C H A P T E R 2 4 
Oxygen Toxicity and Hyperoxia
KEY POINTS
■ Breathing oxygen at increased
atmospheric pressure achieves very
high arterial PO2 values but venous PO2,
and therefore minimum tissue PO2, only
increases at 3 atmospheres absolute
pressure.
■ Normal metabolic processes, particularly
in the mitochondria, produce a range of
powerful oxidizing derivatives of oxygen,
collectively referred to as reactive
oxygen species.
■ The harmful effects of reactive oxygen
species are countered by a combination
of ubiquitous enzymes that inactivate
reactive oxygen species and endogenous
antioxidant molecules.
■ The lungs are susceptible to oxygen
toxicity, the first measurable signs
occurring in healthy subjects
after breathing 100% oxygen for
approximately 24 h.
■ Hyperbaric oxygen is used to treat a
variety of conditions such as tissue
infections, carbon monoxide poisoning
and sports injuries, but its use remains
controversial.
Chapter 22 described the disastrous conse-
quences of lack of oxygen for life forms that
depend on it, but for most organisms hypoxia is
an infrequent event. However, oxygen itself also
has toxic effects at the cellular level, which
organisms have had to oppose by the develop-
ment of complex antioxidant systems. The activ-
ity of toxic oxygen derivatives and antioxidant
systems is perfectly balanced for most of the
time. Nevertheless, there is a strengthening
opinion that over many years oxidative mecha-
nisms predominate and may be responsible for
the generalized deterioration in function associ-
ated with ageing.1 In a variety of diseases, or
when exposed to extra oxygen, the balance is
radically disturbed and unwanted physiological
changes or direct tissue damage results.
HYPEROXIA
Hyperventilation, while breathing air, can raise
the arterial Po2 to about 16 kPa (120 mm Hg).
Higher levels can be obtained only by oxygen
enrichment of the inspired gas and/or by eleva-
tion of the ambient pressure. Although the
arterial Po2 can be raised to very high levels, the
increase in arterial oxygen content is usually
relatively small (Table 24.1). The arterial oxygen
saturation is normally greater than 95% and,
apart from raising saturation to 100%, additional
oxygen can be carried only in physical solution.
Provided that the arterial/mixed venous oxygen
content difference remains constant, it follows
that venous oxygen content will rise by the same
value as the arterial oxygen content. The conse-
quences in terms of venous Po2 (Table 24.1) are
important because minimum tissue Po2 approxi-
mates more closely to venous than to arterial
Po2. The rise in venous Po2 is trivial when
breathing 100% oxygen at normal barometric
pressure, and it is necessary to breathe oxygen
at 3 atmospheres absolute (ATA) pressure before
there is a large increase in venous and therefore
tissue Po2. This is because most of the body
requirement can then be met by dissolved
oxygen, and the saturation of capillary and
venous blood remains close to 100%.
It is convenient to consider two degrees of
hyperoxia. The first applies to the inhalation
of oxygen-enriched gas at normal atmospheric
pressure, whereas the second involves inhaling
oxygen at raised pressure and is termed hyper-
baric oxygenation. But first, it is necessary to
understand the molecular basis by which oxygen
causes damage to biological molecules.
OXYGEN TOXICITY
The Oxygen Molecule and Reactive
Oxygen Species2,3
Although ground state oxygen (dioxygen) is a
powerful oxidizing agent, the molecule is stable
and has an indefinite half-life. However, the
oxygen molecule can be transformed into a range
of reactive oxygen species (ROS) and other
341
342 PART 2  Applied Physiology

TABLE 24.1  Oxygen Levels Attained in the Normal Subject by Changes in the Oxygen
Partial Pressure of Inspired Gas
At Normal Barometric Pressure At 2 ATA At 3 ATA
AIR OXYGEN OXYGEN OXYGEN

Inspired gas PO2 (humidified)

  (kPa) 20 96 190 285
  (mm Hg) 150 713 1425 2138
Arterial PO2*
  (kPa) 13 80 175 270
  (mm Hg) 98 600 1313 2025
Arterial oxygen content†
−1
  (ml.dl ) 19.3 21.3 23.4 25.5
Arterial/venous oxygen content difference
  (ml.dl−1) 5.0 5.0 5.0 5.0
Venous oxygen content
−1
  (ml.dl ) 14.3 16.3 18.4 20.5
Venous PO2
  (kPa) 5.2 6.4 9.1 48.0
  (mm Hg) 39 48 68 360

Note: Oxygen-induced vasoconstriction means tissue perfusion may be reduced by elevation of PO2. This tends to
increase the arterial/venous oxygen content difference, which will limit the rise in venous PO2. The increases in
venous PO2 shown in this table are therefore likely to be greater than in vivo.
*Reasonable values have been assumed for PCO2 and alveolar/arterial PO2 difference.
†
Normal values assumed for Hb, pH, etc.

highly toxic substances, most of which are far
more reactive than oxygen itself.
The dioxygen molecule (Fig. 24.1) is unusual
because it has two unpaired electrons in the
outer (2P) shell, but stability is conferred because
the orbits of the two unpaired electrons are
parallel. The two unpaired electrons also confer
the property of paramagnetism, which has been
exploited as a method of gas analysis that is
almost specific for oxygen (page 196).
Singlet Oxygen
Internal rearrangements of the unpaired elec-
trons of dioxygen result in the formation of two
highly reactive species, both known as singlet
oxygens (1O2). In 1ΔgO2 one unpaired electron
is transferred to the orbit of the other (Fig. 24.1),
imparting an energy level of 22.4 kcal.mol−1
reduced by receiving a single electron, which
pairs with one of the unpaired electrons forming
the superoxide anion (O•−2 in Fig. 24.1), which is
both an anion and a ROS. It is the first and
crucial stage in the production of a series of toxic
oxygen-derived ROS and other compounds.
The superoxide anion is relatively stable in
aqueous solution at body pH, but has a rapid
biological decay due to the ubiquitous presence
of superoxide dismutase (see later). Because it is
charged, a superoxide anion does not readily
cross cell membranes.
Hydroperoxyl Radical
A superoxide anion may acquire a hydrogen ion
to form the hydroperoxyl radical thus:
2 + H = HO 2
O•− + •

above the ground state. With no remaining

unpaired electron, 1ΔgO2 is not a ROS. In 1Σg+
the rotation of one unpaired electron is reversed,
which imparts an energy level of 37.5 kcal.mol−1
above the ground state, and this molecule is a
ROS. 1Σg+ is extremely reactive and rapidly
decays to the 1ΔgO2 form, which is particularly
relevant in biological systems and especially in
lipid peroxidation.
Superoxide Anion
Under a wide range of circumstances, consid-
ered later, the oxygen molecule may be partially
The reaction is pH dependent with a pK
of 4.8, so the equilibrium is far to the left in
biological systems.
Hydrogen Peroxide
Superoxide dismutase (SOD) catalyses the trans-
fer of an electron from one molecule of the
superoxide anion to another. The donor mole-
cule becomes dioxygen while the recipient
rapidly combines with two hydrogen ions to
form hydrogen peroxide (Fig. 24.1). Although
hydrogen peroxide is not a ROS, it is a powerful
 24  Oxygen Toxicity and Hyperoxia 343

O O O O
(••)
O2 O2• –

O O O O
1O2 1Σg+
1∆gO2

H
H H

O O O O

HO2• H2O2

O H O H

OH• OH–

O H

H2O
FIG. 24.1  ■  Outer orbital ring of electrons in (from the top left): ground-state oxygen or dioxygen (O2); superoxide
anion (O•− •
2 ); two forms of singlet oxygen (1O2); hydroperoxyl radical (HO2 ); hydrogen peroxide (H2O2); hydroxyl
radical (OH•); hydroxyl ion (OH–); and water. The arrows indicate the direction of rotation of unpaired electrons.
See text for properties and interrelationships.

and toxic oxidizing agent that plays an important R-OOH + 2G-SH →

role in oxygen toxicity. The overall reaction is as
follows:
2 + 2H → H 2O 2 + O 2 .
2O•− +
Hydrogen peroxide is continuously generated
in the body. Two enzymes ensure its rapid
re­moval. Catalase is a highly specific enzyme
active against only hydrogen, methyl and ethyl
peroxides. Hydrogen peroxide is reduced to
water thus:
2H 2O2 → 2H 2O + O2 .
Glutathione peroxidase acts against a much
wider range of peroxides (R–OOH), which react
with glutathione (GSH) thus:
R-OH + G − S − S − G + H 2O.
Catalase and glutathione peroxidase are dis-
cussed further in a later section.
Three-Stage Reduction of Oxygen
Figure 24.2 summarizes the three-stage reduc-
tion of oxygen to water, which is the fully reduced
and stable state. This contrasts with the more
familiar single-stage reduction of oxygen to
water that occurs in the terminal cytochrome
(page 190). Unlike the single-stage reduction of
oxygen, the three-stage reaction shown in Figure
24.2 is not inhibited by cyanide.
344 PART 2  Applied Physiology

O2 form hypochlorous acid. This occurs in the

e– phagocytic vesicle of the neutrophil and plays a
role in killing bacteria, facilitated by the enzyme
myeloperoxidase. The myeloperoxidase reaction
O2•–
Superoxide also occurs immediately after fertilization of
2H+ dismutase the ovum, and hypochlorous acid thus formed
O2 causes polymerization of proteins to form the
H2O2 membrane that prevents further entry of
Catalase spermatozoa.
or The changes previously described have many
O2 Glutathione features in common with those caused by ioniz­
peroxidase
H2O ing radiation; the hydroxyl radical (OH•) is the
most dangerous product in both cases. It is,
FIG. 24.2  ■  Three-stage reduction of oxygen to water.
The first reaction is a single electron reduction to form therefore, hardly surprising that the effect of
the superoxide anion reactive oxygen species. In the radiation is increased by high partial pressures
second stage the first products of the dismutation of oxygen. As tissue Po2 is reduced below about
reaction are dioxygen and a short-lived intermediate, 2 kPa (15 mm Hg), there is progressively
which then receives two protons to form hydrogen
peroxide. The final stage forms water, the fully reduced
increased resistance to radiation damage until, at
form of oxygen. zero Po2, resistance is increased threefold. This
unfortunate effect promotes resistance to radio-
therapy of malignant cells in hypoxic areas of
O2 tumours (page 432).
Nitric oxide may behave as a ROS by reacting
with the superoxide anion to produce peroxyni-
O2• – OH• trite (ONOO−). This molecule can either rear-
range itself into relatively harmless nitrite or
OH– nitrate (page 184), or give rise to derivatives with
Cl–
similar biological activity to the hydroxyl radical.
HOCl H2O2 1O2 Conversely, nitric oxide may act as an antioxi-
Myeloperoxidase Fenton or dant, binding to ferrous iron molecules and pre-
system Haber-Weiss reaction
venting them from contributing to the formation
H2O of a superoxide anion (see next) or the Fenton
reaction. The in vivo role of nitric oxide as a
FIG. 24.3  ■  Interaction of superoxide anion and hydro-
gen peroxide in the Fenton or Haber–Weiss reaction ROS or antioxidant therefore remains unclear.5
to form hydroxyl free radical, hydroxyl ion and singlet
oxygen. Hypochlorous acid is formed from hydrogen
peroxide by the myeloperoxidase system. (After refer- Sources of Electrons for
ence 4 by courtesy of the Editor of the Journal of the
Royal Society of Medicine.) the Reduction of Oxygen to
Superoxide Anion
Secondary Derivatives of the Figure 24.3 shows the superoxide anion as the
starting point for the production of many other
Products of Dioxygen Reduction ROS. The first stage reduction of dioxygen
Although both the superoxide anion and hydro- to the superoxide anion is therefore critically
gen peroxide have direct toxic effects, they inter- important in oxygen toxicity.
act to produce even more dangerous species. On
the right side of Figure 24.3 is the Fenton or Mitochondrial Enzyme
Haber–Weiss reaction, which results in the forma-
tion of the harmless hydroxyl ion together with Complex 1 (NADH oxidoreductase) and a
two extremely reactive species, the hydroxyl free variety of other mitochondrial enzymes may
radical (OH•) and singlet oxygen (1O2) ‘leak’ electrons to molecular oxygen producing
superoxide anions during normal oxidative res-
2 + H 2O 2 → OH + OH + 1O 2 .
O•− − • piration.6 Animal studies indicate that this may
account for almost 2% of total mitochondrial
The hydroxyl free radical is the most danger- oxygen consumption, indicating the importance
ous ROS derived from oxygen. of the highly efficient mitochondrial form of
On the left side of Figure 24.3 is the reaction SOD (see later). The concentration of mito-
of hydrogen peroxide with a chloride ion to chondrial ROS molecules must be carefully

controlled, a task undertaken by the mitochon-
drial permeability transition pore (mPTP)
channels in the mitochondrial membrane. In
response to an unfavourable redox state within
the mitochondrion, the mPTP channels open
very briefly to allow the ROS out into the cell
for removal by cytoplasmic antioxidant systems.
Excess ROS in the mitochondrion leads to more
prolonged opening of mPTP channels which
can damage the mitochondrion and cell. Thus
ROS are acting as a signalling pathway during
normal circumstances to control their own
levels, but can easily become a pathological
cause of cell damage.6
NADPH Oxidase System
The NADPH oxidase system is the major elec-
tron donor in neutrophils and macrophages.
The electron is donated from NADPH by
the enzyme NADPH oxidase, which is located
within the membrane of the phagocytic vesicle.
This mechanism is activated during phagocyto-
sis and is accompanied by a transient increase in
the oxygen consumption of the cells, a process
known to be cyanide resistant. This is the
so-called respiratory burst and occurs in all
phagocytic cells in response to a wide range of
stimuli including bacterial endotoxin, immu-
noglobulins and interleukins. Superoxide anion
is released into the phagocytic vesicle, where it
is reduced to hydrogen peroxide which then
reacts with chloride ions to form hypochlorous
acid in the myeloperoxidase reaction (Fig. 24.3).
For many years the release of ROS into the
phagocyte was believed to be the main way in
which bacteria were killed by phagocytes. Recent
work on pulmonary neutrophils in mice with
pneumococcal infection has refuted this claim,
finding no evidence of bacterial killing by
neutrophil-generated ROS, though ROS were
involved in neutrophil regulation.7 Powerful
protease enzymes released into the phagosome
by the neutrophil may be the most important
bactericidal mechanism.
Although the NADPH oxidase system has
extremely important biological functions, there
seems little doubt that its inappropriate activa-
tion in marginated neutrophils can damage the
endothelium of the lung, and it may well play
a part in the production of acute lung injury
(Chapter 30).
Xanthine Oxidoreductase and
Reperfusion Injury 8
The enzyme xanthine oxidoreductase (XOR) is
responsible for the conversion of hypoxanthine
24  Oxygen Toxicity and Hyperoxia 345
and xanthine to uric acid (Fig. 24.4). XOR is a
large (300 kDa) protein involving two separate
substrate binding sites, one including flavine
adenine dinucleotide cofactor and the other a
molybdenum molecule. In vivo, XOR exists in
two interchangeable forms, with about 80%
existing as xanthine dehydrogenase and the
remainder as xanthine oxidase. In both forms
XOR catalyses the conversion of both hypoxan-
thine to xanthine and of xanthine to uric
acid, and under normal conditions uses NADH
as a cofactor. In ischaemic or hypoxic tissue
large quantities of hypoxanthine accumulate
(page 327), the availability of NADH declines
and the ratio of the oxidase and dehydrogenase
forms of XOR may be reversed. As a result of
these changes, when oxygen is restored to the
cell, the XOR catalysis of xanthine and hypox-
anthine is altered with NAD+ and dioxygen now
used as cofactors, resulting in the production of
hydrogen peroxide and superoxide anions (Fig.
24.4). Thus during reperfusion there may be
extensive production of ROS.
Ferrous Iron
Ferrous iron (Fe2+) loses an electron during
conversion to the ferric (Fe3+) state. This is an
important component of the toxicity of ferrous
iron. A similar reaction also occurs during the
spontaneous oxidation of haemoglobin to meth-
aemoglobin (page 185). It is for this reason that
large quantities of SOD, catalase and other pro-
tective agents are present in the young red blood
cell. Their depletion may well determine the life
span of the cell. Apart from ferrous iron acting
as an electron donor, it is a catalyst in the Fenton
reaction (see previous discussion).
High PO2
Whatever other factors may apply, the produc-
tion of ROS is increased at high levels of Po2 by
the law of mass action. It would seem that the
normal tissue defences against ROS (discussed
later) are usually effective only up to a tissue Po2
of about 60 kPa (450 mm Hg). This accords with
the development of clinical oxygen toxicity as
discussed in a later section.
Exogenous Compounds
Various drugs and toxic substances can act as an
analogue of NADPH oxidase and transfer an
electron from NADPH to molecular oxygen.
The best example of this is paraquat which can,
in effect, insert itself into an electron transport
chain, alternating between its singly and doubly
346 PART 2  Applied Physiology

ATP

ADP

AMP

Normal Adenosine Ischaemia

oxygen reperfusion
levels injury
Inosine

Hypoxanthine
NADH NAD+ + O2
XOR XOR
FAD Mo Mo FAD

NAD+ NADH + H2O2 + O2• –

Xanthine
NADH NAD+ + O2
XOR XOR
FAD Mo Mo FAD

NAD+ NADH + H2O2 + O2• –

Uric acid

FIG. 24.4  ■  Generation of superoxide anion from oxygen by the activity of xanthine oxidoreductase (XOR). With
normal cellular oxygen levels (left side) NADH is the cofactor, binding at the flavine adenine dinucleotide (FAD)
site whilst the substrate reacts with the molybdenum binding site at the opposite side of the XOR molecule.
Following a period of ischaemia (right side), reperfusion causes NAD+ and oxygen rather than NADH to react at
the FAD binding site of XOR, resulting in the production of hydrogen peroxide or superoxide anion.

ionized forms. This process is accelerated at high
levels of Po2, and so there is a synergistic effect
between paraquat and oxygen. Paraquat is con-
centrated in the alveolar, epithelial type II cell
where the Po2 is as high as anywhere in the body.
Because of the very short half-life of ROS,
damage is confined to the lung. Bleomycin and
some antibiotics (e.g. nitrofurantoin) can act in
a similar manner (see next).
Biological Effects of ROS
Their use in the regulation of phagocytes, and
possibly in the killing of microorganisms, is a
beneficial role for ROS. Elsewhere within cells,
the balance between the detrimental effects of
ROS and the antioxidants that counter these (see
later discussion) is described as the redox state
of the cell. Cellular, and more specifically mito-
chondrial, redox state is believed to be part of an
essential, and poorly understood, cell signalling
system6,9 involved, for example, in the sensing of
oxygen levels in the carotid body. Otherwise,
most effects of ROS on biological systems are
harmful, and alterations in redox state are linked
to a diverse range of diseases.
The three main biochemical targets for
ROS damage are DNA, lipids and sulphydryl-
containing proteins. All three are also sensitive
to ionizing radiation. The mechanisms of both
forms of damage have much in common and
synergism occurs.
1. DNA. Breakage of chromosomes in cultures
of animal lung fibroblasts by high concentra-
tions of oxygen was first demonstrated in
1978.10 Subsequent work has demonstrated
that ROS are involved in damaging both
nuclear and mitochondrial DNA, including
repair errors and double-strand breaks, and
activation of transcription factors and signal
proteins, all mechanisms that are believed to
underpin the role of ROS in carcinogenesis.11
In vivo studies of therapeutic hyperbaric
oxygen in humans have also shown DNA

Formation of
chemotactic factors
Cytokine release
+ NO
O•2–
Catecholamine
inactivation
Increased adhesion
molecules
FIG. 24.5  ■  Biochemical effects of superoxide anion and peroxynitrite. These potent cellular effects initiate numer-
ous pathological processes including inflammation, malignancy or cell death. MnSOD, manganese superoxide
dismutase. (After reference 13 with permission of the authors.)
damage. However, adverse clinical outcomes
from hyperbaric oxygen have not been dem-
onstrated, though susceptible subgroups, who
have less effective cellular antioxidant or
DNA repair systems, may exist.12
2. Lipids. There is little doubt that lipid peroxi-
dation is a major mechanism of tissue damage
by ROS. The interaction of a ROS with
an unsaturated fatty acid not only disrupts
that particular lipid molecule but also gener-
ates another ROS so that a chain reaction
ensues until stopped by an antioxidant.
Lipid peroxidation disrupts cell membranes
and accounts for the loss of integrity of
the alveolar/capillary barrier in pulmonary
oxygen toxicity.
3. Proteins. Damage to sulphydryl-containing
proteins results in formation of disulphide
bridges, which inactivates a range of
proteins.
Interference with these fundamental cellular
molecules has widespread physiological implica-
tions. Superoxide anion, and the peroxynitrite
formed from nitric oxide, initiate a wide range
of pathological processes, including the inactiva-
tion of neurotransmitters, inhibition of proteins,
release of cytokines and direct cytotoxic effects
(Fig. 24.5).13 Inevitably, cell dysfunction will
rapidly occur, followed over the long term by the
occurrence of inflammation, malignancy or cell
death. Over an animal’s lifetime, ROS-induced
damage is now closely linked with cardiovascular
and neurologic disease, cancer and the degenera-
tive changes of ageing.1,11,14
DEFENCES AGAINST REACTIVE
OXYGEN SPECIES
Life in an oxidizing environment is possible
only because of powerful antioxidant defences,
24  Oxygen Toxicity and Hyperoxia 347
Receptor inactivation
Lipid peroxidation
(e.g. steroid)
ONOO– DNA damage
Enzyme inactivation
Cytotoxicity
(e.g. MnSOD)
which all aerobes have developed (Chapter
Online 1).
Antioxidant Enzymes
These enzymes are widely distributed in differ-
ent organs and different species but are deficient
in most obligatory anaerobic bacteria. Young
animals normally have increased levels of SOD
and catalase, which confer greater resistance to
oxygen toxicity. The reactions catalysed by anti-
oxidant enzymes were described earlier.
Superoxide Dismutase15,16
Three types of SOD exist, each derived from a
separate gene: extracellular SOD, cytoplasmic
SOD containing manganese (MnSOD) and
mitochondrial SOD containing both copper and
zinc (CuZnSOD). Extra production of SOD
may be induced by several mechanisms, of which
hyperoxia is the most notable, but inflammatory
cytokines such as interferon, tumour necrosis
factor, interleukins and lipopolysaccharide are
important stimulants of SOD production in the
intact animal.
Animal studies have consistently shown that
induction of SOD confers some protection
against the toxic effects of oxygen,2 and, by
implication, enhanced SOD activity may be pro-
tective against the wide range of pathological
processes already described. There are difficul-
ties in the therapeutic use of SOD because the
most important forms are intracellular or mito-
chondrial enzymes which have very short half-
lives in plasma. Therefore there is little scope for
their use by direct intravenous injection. It is
possible for SOD to enter cells if it is adminis-
tered in liposomes, and extracellular SOD has
been used by direct instillation into the lungs.17
Recent attempts to enhance SOD activity for
348 PART 2  Applied Physiology
therapeutic purposes have switched to the devel-
opment of SOD mimetics.13 A number of small
polycyclic compounds, mostly containing a
central manganese molecule, have been found to
catalyse the same reactions as SOD, but because
of their small size and nonpeptide nature they
can freely enter the intracellular environment.
SOD mimetics have yet to begin clinical trials,
but their therapeutic potential for the future
looks promising.
Catalase has a cellular and extracellular distri-
bution similar to SOD, with which it is closely
linked in disposing of the superoxide anion (Fig.
24.2). Although studied less extensively, catalase
production is believed to be induced by the
same factors as SOD. Similarly, trials of exoge-
nous antioxidant enzymes have usually given
better results when both SOD and catalase are
administered.
Glutathione peroxidase system scavenges not
only the ROS but also reactive species formed
during lipid peroxidation. Two molecules of the
tripeptide (glycine-cysteine-glutamic acid) GSH
are oxidized to one molecule of reduced glutath-
ione (GSSG) by the formation of a disulphide
bridge linking the cysteine residues. GSH is
reformed from GSSG by the enzyme glutathione
reductase, with protons supplied by NADPH.
Endogenous Antioxidants
Ascorbic acid is a small molecule with significant
antioxidant properties which are particularly
important for removal of the hydroxyl free
radical. Apart from a direct chemical effect on
the cell redox state, ascorbate also has effects on
nitric oxide synthesis and may influence cell bio-
chemistry by this mechanism as well.18 Humans,
along with guinea pigs and bats, lack the enzyme
required for the production of ascorbate and
must ingest sufficient vitamin C to compensate.
In these mammals, SOD activity is markedly
higher than in those able to produce endogenous
ascorbate.19
Vitamin E (α-tocopherol) is a highly fat-soluble
compound and is therefore found in high
concentrations in cell membranes. Predictably,
its main antioxidant role is in the prevention of
lipid peroxidation chain reactions as described
earlier.
Glutathione is found in high concentrations in
the airway lining fluid as part of the glutathione
peroxidase system previously described. Wide-
spread use of paracetamol, which at high doses
can reduce glutathione levels in the lung, may
attenuate the antioxidant activity provided
by glutathione, increasing oxidative stress and
possibly contributing to the increasing inci-
dences of asthma and chronic obstructive pul-
monary disease (COPD; Chapter 27).20
Surfactant may act as an antioxidant in the
lung. Animal studies have shown that adminis-
tration of exogenous surfactant prolongs the
duration of oxygen exposure required to cause
lung damage.21
Exogenous Antioxidants
Allopurinol. Because XOR plays a pivotal role
in the reactions shown in Figure 24.4 it
seemed logical to explore the use of allopu-
rinol, which inhibits a range of enzymes
including XOR. As expected, benefit
was seen mainly following ischaemia–
reperfusion injury, but under these condi-
tions allopurinol has multiple effects on
purine metabolism and may not be acting
as a XOR inhibitor at all.8
Iron-chelating agents. Because ferrous iron is
both a potent source of electrons for con-
version of oxygen to the superoxide anion
and a catalyst in the Fenton reaction, the
iron chelating agent desferrioxamine has
antioxidant properties in vitro.22
These compounds, along with other in vitro
antioxidants such as n-acetyl cysteine, β-carotene
and dimethylsulphoxide have generally failed to
live up to their expectations in human disease.
There are three possible explanations. First,
studies of ROS production and antioxidants in
human cells are relatively rare, and there is
known to be considerable species variability.2
Second, penetration of the exogenous antioxi-
dant to the site of ROS generation (e.g. mito-
chondria) or damage (e.g. nuclear DNA) is likely
to be poor. Finally, ROS involvement in physi-
ological systems such as neutrophil regulation is
crucial, so any nonspecific antioxidant activity
may be detrimental. Their therapeutic role in
oxygen toxicity or diseases known to involve
ROS is therefore far from fully clarified.
NORMOBARIC HYPEROXIA
The commonest indication for oxygen enrich-
ment of the inspired gas at normal atmospheric
pressure is the prevention of arterial hypoxae-
mia (‘anoxic anoxia’) caused either by hypoven-
tilation (page 385) or by venous admixture
(page 176). Increasing the FiO2 may also be used
to mitigate the effects of hypoperfusion (‘stag-
nant hypoxia’). The data in Table 24.1 show
that there will be only marginal improvement
in oxygen delivery (page 192), but it may be
critical in certain situations. ‘Anaemic anoxia’
 24  Oxygen Toxicity and Hyperoxia 349

respiratory system; that is, the oxygen concen-

TABLE 24.2  Normal Arterial and Mixed
tration delivered is unaffected by respiratory
Venous Blood Gas Partial Pressure
rate, tidal volume and inspiratory flow rate.
kPa mm Hg Methods may be divided into low-flow (closed)
ARTERIAL VENOUS ARTERIAL VENOUS
or high-flow (open) delivery systems.
BLOOD BLOOD BLOOD BLOOD Closed delivery systems include a seal between
the apparatus delivering the flow of gas and the
Breathing air patient’s airway. Airtight seals may be obtained
  PO2 13.3 5.2 98 39
  PCO2 5.3 6.1 40 46 with cuffed tracheal or tracheostomy tubes or, at
  PN2 76.0 76.0 570 570 low airway pressures, with a tight-fitting face-
  Total gas 94.6 87.3 708 655 mask or laryngeal mask airway. These devices
partial should give complete control over the composi-
pressure
Breathing oxygen tion of the inspired gas. Any closed delivery
  PO2 80.0 6.4 600 48 system requires the use of a breathing system
  PCO2 5.3 6.1 40 46 that provides suitable separation of inspired and
  PN2 0 0 0 0 expired gases to prevent rebreathing and does
  Total gas 85.3 12.5 640 94
partial
not present significant resistance to breathing.
pressure Alternatively, the oxygen level may be controlled
in the patient’s gaseous environment. The popu-
larity of oxygen tents declined because of their
will be only partially relieved by oxygen therapy large volume and high rate of leakage, which
but, because the combined oxygen is less than made it difficult to attain and maintain a high
what is seen in a subject with normal haemo- oxygen concentration unless the volume was
globin concentration, the effect of additional reduced and a high gas flow rate used. In addi-
oxygen carried in solution will be relatively tion, the fire hazard cannot be ignored. These
more important. problems are minimized when the patient is an
Clearance of gas loculi in the body may be infant, and oxygen control within an incubator
greatly accelerated by the inhalation of oxygen, is a satisfactory method of administering a
which greatly reduces the total partial pressure precise oxygen concentration. A similar system
of the dissolved gases in the venous blood (Table is used with the hood (‘space helmet’) in critical
24.2). This results in the capillary blood having care environments in which the patients head
additional capacity to carry away gas dissolved is enclosed within a small, clear respirable
from the loculi. Total gas partial pressures in atmosphere.
venous blood are always slightly less than atmos- Open delivery systems make no attempt to
pheric, and this is critically important in pre- provide an airtight seal; instead they provide a
venting the accumulation of air in potential high flow of gas, which can vent to atmosphere
spaces such as the pleural cavity, where the pres- between the mask and the face, thus preventing
sure is subatmospheric. Oxygen is therefore the inflow of air. The required flow of air/oxygen
useful in the treatment of air embolism (page mixture needs to be in excess of the peak inspira-
415) and pneumothorax (page 434). tory flow rate. For normal resting ventilation
The most important clinical conditions in this is approximately 30 l.min−1, but in patients
which oxygen has been identified as the sole with respiratory distress it may be considerably
precipitating cause are retrolental fibroplasia greater.
and pulmonary oxygen toxicity, though there Oxygen may be passed through the jet of a
are many other clinical situations where excess Venturi to entrain air. Venturi-based devices are
oxygen has adverse effects. a convenient and highly economical method for
preparing high flows of oxygen mixtures in
Increasing the Inspired Oxygen the range of 25% to 40% concentration. For
example, 3 l.min−1 of oxygen passed through
Concentration23 the jet of a Venturi with an entrainment ratio
Many systems exist for increasing the inspired of 8 : 1 will deliver 27 l.min−1 of 30% oxygen.
oxygen concentration, and an understanding of Higher oxygen concentrations require a lower
these is crucial for effective therapy. entrainment ratio and therefore a higher oxygen
flow to maintain an adequate total delivered
Fixed Performance Devices flow rate. With an adequate total flow rate of
the air/oxygen mixture, the Venturi mask need
These allow the delivery of a known concentra- not fit the face with an airtight seal. The high
tion of oxygen, independent of the patient’s flow rate escapes round the cheeks as well as
350 PART 2  Applied Physiology
through the holes in the mask, and room air
is effectively excluded. Numerous studies have
indicated that the Venturi mask gives good
control over the inspired oxygen concentration
that is mostly unaffected by variations in the
ventilation of the patient, except at high oxygen
concentrations.24
An alternative to Venturi masks has recently
been developed which includes an efficient
oxygen/air mixer and humidifier, allowing a
large flow of fully humidified gas of a precisely
controlled oxygen concentration to be delivered
via soft nasal cannulae. Referred to as high-flow
nasal cannula oxygen therapy the device is very
well tolerated by patients and can deliver up to
70 l.min−1 flow, at which level there is some evi-
dence of a raised end-expiratory pressure and
lung volume.25 This technique has been shown
to be an efficient and minimally invasive method
of preoxygenating patients before induction for
high-risk anaesthesia26 and before intubation for
respiratory failure,27 though there are concerns
that the latter use may delay more definitive
airway management and ventilation.28
Variable Performance Devices
Simple disposable oxygen masks and nasal cath-
eters aim to blow oxygen at or into the air pas-
sages. The oxygen is mixed with inspired air to
give an inspired oxygen concentration that is a
complex function of the geometry of the device,
the oxygen flow rate, the patient’s ventilation and
whether the patient is breathing through their
mouth or nose. The effective inspired oxygen
concentration is impossible to predict and may
vary between very wide limits. These devices
cannot be used for oxygen therapy when the
exact inspired oxygen concentration is critical
but are useful in many other situations such as
recovery from routine anaesthesia. With simple
oxygen masks a small inspiratory reservoir will
store fresh gas during expiration for use during
inspiration, which will tend to increase the
inspired oxygen concentration but, again, in a
somewhat unpredictable fashion.
With a device such as a nasal catheter or
prongs, the lower the ventilation, the greater will
be the fractional contribution of the fixed flow
of oxygen to the inspired gas mixture. There is
thus an approximate compensation for hypoven-
tilation, with greater oxygen concentrations
delivered at lower levels of ventilation. Arterial
Po2 may then be maintained in spite of a pro-
gressively falling ventilation, but this will do
nothing to prevent the rise in Pco2, which may
reach a dangerous level without the development
of low oxygen saturations.
Retinopathy of Prematurity29
Previously known as retrolental fibroplasia,
retinopathy of prematurity (RP) was first
described in 1942, and soon afterwards it was
established that hyperoxia was a major aetio-
logical factor. Oxygen use in neonates was
strictly curtailed, but resulted in an increase in
morbidity and mortality attributable to hypoxia.
Thereafter oxygen was carefully titrated in the
hope of steering the narrow course between the
Scylla of hypoxia and the Charybdis of RP.
The same balance between oxygenation and RP
continues today, with uncertainty about the
optimal target oxygen saturation to use in pre-
mature neonates.30 RP develops in two phases.
In phase 1 there is delayed vascular develop-
ment of the retina with avascular peripheral
areas, and in phase 2 there is vasoproliferation
leading to intravitreal angiogenesis. These
abnormalities are believed to result from
changes in Po2 affecting the activity of hypoxia-
inducible factor (page 330) and in particular its
effect on vascular growth factors at this crucial
stage of eye development for humans. Antioxi-
dants such as vitamin E have showed some
promise for treatment of RP but often with
unacceptable side effects, and current therapeu-
tic strategies are therefore aimed at inhibiting
vascular growth factors.
Pulmonary Oxygen Toxicity
Pulmonary tissue Po2 is the highest in the body.
In addition, a whole range of other oxidizing
substances may be inhaled, including common
air pollutants and the constituents of cigarette
smoke (Chapter 19). The lung is therefore the
organ most vulnerable to oxygen toxicity and a
range of defence mechanisms have developed.
Overall antioxidant activity from both enzymes
and other endogenous antioxidants is very high
in the fluid lining of the respiratory tract. Extra-
cellular SOD is abundant in pulmonary airway
tissues, and abnormalities in its regulation may
contribute to some lung diseases.31 Type II alve-
olar epithelial cells, which produce surfactant
(page 18), are believed to also incorporate
vitamin E into the surfactant lipids.32
Pulmonary oxygen toxicity is unequivocal
and lethal in laboratory animals such as the
rat. Humans seem to be far less sensitive, but
there are formidable obstacles to investigation
of both human volunteers and patients. Study
of oxygen toxicity in the clinical environment
is complicated by the presence of the pulmo-
nary pathology that necessitated the use of
oxygen.

Symptoms33
High concentrations of oxygen cause irritation
of the tracheobronchial tree, which gives rise
initially to a sensation of retrosternal tightness.
Continued exposure leads to chest pain, cough
and an urge to take deep breaths. Reduced vital
capacity is the first measurable change in lung
function, occurring after about 24 h of normo-
baric 100% oxygen. Oxygen exposure beyond
this point leads to the widespread structural
changes described next, which ultimately give
rise to acute lung injury and possibly irreversible
changes in lung function.
Cellular Changes34
Electron microscopy has shown that, in rats
exposed to 1 atm of oxygen, the primary change
is in the capillary endothelium, which becomes
vacuolated and thin. Permeability is increased
and fluid accumulates in the interstitial space. At
a later stage, in monkeys, the epithelial lining is
lost over large areas of the alveoli. This process
affects the type I cell (page 13) and is accompa-
nied by proliferation of the type II cell, which
is relatively resistant to oxygen. The alveolar/
capillary membrane is greatly thickened, partly
because of the substitution of type II for type I
cells and partly because of interstitial accumula-
tion of fluid.
Limits of Survival
Pulmonary effects of oxygen vary greatly between
different species, probably because of different
levels of provision of defences against ROS.
Most strains of rat will not survive for much
more than 3 days in 1 atm of oxygen. Monkeys
generally survive oxygen breathing for about 2
weeks, and humans are probably even more
resistant. Oxygen tolerance in humans has been
investigated,35 but these studies are based on
reduction in vital capacity, etc., which is a very
early stage of oxygen toxicity. There is an
approximately inverse relationship between Po2
and duration of tolerable exposure. Thus 20 h of
1 atm had a similar effect to 10 h of 2 atm or 5 h
of 4 atm.
Pulmonary oxygen toxicity seems to be related
to Po2 rather than inspired concentration. Early
American astronauts breathed 100% oxygen
at a pressure of about one-third of an atmos-
phere for many days (Table 17.1) with no
apparent ill effects. There is abundant evidence
that prolonged exposure to this environment
does not result in demonstrable pulmonary
oxygen toxicity thus establishing a Po2 of 34 kPa
(255 mm Hg) as a safe level. It also confirms that
24  Oxygen Toxicity and Hyperoxia 351
the significant factor is partial pressure and not
concentration. In contrast, the concentration of
oxygen rather than its partial pressure is the
important factor in absorption collapse of the
lung (see later).
Clinical Studies
Some limited information on human pulmonary
oxygen toxicity has been obtained from patients
in the course of therapeutic administration of
oxygen. A study in 1967 of patients who died
after prolonged artificial ventilation found more
structural pulmonary abnormalities (fibrin mem-
branes, oedema and fibrosis) in those who had
received 100% oxygen.36 However, the higher
concentrations of oxygen would probably have
been used in the patients with more severe
defects in gas exchange, and it is therefore dif-
ficult to distinguish between the effects of oxygen
itself and the conditions which required its use.
A similar group of patients ventilated for long
periods with high concentrations of oxygen were
reviewed in 1980,37 and these authors concluded
that adverse effects of oxygen on the alveolar
epithelium were rarely of practical importance
in hypoxaemic patients. An attempt to avoid the
complicating factor of preexisting pulmonary
disease was made in 197038 by ventilating a group
of patients with 100% oxygen for 24 h after
cardiac surgery. Various indices of pulmonary
function (Vd/Vt ratio, shunt and compliance)
were not significantly different from a control
group receiving less than 42% oxygen. In con-
trast to these essentially negative findings, a
study in 1987 obtained positive findings in a
randomized trial involving patients ventilated
after cardiac surgery.39 Venous admixture was
significantly greater and arterial Po2 less in
patients receiving 50% oxygen compared with
the group receiving less than 30%. There are
many possible causes for these changes, but the
authors concluded that unnecessary elevation of
inspired oxygen concentration should be avoided.
This is a view from which few would dissent
at present, including a recent suggestion that
inspired oxygen in artificially ventilated patients
should be titrated to a target oxygen saturation,
as already advocated in other acutely ill patients
as described later.40
Pulmonary Absorption Collapse
Whatever the uncertainties about the suscepti-
bility of humans to pulmonary oxygen toxicity,
there is no doubt that high concentrations of
oxygen in zones of the lung with low ventilation/
perfusion ratios will result in collapse. This
352 PART 2  Applied Physiology
occurs routinely during anaesthesia (page 299),
and may be demonstrated in healthy volun-
teers. A few minutes of breathing oxygen at
residual lung volume results in radiological
evidence of collapse, a reduced arterial Po2 and
substernal pain on attempting a maximal
inspiration.41
Bleomycin Lung Toxicity
Bleomycin is an intravenous cytotoxic drug used
for chemotherapy of germ-cell tumours and has
been known for decades to cause severe and
sometimes fatal pulmonary toxicity. Its cytotoxic
action includes binding to both DNA and
an iron molecule which is then oxidized to
its Fe3+ state, releasing ROS that damage the
DNA. With lung toxicity bleomycin in the cir-
culation initially damages pulmonary capillary
endothelial cells causing leakage of fluid into
the interstitial space where the drug gains access
to type 1 alveolar cells vulnerable to ROS
damage resulting in lung injury.42 Animal studies
have demonstrated the critical role of ROS
by showing that SOD mimetic molecules can
attenuate the lung damage.43 Lung toxicity has
been reported as occurring in 2.8%–6.3% of
patients treated with the drug with predictors
of this complication including older age,
renal impairment and total dose of bleomycin
used.44,45 The role of supplemental oxygen in
exacerbating lung toxicity and the duration after
treatment when patients are at risk are contro-
versial, with conflicting reports from heteroge-
neous case series. One possible explanation
for the lack of clear findings is that hyperoxia
simply exacerbates preexisting lung damage,
irrespective of whether this is clinically
apparent or subclinical, as indicated by reduced
pulmonary-diffusing capacity.42 It therefore still
seems sensible to minimize oxygen exposure for
any patient who has been treated with bleomy-
cin, with most clinicians currently adopting
target oxygen saturations to guide the FiO2 as
described next.
Hyperoxia in Clinical Practice
Therapeutic Use of
Normobaric Hyperoxia
The ease with which FiO2 can be increased
during anaesthesia means that hyperoxia has
mostly been used for therapeutic reasons in the
perioperative period. Most studies compare FiO2
values of 0.3–0.4 with greater than 0.8.46 Hyper-
oxia has been proposed to reduce postoperative
nausea and vomiting (PONV), purportedly from
improved oxygen delivery to the gut mucosa.
Results from trials and meta-analyses have shown
conflicting results, with the largest of these
finding that hyperoxia was only beneficial in
patients at high risk of PONV who received no
prophylactic drugs, giving a ‘number needed to
treat’ of 15 patients for one patient to benefit.46
Results are even more uncertain for hyperoxia
preventing surgical site infections, with a similar
variation in outcomes from trials and no agree-
ment yet on which groups of patients gain a
clinically useful benefit.46-49 In this situation,
hyperoxia is believed to increase tissue Po2
improving ROS availability for the killing of
pathogens by neutrophils.48 Although clinical
benefits of a perioperative FiO2 of around 0.8
remain mostly unproven,50 there is also some
reassuring evidence that the high FiO2 does not
worsen pul­monary function,46 supporting the
idea that 100% oxygen is required to maximize
atelectasis formation (page 300).
Oxygen Use in Acute Medicine
In clinical practice the administration of oxygen
to acutely ill patients has become almost ubiqui-
tous, both in hospital and community settings.
Prevention of dangerous hypoxia is always the
first priority and hypoxia must be treated in spite
of the various hazards associated with the use
of oxygen. Widely accepted guidelines23 have
sought to challenge this ‘oxygen culture’51 and
suggest that emergency oxygen therapy should
always by targeted at a predetermined oxygen
saturation, with suggested values of 94% to 98%
in most acutely ill patients or 88% to 92% for
those at risk of hypercapnia.23 When these
targets are not achievable by increasing inspired
oxygen alone, it is important to remember that
oxygen delivery can also be increased by improv-
ing cardiac output and haemoglobin levels. Clin-
ical situations where the routine use of oxygen is
now being challenged include:
• Exacerbations of COPD. The mechanisms of
the adverse effects are described on page 399.
Uncontrolled use of oxygen is associated with
increased mortality in these patients.50
• Acute myocardial infarction (AMI). Although
not yet conclusively proven, there is some evi-
dence that oxygen therapy in the first few
hours after AMI does not improve survival and
may be associated with worse outcomes.52,53
Hyperoxia causes vasoconstriction of systemic
blood vessels, an effect inhibited by vitamin C,
suggesting a mechanism involving ROS.54,55
The same is true for coronary blood flow,56
with a suggestion from some work that the
effect is more pronounced in diseased arteries
that are already under oxidative stress.57

• Acute ischaemic stroke. There is some evidence
that hyperoxia causes an increased mortality
in patients following severe ischaemic strokes
who need artificial ventilation.58 Hyperoxia is
known to reduce cerebral blood flow, and the
same vasoconstrictor effects described earlier
are believed to be the cause of the worse out-
comes following stroke.
• Cardiopulmonary resuscitation (CPR).59 There
has never been any doubt that during CPR
(page 472) 100% oxygen should be adminis-
tered to maximize the oxygen content in the
poor circulation generated by cardiac com-
pressions. However, at the return of spontane-
ous circulation (ROSC) it has been shown that
the FiO2 used impacts subsequent patient sur-
vival, with an odds ratio of 1.8 (CI 1.5–2.2) for
death in patients receiving hyperoxia (PaO2
>40 kPa, 300 mm Hg).60 Once the ROSC is
established well enough for a pulse oximeter
to give a reliable reading, FiO2 should be
titrated to a normal level.
These adverse clinical outcomes with hyperoxia
have led to debate regarding the optimal level of
target oxygen saturation or Po2. There are now
calls for much more precise control of oxygen
levels, particularly in critically ill patients where
this is easily achieved, including a suggestion
that target levels should be deliberately lower
than normal. This proposed ‘permissive hypox-
aemia’ strategy has much in common with the
widely used permissive hypercapnia (page 445),
and in the future may prove useful to improve
clinical outcomes by allowing patients to adapt
to hypoxia, as occurs so effectively at altitude.61
HYPERBARIC OXYGENATION
Oxygen Convulsions
(The Paul Bert Effect)
It is well established that exposure to oxygen
at a partial pressure in excess of 2 ATA may
result in convulsions, usually preceded by a
variety of nonspecific neurological symptoms
such as headache, and visual disturbances.62 This
limits the depth to which closed-circuit oxygen
apparatus can be used. It is interesting that the
threshold for oxygen convulsions is close to that
at which brain tissue Po2 is likely to be sharply
increased (Table 24.1). The relationship to cer-
ebral tissue Po2 is supported by the observation
that an elevation of Pco2 lowers the threshold for
convulsions. High Pco2 increases cerebral blood
flow, therefore raising the tissue Po2 relative to
the arterial Po2. Hyperventilation and anaesthe-
sia each provide limited protection.
24  Oxygen Toxicity and Hyperoxia 353
Convulsions result from poorly understood
changes in cellular interactions between γ-
aminobutyric acid (GABA) and nitric oxide. As
GABA is an inhibitory neurotransmitter, it is not
unreasonable to suggest that a reduced level
might result in convulsions. Nitric oxide sensi-
tizes neurones to the toxic effects of GABA in
hypoxia, and is also involved in hyperoxic con-
vulsions. Nitric oxide inhibitors delay the onset
of convulsions in hyperoxia,63 but paradoxically,
the same effect is seen with some nitric oxide
donors.64 Whatever the role of nitric oxide, the
final common pathway seems to be mediated by
disturbed calcium fluxes and increased cyclic-
GMP concentration.63
Incidence
Hyperbaric oxygen used therapeutically as
described later; that is, intermittent exposure to
less than 3 ATA, carries little risk of oxygen con-
vulsions. At 2 ATA, a large series reported no
convulsions in over 12 000 treatments.65 Treat-
ment for carbon monoxide poisoning is associ-
ated with a greater incidence of convulsions
because of the higher pressures used (normally
2.8–3.0 ATA) and the toxic effects of carbon
monoxide on the brain. In this case 1% to 2%
of patients experience convulsions.66
Therapeutic Hyperbaric Oxygen
Administration of short periods of very high Po2
may bring about therapeutic effects by a variety
of mechanisms as follows.
Effect on Po2. Hyperbaric oxygenation is the
only way arterial Po2 values in excess of
90 kPa (675 mm Hg) may be obtained.
However, it is easy to be deluded into
thinking that the tissues will be exposed to
a similar Po2 as found in the chamber.
Terms such as ‘drenching the tissues with
oxygen’ have been used but are meaning-
less. In fact, the simple calculations shown
in Table 24.1, supported by experimental
observations, show that large increases in
venous and presumably therefore minimum
tissue Po2 do not occur until the Po2
of the arterial blood is of the order of
270 kPa (2025 mm Hg), when the whole
tissue oxygen requirements can be met
from the dissolved oxygen. However, the
relationship between arterial and tissue
Po2 is highly variable (page 147), and
hyperoxia-induced vasoconstriction in the
brain and other tissues limits the rise in
venous and tissue Po2. Direct access of
ambient oxygen will increase Po2 in
354 PART 2  Applied Physiology
superficial tissues, particularly when the
skin is breached.
Effect on Pco2. An increased haemoglobin
saturation of venous blood reduces its
buffering power and carbamino carriage
of carbon dioxide, possibly resulting in
carbon dioxide retention. The increase in
tissue Pco2 from this cause is unlikely to
exceed 1 kPa (7.5 mm Hg). However, in
the brain this might result in a significant
increase in cerebral blood flow, causing a
secondary rise in tissue Po2.
Vasoconstriction. As described earlier, high
Po2 causes vasoconstriction, which may be
valuable for reduction of oedema in the
reperfusion of ischaemic limbs and in
burns (see later discussion).
Angiogenesis. The growth of new blood vessels
is improved when oxygen is increased
to more than 1 ATA pressure, though
the mechanism by which angiogenesis is
stimulated is uncertain. When normoxia
follows a period of hypoxia, ROS are pro-
duced, and these are known to stimulate
the production of a variety of growth
factors that initiate angiogenesis.67 The
same mechanism may occur during hyper-
baric oxygenation.68
Antibacterial effect. For many years oxygen was
believed to play a role in bacterial killing
by the formation of ROS, particularly in
polymorphs and macrophages, though this
has recently been refuted (page 345).
However, oxygen will still have a direct
toxic effect on microorganisms, particu-
larly on anaerobic bacteria, and relief of
hypoxia improves the performance of
polymorphs.
Boyle’s law effect. The volume of gas spaces
within the body is reduced inversely
to the absolute pressure according to
Boyle’s law (page 501). This effect is addi-
tional to that resulting from reduction of
the total partial pressure of gases in venous
blood (Table 24.2).
Clinical Applications of
Hyperbaric Oxygenation
In practice, hyperbaric oxygen therapy means
placing a patient into a chamber at 2 to 3 ATA
and providing apparatus to allow them to
breathe 100% oxygen, normally a tight-fitting
facemask. Treatment is usually for about 1 to
2  h, and repeated daily for up to 30 days. Since
its first use in 1960 enthusiasm for hyperbaric
oxygenation has waxed and waned, and its use
is still confined to relatively few centres. Clear
indications of its therapeutic value have been
slow to emerge from controlled trials, which are
admittedly very difficult to conduct in the con-
ditions for which benefit is claimed. In particu-
lar, a proper ‘control’ group of patients must
undergo a sham treatment in a hyperbaric
chamber, which has been used in very few trials.
The most commonly accepted indications are
as follows.
Infection is the most enduring field of applica-
tion of hyperbaric oxygenation, particularly
anaerobic bacterial infections. High partial pres-
sures of oxygen increase the production of
ROS, which are cidal not only to anaerobes but
also to aerobes. The strongest indications are for
clostridial myonecrosis (gas gangrene), refrac-
tory osteo­myelitis and necrotizing soft tissue
infections, including cutaneous ulcers.
Gas embolus and decompression sickness are une-
quivocal indications for hyperbaric therapy and
the rationale of treatment was considered earlier
and in Chapter 16.
Carbon monoxide poisoning may occur from
exposure to automobile exhaust fumes, fires and
defective heating appliances. Indications for
hyperbaric oxygenation following carbon mon-
oxide poisoning include loss of consciousness,
neurological deficits, ischaemic cardiac changes,
significant metabolic acidosis or carboxyhaemo-
globin (COHb) levels of more than 25%, and
the aim is to reduce neurological sequelae.69-71
The original rationale for therapy, increased
rate of dissociation of COHb, seems simple
when the half-life of COHb is approximately 4
to 5 h whilst breathing air and only 20 minutes
with hyperbaric oxygen. However, breathing
100% oxygen at normal pressure reduces the
half-life of COHb to just 40 minutes; therefore
in many cases, by the time transport to a hyper-
baric chamber is achieved, COHb levels will
already be considerably reduced. Other poten-
tial benefits of hyperbaric oxygen are believed
to derive from minimizing the effects of carbon
monoxide on cytochrome c oxidase and reduc-
ing lipid peroxidation by neutrophils to attenu-
ate the immune-mediated and inflammatory
sequelae.70,71
Wound healing is improved by hyperbaric oxy-
genation, even when used intermittently. It is
particularly useful when ischaemia contributes
to the ineffective healing, for example, in diabe-
tes mellitus or peripheral vascular disease. The
mechanisms involve improved tissue oxygen
levels probably resulting from direct diffusion of
oxygen into the affected superficial tissues and
increased release of growth factors.68 Hyperbaric
oxygen is believed to expedite recovery from

soft-tissue injuries and fractures incurred during
competitive sports.72 Early treatment (within
8 h) is most effective, indicating a probable effect
on neutrophil activity at the site of injury.73
In the early 1980s there was great interest in
the therapeutic value of hyperbaric oxygenation
in multiple sclerosis. A small study reported a
favourable response in a double-blind controlled
trial in which the treated group received 2 ATA
oxygen, and the placebo group inhaled 10%
oxygen in nitrogen, also at 2 atm.74 Unfortu-
nately, these findings were not confirmed in sub-
sequent studies, and a review of 14 controlled
trials concluded that hyperbaric oxygen cannot
be recommended for the treatment of multiple
sclerosis.75
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CHAPTER 24  OXYGEN TOXICITY
AND HYPEROXIA
• Breathing high concentrations of oxygen at
normal atmospheric pressure causes large
increases in arterial Po2 but has only a small
effect on blood oxygen content, and so
venous Po2, as only the dissolved oxygen
component can be increased. At increased
atmospheric pressure (hyperbaria) the dis-
solved oxygen content can become much
higher until 3 atmospheres absolute pressure
when the dissolved gas alone is sufficient for
normal tissue oxygen consumption.
• The oxygen molecule can be transformed
into a variety of highly reactive derivatives
called reactive oxygen species (ROS) con-
taining unpaired electrons in their outer
shell. These include superoxide anion, which
may then react with hydrogen ions to produce
the hydroperoxyl radical and hydrogen per-
oxide (H2O2), which ultimately can be con-
verted to water and oxygen. Nitric oxide
may also act as a ROS, particularly when it
combines with superoxide to form the perox-
ynitrite ROS. Sources of electrons for the
generation of ROS include mitochondrial
enzymes and the NADPH and xanthine oxi-
doreductase enzymes.
• ROS are harmful due to their ability to react
with other biological molecules, for example,
causing direct damage to nearby proteins
and DNA. The reaction of ROS molecules
with the unsaturated fatty acids of lipid
membranes not only damages the mem-
brane itself but initiates a chain reaction of
lipid peroxidation, causing extensive cellular
damage.
• All aerobic organisms have extensive systems
to protect them from ROS damage. Two
ubiquitous enzymes, superoxide dismutase
and catalase, rapidly and completely convert
most ROS into harmless water and oxygen.
Ascorbic acid, vitamin E and glutathione in
cells also inactivate ROS by direct chemical
reactions. Some exogenous molecules also
have antioxidant activity such as allopurinol,
which inhibits xanthine oxidoreductase and
desferrioxamine, the iron-chelating mole-
cule, which prevents iron catalysing the
formation of ROS.
• Administration of oxygen at normal atmos-
pheric pressure is usually under­taken to treat
hypoxaemia caused by hypoventilation or
venous admixture. Attempts to treat tissue
hypoxia due to inadequate blood flow or
anaemia by breathing supplemental oxygen
24  Oxygen Toxicity and Hyperoxia 356.e1
are unlikely to have a large effect because of
failure to significantly increase blood oxygen
content.
• Additional oxygen may be administered by a
variety of techniques. Fixed performance
devices deliver a known concentration of
oxygen independent of the patient’s breath-
ing pattern. These include closed delivery
systems which have a seal between the
breathing system and the patient’s airway,
such as a tracheal tube or tracheostomy.
Alternatively, the patient, or at least their
head, can be enclosed in a sealed system
including oxygen tents and hoods. Open
delivery systems are not sealed with the
patient’s airway, but aim to deliver a flow of
gas equal to the patient’s peak inspiratory
flow, ensuring the concentration breathed
by the patient is as determined by the device.
Variable performance devices such as simple
disposable oxygen masks and nasal catheters
supply a constant flow of oxygen into the gas
being breathed. The actual concentration
achieved is unknown, and is usually low and
dependent on the amount of air entrained on
inspiration which is highly dependent on the
patient’s inspiratory flow rate.
• The lungs are always exposed to the highest
Po2 of all body tissues, and so are the organs
most vulnerable to oxygen toxicity. Early
symptoms include tracheobronchial irri
tation, retrosternal tightness, cough,
reduced lung volumes and ultimately acute
lung injury. In humans, minor changes
occur after 24 h of breathing 100% oxygen,
but the dose required for lung damage is
unknown and seems to be related to expo-
sure time and Po2 rather than oxygen con-
centration. Bleomycin, a cytotoxic drug used
to treat some cancers, acts by generating
ROS to damage nuclear DNA, and the pul-
monary toxicity it sometimes causes may be
exacerbated by breathing oxygen.
• Hyperoxia in the perioperative period,
involving breathing ≥80% oxygen, has been
shown in some studies to reduce postopera-
tive nausea and vomiting and surgical site
infections. This benefit may arise from
improved oxygen delivery to the gut mucosa
and skin. There is currently no agreement
on which patient groups might benefit from
this intervention. In acute medical emer-
gencies evidence is now accumulating that
unrestricted use of oxygen may be harmful,
for example, during exacerbations of chronic
obstructive pulmonary disease, myocardial
infarction, ischaemic stroke and following
successful cardiopulmonary resuscitation.
356.e2 PART 2  Applied Physiology
The most likely mechanism for these obser-
vations is the fact that hyperoxia causes vaso-
constriction of systemic blood vessels, an
effect which is mediated by ROS and possi-
bly more pronounced in diseased arteries
already under oxidative stress.
• Hyperbaric oxygenation involves breathing
100% oxygen in a high-pressure chamber,
typically at 2 to 3 atm. At higher pressures,
oxygen convulsions can occur (the Paul Bert
effect) from disturbances in GABA and
nitric oxide in the brain. Hyperbaric oxygen
may have therapeutic effects by increasing
tissue Po2, vasoconstriction in oedematous
tissues, promoting angiogenesis or a direct
antibacterial effect of ROS. Conditions for
which it is used include bacterial infections
(particularly with anaerobic bacteria), decom-
pression sickness, carbon monoxide poi-
soning and sports injuries.