144-6

Beasley R, Patel M, Perrin K, et al.

High-concentration oxygen therapy in
COPD. Lancet 2011;378:969-70

67.

Kane B, ODriscoll BR. Emergency oxygen

therapy: from guideline to implementation.
Breathe 2013;9:246-53

Denniston AK, OBrien C, Stableforth D.

The use of oxygen in acute exacerbations of
chronic obstructive pulmonary disease:
a prospective audit of pre-hospital and
hospital emergency management. Clin Med
2002;2:449-51
Hale KE, Gavin C, ODriscoll BR. Audit of
oxygen use in emergency ambulances and in
a hospital emergency department. Emerg
Med J 2008;25:773-6
Chien JW, Ciufo R, Novak R, et al.
Uncontrolled oxygen administration and
respiratory failure in acute asthma. Chest
2000;117:728-33
Rodrigo GJ, Rodriquez Verde M,
Peregalli V, et al. Effects of short-term 28%
and 100% oxygen on PaCO2 and peak
expiratory flow rate in acute asthma:
a randomized trial. Chest 2003;124:1312-17
Perrin K, Wijesinghe M, Healy B, et al.
Randomised controlled trial of high
concentration versus titrated oxygen therapy
in severe exacerbations of asthma. Thorax
2011;66:937-41

54.

Wijesinghe M, Perrin K, Healy B, et al.

Randomized controlled trial of high
concentration oxygen in suspected
community-acquired pneumonia. J R Soc
Med 2011;105:208-16

55.

56.

Lim TK, Tan WC. Acute carbon dioxide

narcosis during inhalational therapy with
oxygen powered nebulizers in patients with
chronic airflow limitation. Ann Acad Med
Singapore 1985;14:439-41

57.

informahealthcare.com

58.

53.

Austin SJ, Chan C. Oxygen as a driving gas

for nebulisers: safe or dangerous? Br Med J
(Clin Res Ed) 1984;288:488

Hadfield JW, Stinchcombe SJ, Bateman JR.

Oxygen as a driving gas for nebulisers: safe
or dangerous? Br Med J (Clin Res Ed)
1984;288:795

Brocklebank D, Ram F, Wright J, et al.

Comparison of the effectiveness of inhaler
devices in asthma and chronic obstructive
airways disease: a systematic review of the
literature. Health Technol Assess 2001;5:
1-149

Review

Wijesinghe M, Williams M, Perrin K, et al.

The effect of supplemental oxygen on
hypercapnia in subjects with
obesity-associated hypoventilation:
a randomized, crossover, clinical study.
Chest 2011;139:1018-24

An overview of the proposed mechanisms

responsible for oxygen-induced
hypercapnia.

293