C L I N I C A L A N D E X P E R I M E N T A L

OPTOMETRY
REVIEW

Hyperbaric oxygen therapy and the possibility of ocular

complications or contraindications

Clin Exp Optom 2015; 98: 122125 DOI:10.1111/cxo.12203

Charles W McMonnies MSc
School of Optometry and Vision Science, University
of New South Wales, Kensington, Australia 2052
E-mail: c.mcmonnies@unsw.edu.au
Submitted: 3 May 2014
Revised: 20 June 2014
Accepted for publication: 21 June 2014
Hyperbaric oxygen therapy increases oxygen pressure and the concentration of reactive
oxygen species in blood and tissues. Increased oxygen pressure may be beneficial in some
diseases, such as in the treatment of diabetic leg ulcers and diabetic retinopathy; however,
due to their cytotoxic properties, an excess of reactive oxygen species in tissues and/or
deficiencies in antioxidant activity, may contribute to complications of hyperbaric oxygen
therapy, such as cataract.
This review examines the possibility that increased tissue concentrations of reactive
oxygen species may also exacerbate other ocular diseases. For example, reactive oxygen
species and deficiencies in antioxidant activities contribute to the pathogenetic processes in
keratoconus. Such impact may be exacerbated by exposure to additional reactive oxygen
species during hyperbaric oxygen therapy.
The senescent eye may be particularly prone to oxidative damage as exemplified by
conditions such as macular degeneration and cataract. Because of its high consumption of
oxygen, the retina is particularly susceptible to oxidative stress, which plays a major role in
retinopathy. For example, under normal conditions age-related macular degeneration
involves oxidative stress and death of the retinal pigment epithelial cells. Hyperbaric oxygen
therapy may exacerbate these processes.
In addition to cataract, age-related macular degeneration and keratoconus, there may be
other ocular diseases for which exposure to hyperbaric oxygen therapy-related oxidative
stress may be significantly adverse. In all such cases, careful pre-examination and evaluation
of the potential risk and benefit from this form of therapy appears to be warranted. Unless
it could interfere with the benefits of hyperbaric oxygen therapy, antioxidant dietary
supplementation may be indicated in conjunction with any hyperbaric oxygen therapy,
when there are co-existing diseases for which oxidative stress could have significantly adverse
side effects. Delivery of hyperbaric oxygen therapy may need to be modified or it may even
be contraindicated in these cases.

Key words: eye disease, hyperbaric oxygen therapy, oxidative stress

At sea level, the 20.93 per cent concentration
of oxygen (O2) in air is almost sufficient to
fully saturate haemoglobin.1 Accordingly,
breathing higher pressures of oxygen causes
little difference to the saturation level of
haemoglobin but does cause significant
amounts of unburnt oxygen (that which is
excess to tissue requirements or capacity to
use available oxygen) to pass into physical
solution in the blood plasma as the pressure
of breathed oxygen rises.1 Breathing oxygen
at high pressures during hyperbaric oxygen
therapy (HBOT) leads to an increase of dis-
solved oxygen in the tissues as well as in the
blood.2 Tissue oxygen concentration is not
only determined by arterial partial pressure
of oxygen but also by blood flow and cellular
oxygen consumption rate.3 Hyperbaric oxy-
gen therapy to raise tissue oxygen tension4 is
achieved by exposing the patient to a baro-
metric pressure higher than the sea level
ambient pressure of one standard atmos-
phere absolute (ATA), while the patient
breathes 100 per cent oxygen.2 Exposure to
oxygen at high pressures can increase the
transfer of oxygen into the tissues up to 20
times normal levels.5 Hyperbaric oxygen
therapy has been successfully used for the
treatment of a variety of conditions related
to hypoxia, including decompression sick-
ness, acute carbon monoxide intoxication,
air embolism, soft tissue infections, radiation
necrosis and impaired wound healing.2,5 For
example, diabetic patients can be compro-
mised as far as wound healing is concerned
and adjunctive hyperbaric oxygen therapy
can be valuable for treating selected cases of
infected4 and hypoxic diabetic foot ulcers.4,6
Primary indications for hyperbaric oxygen
therapy in ophthalmology include: occlusive
vasculopathies, cystoid macular oedema
of vascular origin, scleral necrosis, orbital
infections, non-healing corneal oedema and
anterior segment ischaemia.5 Secondary
indications include proliferative vitreore-
tinopathy due to Sickle cell disease, primary
open-angle glaucoma, visual field defect
after macular hole surgery, macular detach-
ment and optic neuropathies of vascular
origin.5 Hyperbaric oxygen therapy may be
beneficial by ameliorating the blood-retinal

Clinical and Experimental Optometry 98.2 March 2015 2014 The Author
122 Clinical and Experimental Optometry 2014 Optometry Australia

barrier breakdown in diabetic retinopathy;7
however, exposure to hyperbaric oxygen
therapy not only leads to an increase in the
amount of dissolved oxygen but also to an
increase in reactive oxygen species in the
blood with the associated risk of oxidative
damage.8 Cataractogenesis is known to be a
potential consequence of hyperbaric oxygen
therapy-associated oxidative damage.9 This
review examines the possibility that hyper-
baric oxygen therapy-related increased tis-
sue concentration of reactive oxygen species
and any associated tissue oxidative damage,
could contribute to the pathogenesis of
other ocular diseases, such as keratoconus
and age-related macular degeneration.
COMPLICATIONS ASSOCIATED WITH
HYPERBARIC OXYGEN THERAPY
On the Earths surface (one standard atmos-
phere), human beings can safely breathe
100 per cent oxygen continuously for
between 24 and 36 hours.1 After that the
symptoms of pulmonary oxygen toxicity
ensue.1 When 100 per cent oxygen is
breathed at two standard atmospheres, the
early symptoms of pulmonary oxygen toxic-
ity become manifest after about six hours.1
At pressures greater than two standard
atmosphere, pulmonary oxygen toxicity no
longer becomes the primary concern, as
oxygen at this level can cause seizures sec-
ondary to cerebral oxygen toxicity.1 For
example, neurotoxicity in the form of a
grand mal seizure is likely to occur if 100 per
cent oxygen is breathed at three standard
atmospheres for longer than three continu-
ous hours.1 The risk of oxygen toxicity is
reduced, if five-minute periods of breathing
air occur every 20 to 25 minutes.1 In a
Cochrane review of clinical trials, Kranke
and colleagues10 found that two of five
studies explicitly stated that there were no
complications or adverse events associated
with hyperbaric oxygen therapy, whereas the
other three studies did not report on the
possibility of adverse outcomes.
PATHOPHYSIOLOGY OF HYPERBARIC
OXYGEN THERAPY
Commonly used hyperbaric oxygen therapy
pressures range from 2.0 to 2.8 standard
atmospheres.2 Each session of hyperbaric
oxygen therapy takes from 45 minutes to five
hours, with most averaging roughly 90
minutes.5 In general, hyperbaric oxygen
therapy exposure is repeated daily, or at
2014 The Author
Clinical and Experimental Optometry 2014 Optometry Australia
most twice daily in urgent or emergency
situations.2 Arterial partial pressure of
oxygen is 90 to 110 mmHg at sea level3
but during hyperbaric oxygen therapy,
arterial oxygen pressure can increase to
2,000 mmHg5 with associated increased con-
centration of reactive oxygen species in the
blood.8 Under hyperbaric oxygen therapeu-
tic conditions, tissue oxygen pressure can
increase to about 400 mmHg.5 Application
of oxygen at this pressure can have many
biochemical, cellular and physiologically
useful effects by greatly increasing the trans-
fer of oxygen into the tissues.5 The level of
oxygen pressure in tissues may vary with
access to arterial blood or to other sources
of oxygen. Excess production of reactive
oxygen or nitrogen species, their produc-
tion in inappropriate relative amounts or
deficiencies in antioxidant defences may
result in pathological stress to cells and
tissues.11 For example, Benedetti and col-
leagues2 found that repeated exposures to
hyperbaric oxygen therapy led to a signifi-
cant accumulation of reactive oxygen
metabolites and malondialdehyde. They
concluded that in the absence of antioxidant
supplementation, prolonged hyperbaric
oxygen therapy leads to a condition of oxi-
dative stress that seems to affect in particular,
the response of the enzymatic antioxidant
defence system.2 It is clear that hyperbaric
oxygen therapy exposure causes oxidative
stress.12 After 15 sessions of hyperbaric
oxygen therapy, a level of medium to high
oxidative stress was reached.2 These findings
seemed to indicate that when hyperbaric
oxygen therapy is prolonged, the antioxi-
dant defence systems fail to maintain normal
levels of reactive oxygen metabolites,2 giving
rise to the potential for oxidative damage.
For example, hyperbaric oxygen therapy can
cause oxidative DNA base damage,13 which
can lead to mutations, pathology, cellular
aging and death.14 Oxidation of proteins
appears to play a causative role in many
chronic diseases of aging, including catarac-
togenesis, rheumatoid arthritis and various
neurodegenerative diseases, including Alz-
heimers disease.14
OCULAR COMPLICATIONS
Although they are rare, hyperbaric oxygen
therapy may cause complications in ocular
tissues.5 The prevalence of complications
may be underestimated, if they are confused
with age-related changes. Assessment of eyes
before, during and after treatment may be
Hyperbaric oxygen therapy McMonnies
necessary to detect unusual changes, includ-
ing increased rates of change which are the
result of hyperbaric oxygen therapy. Previ-
ously noted possible complications include
myopia and cataract.15
Myopia
Myopia can be a direct toxic effect of oxygen
on the crystalline lens and is the most
common side effect.16 Because hyperbaric
oxygen therapy can cause reversible myopia,
all keratorefractive surgery should be
postponed unless otherwise indicated for
patients undergoing hyperbaric oxygen
therapy.5
Cataract
Vitrectomy (unrelated to hyperbaric oxygen
therapy) significantly increases intraocular
oxygen exposure of the crystalline lens for
prolonged periods after surgery and leads to
accelerated nuclear cataract formation.17
Similarly, long-term exposures to intensive
hyperbaric oxygen therapy (which included
antioxidant supplementation) were found
to be associated with the development of
nuclear cataract in support of the theory of
associated oxidative damage to the lens pro-
teins.9 Of 15 patients with clear lenses before
treatment, seven developed nuclear cataract
during long-term intensive hyperbaric
oxygen therapy;9 however, another series of
patients treated with less intense hyperbaric
oxygen therapy did not develop cataracts.18
Nuclear cataract formation by oxidative
stress in lens proteins is more prevalent
among patients of advanced age.5 Apart
from age-associated risk, other forms of
increased susceptibility to develop cataract
may increase the chance of this complica-
tion occurring.17 Increased oxygen supply
for the crystalline lens during hyperbaric
oxygen therapy and associated oxygen stress
appears to explain cataract formation, even
though the crystalline lens is an avascular
tissue. Both keratoconus and age-related
macular degeneration also involve increased
oxidative stress and could be exacerbated by
hyperbaric oxygen therapy. They do not
appear to have been identified previously
as having the potential for this hyperbaric
oxygen therapy-related complication.
Keratoconus
A considerable body of evidence implicates
oxidative/nitrosative stress in the pathogen-
esis of numerous traumatic, metabolic,
inflammatory and iatrogenic diseases of the
Clinical and Experimental Optometry 98.2 March 2015
123
Hyperbaric oxygen therapy McMonnies
cornea.19 Keratoconus is a bilateral corneal
ectasia involving a localised area of thinning
and tissue weakening, with irregular astig-
matism and conical protrusion occurring
in response to the distending forces of
intraocular pressure.20 Hyperbaric oxygen
therapy increases oxygen concentration in
all body tissues, even those with reduced or
blocked blood flow.21 For example, healing
of ischaemic diabetic foot ulcers can be
improved with hyperbaric oxygen therapy,4,6
even though the microcirculation for the
ulcerated tissue is compromised.22 Although
the crystalline lens is avascular, its oxygen
concentration as a result of hyperbaric
oxygen therapy appears to be sufficiently
elevated to promote cataractogenesis in
some patients. Increased oxygen concentra-
tion in the aqueous humour could help raise
oxygen concentration in the crystalline lens
as well as contributing to increases in the
cornea. Under open eye conditions and
apart from the aqueous humour, oxygen can
be supplied to the cornea directly from the
atmosphere as well as from the limbic circu-
lation.23 Under normal conditions, oxygen
contributions from the limbal circulation
are minor24 and are possibly limited to sup-
plying the peripheral cornea. Under sea
level open-eye conditions, the contribution
from the aqueous humour is about one-third
of that from the atmosphere (oxygen satu-
rated tears) with oxygen tensions of about
55 mmHg and 155 mmHg, respectively.24
Thus, during hyperbaric oxygen therapy,
the cornea appears to not only have access
to greatly increased oxygen supply from
the atmosphere (its principle source) but
also from the aqueous and probably much
less significantly from the limbal circulation.
Thus, it appears likely that the avascular
cornea will develop increased oxygen
concentration during hyperbaric oxygen
therapy. This increase appears likely to be
greater for a cornea which has become
vascularised.
Reactive oxygen species can develop in
response to exposure to cigarette smoke,
ozone and ionising radiation8 and can be
generated by normal cellular functions, such
as mitochondrial metabolism and activation
of neutrophils.14 Sources of reactive oxygen
species associated with keratoconus corneas
include ultraviolet radiation, mechanical
trauma due to rubbing or contact lens wear
as well as in association with atopic and aller-
gic processes.25 For example, the cornea
absorbs approximately 80 per cent of inci-
dent ultraviolet-B radiation and there is the
Clinical and Experimental Optometry 98.2 March 2015
124
associated potential for generating signifi-
cant amounts of free radicals and reactive
oxygen species.26 Evidence that keratoconus
corneas accumulate large amounts of
cytotoxic by-products from both the lipid
peroxidation and nitric oxide pathways25
supports a potential role for ultraviolet irra-
diation. Oxidative stress occurs when the
presence of injurious molecules overcomes
the capacity for them to be counteracted.27 It
is unclear whether the oxidative damage
found in keratoconus corneas results from
innate defects of corneal fibroblasts or is
due to excessive environmental challenges
encountered by some patients who develop
keratoconus.28 In a study of cultured cells
from keratoconic corneas, the keratocytes
had an inherent hypersensitive response to
oxidative stressors, which involves mitochon-
drial dysfunction and mitochondrial DNA
damage.28 These findings suggest a role for
fibroblastic hypersensitivity to oxidative
stressors in the development and progres-
sion of keratoconus.28 In addition, the role of
inflammation during the development of
keratoconus may be underestimated27 due to
the association of inflammatory processes
with increased reactive oxygen species and
wound healing25 (and McMonnies, unpub-
lished data). Abnormal corneal wounding
mechanisms could result in the need for
continual repair processes to become exces-
sive in keratoconic corneas.27 A pathway for
corneal trauma is supported by evidence
of stromal apoptosis being stimulated by
mechanical trauma to the epithelium.25,29 In
addition to a repair mechanisms for abnor-
mal trauma, an expanding number of inves-
tigations indicate an association of free
radical-mediated damage with the develop-
ment of keratoconus.27 During corneal
wounding healing, nicotinamide adenine
dinucleotide phosphate-oxidase in inflam-
matory polymorphonuclear cells is the
prime source of reactive oxygen species.
They have a deleterious impact on wound
healing in keratoconus27 and contribute
to its pathogenesis,25 which may be exacer-
bated by exposure to increased reactive
oxygen during hyperbaric oxygen therapy.
Keratoconic corneas have reduced levels
of aldehyde dehydrogenase Class 3, an
important corneal enzyme responsible for
the elimination of reactive aldehydes of the
lipid peroxidation pathway.25 The kerato-
conic cornea also has reduced levels of
superoxide dismutase, which is another
important antioxidant enzyme responsible
for the elimination of reactive oxygen
Clinical and Experimental Optometry 2014 Optometry Australia
species, such as free radicals or super-
oxides.25 The decreased antioxidative
defences in keratoconic corneas increase
the risk of oxidative stress.26 Accumulation of
reactive oxygen species results in the depo-
sition of cytotoxic by-products which can
damage corneal tissue.25 After review of the
pathobiology of keratoconus, it was postu-
lated that underlying abnormalities in
stromal wound healing and reactive species-
linked activities, in addition to the interac-
tion between them, could be involved in the
development of the ectasia.27 Hyperbaric
oxygen therapy could be another environ-
mental source of increased concentrations
of reactive O2 species in keratoconic
corneas, which may be susceptible to adverse
responses to hyperbaric oxygen therapy
depending on any associated elevations
in the level of reactive oxygen species and
the degree to which antioxidant capacity is
reduced.
AGE-RELATED MACULAR
DEGENERATION
Retinal pigment cells are susceptible to oxi-
dative stress, as is the rest of the retina.30 The
retina is particularly susceptible to oxidative
stress because of its high consumption of
oxygen, its high proportion of polyunsatu-
rated fatty acids and its exposure to visible
light.31 Retinal toxicity from hyperoxia at
very high levels has been demonstrated
in experimental studies.5 Oxidative stress
plays a major role in retinopathy.32 Apart
from exposure to ultraviolet radiation (wave
lengths between 400 and 100 nm)33 toxic
oxygen radicals due to photo-oxidative stress
from exposure to short-wavelength blue
light (425 20 nm) can cause acute or
chronic retinal damage.34 For example, age-
related macular degeneration involves oxi-
dative stress and death of the retinal pigment
epithelium.35 The prevalence of age-related
macular degeneration in the United States
increases steeply with age, affecting 11.5 per
cent of Caucasians older than 80 years.35 A
high dietary intake of antioxidants, such as
beta carotene, vitamins C and E and zinc is
associated with a substantially reduced risk
of age-related macular degeneration in
elderly persons.36 Apart from increased age,
reduced dietary intake of antioxidants could
be associated with increased risk of oxidative
stress. In addition, for patients who have
or are at risk for developing age-related
macular degeneration, there may be adverse
consequences from increased exposure to
2014 The Author

reactive oxygen species associated with
hyperbaric oxygen therapy.
DISCUSSION
Oxidative stress, which refers to cellular
damage caused by reactive oxygen species,
has been implicated in many disease pro-
cesses, especially age-related disorders.31
The eye, with its intense exposure to light,
robust metabolic activity and in certain
regions, high oxygen tension, is particularly
susceptible to oxidative damage.19 Reactive
oxygen and nitrogen species have been
implicated in a growing number of medical
conditions affecting the human eye.19 For
example, a considerable body of clinical and
experimental data implicates oxidative/
nitrosative stress in the pathogenesis of
numerous traumatic, metabolic, inflamma-
tory and iatrogenic diseases of the cornea.19
In accord with the prevailing free radical
hypothesis of tissue aging, the senescent
eye may be particularly prone to oxidative
damage, as exemplified by conditions such
as macular degeneration and cataract.19
The same caveat appears to be relevant for
keratoconus. In reference to complications
such as myopia and cataractogenesis, pati-
ents scheduled for hyperbaric oxygen
therapy need careful pre-examination and
monitoring.15
In addition to age-related macular degen-
eration and keratoconus, there may be other
ocular diseases for which exposure to hyper-
baric oxygen therapy-related oxidative stress
may be significantly adverse. In all such
cases, careful pre-examination and evalua-
tion of the potential risk and benefit from
this form of therapy appears to be war-
ranted. Unless it could interfere with the
benefits of hyperbaric oxygen therapy, anti-
oxidant dietary supplementation may be
indicated in conjunction with any hyper-
baric oxygen therapy, when there are co-
existing diseases, for which oxidative stress
could have significantly adverse side effects.
Delivery of hyperbaric oxygen therapy may
need to be modified or it may even be con-
traindicated in these cases. Careful monitor-
ing of ocular health and any pre-existing
ocular disease appears to be required in rela-
tion to hyperbaric oxygen therapy.
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