You are on page 1of 11

WOUND HEALING

Hyperbaric Oxygen: Its Mechanisms


and Efficacy
Stephen R. Thom, M.D.,
Background: This article outlines therapeutic mechanisms of hyperbaric oxy-
Ph.D. gen therapy and reviews data on its efficacy for clinical problems seen by plastic
Philadelphia, Pa. and reconstructive surgeons.
Methods: The information in this review was obtained from the peer-reviewed
medical literature.
Results: Principal mechanisms of hyperbaric oxygen are based on intracellular
generation of reactive species of oxygen and nitrogen. Reactive species are
recognized to play a central role in cell signal transduction cascades, and the
discussion will focus on these pathways. Systematic reviews and randomized
clinical trials support clinical use of hyperbaric oxygen for refractory diabetic
wound-healing and radiation injuries; treatment of compromised flaps and
grafts and ischemia-reperfusion disorders is supported by animal studies and a
small number of clinical trials, but further studies are warranted.
Conclusions: Clinical and mechanistic data support use of hyperbaric oxygen
for a variety of disorders. Further work is needed to clarify clinical utility for some
disorders and to hone patient selection criteria to improve cost efficacy. (Plast.
Reconstr. Surg. 127 (Suppl.): 131S, 2011.)

H
yperbaric oxygen therapy is a treatment The initial effect of pressurizing the human
modality in which a person breathes 100 body is intuitively obvious— elevating hydrostatic
percent oxygen while exposed to increased pressure increases partial pressure of gases and
atmospheric pressure. Hyperbaric oxygen treat- causes a reduction in the volume of gas-filled
ment is carried out in either a mono-place (single spaces according to Boyle’s law. Gas volume re-
person) or multiplace (typically two to 14 pa- duction has direct relevance to treating patholog-
tients) chamber. Pressures applied while in the ical conditions in which gas bubbles are present in
chamber are usually 2 to 3 atmospheres absolute the body, such as arterial gas embolism and de-
(ATA), the sum of the atmospheric pressure (1 compression sickness. The majority of patients
ATA) plus additional hydrostatic pressure equiv- who undergo hyperbaric oxygen therapy are not
alent to 1 or 2 atmospheres (1 atmosphere ⫽ a treated for bubble-induced injuries; hence, ther-
pressure of 14.7 pounds per square inch or 101 apeutic mechanisms are related to an elevated
kPa). Treatments are usually about 1.5 to 2 hours oxygen partial pressure. A summary of these
long, depending on the indication, and may be mechanisms is shown in Figure 1.
performed one to three times daily. Mono-place It is well accepted that breathing greater than
chambers are usually compressed with pure oxy- 1 ATA of oxygen will increase production of re-
gen. Multiplace chambers are pressurized with air active oxygen species.2 This is critically important
and patients breathe pure oxygen through a tight- as it is the molecular basis for a number of ther-
fitting face mask, a hood, or an endotracheal tube. apeutic mechanisms. Reactive oxygen species and
During treatment, the arterial oxygen tension of- also reactive nitrogen species serve as signaling
ten exceeds 2000 mmHg, and levels of 200 to 400 molecules in transduction cascades, or pathways,
mmHg occur in tissues.1,2 for a variety of growth factors, cytokines, and
hormones.3–5 Reactive oxygen species is a collec-
From the Institute for Environmental Medicine and Depart-
ment of Emergency Medicine, University of Pennsylvania
Medical Center.
Received for publication April 12, 2010; accepted July 12, Disclosure: The author has no financial interest in
2010. any products, devices, or drugs mentioned in this
Copyright ©2010 by the American Society of Plastic Surgeons article.
DOI: 10.1097/PRS.0b013e3181fbe2bf

www.PRSJournal.com 131S
Plastic and Reconstructive Surgery • January Supplement 2011

Fig. 1. Overview on therapeutic mechanisms of hyperbaric oxygen related to elevations of tissue oxygen tensions. The initial effects
(denoted by boxes) that occur due to increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and
their consequences are outlined. GF, growth factor; VEGF, vascular endothelial growth factor; HIF, hypoxia-inducible factor; SPCs,
stem/progenitor cells; HO-1, heme oxygenase-1; HSPs, heat shock proteins.

tive term for oxygen-derived free radicals as well as such as myeloperoxidase, can catalyze reactions
oxygen -derived nonradical species, such as hy- between nitrite, a major oxidation product of ni-
drogen peroxide and hypochlorous acid. Reactive tric oxide, and hydrogen peroxide or hypochlor-
oxygen species are generated as part of normal ous acid to generate oxidants, such as nitryl chlo-
metabolism by mitochondria, endoplasmic retic- ride and nitrogen dioxide that are capable of
ulum, peroxisomes, various oxidase enzymes, and nitration and S-nitrosylation reactions.11–13 There
phospholipid metabolism. Reactive oxygen spe- are three forms of nitric oxide synthase. The effect
cies act in conjunction with several redox systems of hyperoxia on catalytic activity is reflected by
involving glutathione, thioredoxin, and pyridine values for the apparent Michaelis-Menten con-
nucleotides and play central roles in coordinating stant for oxygen, and it differs among the three
cell signaling and also antioxidant, protective nitric oxide synthase isoforms. In part, this is be-
pathways.3– 6 Antioxidant systems combat reactive cause enzyme activity is constrained by ferric-fer-
oxygen species. Because clinical hyperbaric oxy- rous conversion at the active site. As a general
gen protocols are relatively brief, studies show that statement, however, hyperoxia augments reactive
antioxidant defenses are adequate so that bio- nitrogen species production.14 –18
chemical stresses are reversible.7–10 This point is Discussion in this review will focus on those
central to the ensuing discussion— oxidative stress hyperbaric oxygen indications most pertinent to
is not synonymous with oxygen toxicity. plastic and reconstructive surgery. General dis-
Reactive nitrogen species include nitric oxide cussions of hyperbaric oxygen indications can
and agents generated by reactions between nitric be found in recent texts and for the general
oxide, or its oxidation products, and reactive ox- plastic surgeon, it is important to mention that
ygen species.2,3,11 Peroxide-dependent enzymes, consultation and advice on hyperbaric oxygen

132S
Volume 127, Number 1S • Hyperbaric Oxygen

may be sought through the Undersea and Hy- amputation.41 Since this publication, two addi-
perbaric Medical Society and more locally with tional groups have reported benefits to use of
board-certified physicians19 –21; that is, undersea hyperbaric oxygen; one was a double-blinded ran-
and hyperbaric medicine subspecialty certifica- domized trial.42,43 The results continue to demon-
tion is obtainable through the American Board strate that hyperbaric oxygen improves outcome.
of Medical Specialists. The double-blinded trial was a single-center study
that enrolled individuals with diabetes foot ulcers.
WOUND HEALING Individuals were randomized to receive either hy-
Hyperbaric oxygen is used to treat refractory perbaric oxygen (100 percent oxygen, 2.5 ATA for
diabetic lower extremity wounds and delayed 85 minutes 5 days per week for 8 weeks) or control
radiation injuries. Clearly, the pathophysiology (room air, 2.5 ATA for 85 minutes 5 days per week
of these disorders differs, but they share several for 8 weeks) and good wound care. The outcome
elements, including depletion of epithelial and was a healed wound by 12 months after the com-
stromal cells, chronic inflammation, fibrosis, an mencement of therapy. A total of 99 individuals
imbalance or abnormalities in extracellular ma- were evaluated, 38 received hyperbaric oxygen
trix components and remodeling processes, and and 37 received control therapy. By 1 year of fol-
impaired keratinocyte functions.22–27 Diabetic low-up, 52 percent of those receiving hyperbaric
wound healing is also impaired by decreased oxygen healed and 29 percent of those receiving
growth factor production, while in postradiation control (p ⫽ 0.03).
tissues, there appears to be an imbalance be- The benefit of hyperbaric oxygen for radi-
tween factors mediating fibrosis versus normal ation injury also has been shown in randomized
tissue healing.22,23,27 The reader is referred to trials and its utilization supported by indepen-
several recent reviews for general discussions on dent evidence-based reviews.44 – 46 It is important
pathophysiology.28 –30 to state that for both diabetic wounds and ra-
diation injuries, hyperbaric oxygen is used in
conjunction with standard wound care manage-
Clinical Efficacy of Hyperbaric Oxygen ment techniques. That was the format followed
Wound-healing hyperbaric oxygen protocols in clinical trials, and it is fully understandable
involve daily treatments of 1.5 to 2 hours for 20 to based on mechanisms of action. If used only in a
40 days. The effectiveness of hyperbaric oxygen as postoperative period, or in the absence of appro-
an adjuvant therapy for diabetic lower extremity priate surgical care, one should expect hyperbaric
ulcerations can be examined from the perspective oxygen to be ineffective treatment.47,48
of hastened healing and also reduced risk of major
amputations. Clearly related, these two vantage
points are not synonymous as current diabetic Mechanisms of Action
wound care often includes a ray or partial foot Animal trials have documented wound-heal-
amputation as an acceptable approach to obtain ing benefits of hyperbaric oxygen.49 –52 The basis
wound closure and prompt rehabilitation. for its efficacy continues to be investigated and
This is the era of meta-analysis and despite appears to be a combination of systemic events
drawbacks with these evaluations they are used as well as local alterations within the wound
regularly as a final judgment on efficacy of an margin (Fig. 1). Neovascularization occurs by
intervention. According to the most recent eval- two processes. Regional angiogenic stimuli in-
uation, employing hyperbaric oxygen as a com- fluence the efficiency of new blood vessel
ponent to refractory diabetic wound management growth by local endothelial cells (termed an-
decreases risk of a major amputation with an odds giogenesis), and they stimulate the recruitment
ratio of 0.236 (95 percent CI, 0.133 to 0.418). and differentiation of circulating stem/progen-
Adjunctive use of hyperbaric oxygen as a compo- itor cells to form vessels de novo in a process
nent to diabetic wound care improves healing with termed vasculogenesis.53–55 Hyperbaric oxygen
an odds ratio of 11.64 (95 percent CI, 3.457 to has effects on both these processes.
39.196).31 This analysis was based on clinical trials Bone marrow endothelial nitric oxide syn-
conducted through 2007.32– 40 The results con- thase activity is required for stem/progenitor
tinue to demonstrate that hyperbaric oxygen cells’ mobilization, and this is compromised by
markedly improves outcome. Another meta-anal- diabetes.56 – 60 Radiation, chemotherapy, and sev-
ysis concluded that only four patients needed to be eral other factors also diminish stem/progenitor
treated with hyperbaric oxygen to prevent one cells’ mobilization, although mechanisms for

133S
Plastic and Reconstructive Surgery • January Supplement 2011

these effects are unclear.61– 64 By stimulating nitric interleukin-8) in normal healthy humans.84,85 Vas-
oxide synthesis in bone marrow, hyperbaric oxy- cular endothelial growth factor and angiopoietin,
gen mobilizes stem/progenitor cells in normal as well as stromal-derived factor, influence stem/
humans, patients previously exposed to radiation, progenitor cells homing to wounds and stem/
and diabetics.65– 67 Importantly, in contrast to progenitor cells’ differentiation to endothelial
stem/progenitor cells’ mobilization stimulated by cells.86,87 Synthesis of vascular endothelial growth
infusion of growth factors; hyperbaric oxygen does factor has been shown to be increased in wounds
not concomitantly elevate the circulating leuko- by hyperbaric oxygen, and it is the most specific
cyte count, which may be thrombogenic.68 In an- growth factor for neovascularization.72 Hyperbaric
imal models, stem/progenitor cells mobilized by oxygen also stimulates synthesis of basic fibroblast
hyperbaric oxygen home to wounds and acceler- growth factor and transforming growth factor ␤1
ate healing.50,52,69 by human dermal fibroblasts,88 angiopoietin-2 by
Separate from its effect on stem/progenitor human umbilical vein endothelial cells,89 and
cells mobilization, hyperbaric oxygen–mediated basic fibroblast growth factor and hepatocyte
oxidative stress at sites of neovascularization will growth factor in ischemic limbs90; and it up-regu-
stimulate stem/progenitor cells’ growth factor lates platelet-derived growth factor receptor in
production.70,71 This is due at least in part to aug- wounds.91 Extracellular matrix formation is closely
mented synthesis and stabilization of hypoxia-in- linked to neovascularization, and it is another ox-
ducible factors (HIF).72–74 These transcription fac- ygen-dependent process.92 Enhanced collagen
tors are heterodimers of HIF-␣ and a constitutively synthesis and cross-linking by hyperbaric oxygen
expressed HIF-␤. It is well recognized that expres- have been described, but whether changes are
sion and activation of HIF-␣ subunits are tightly linked to the oxygen-dependence of fibroblast hy-
regulated and their degradation by the ubiquitin- droxylases, alteration in balance of wound growth
proteasome pathway typically occurs when cells factors, metalloproteinases, and/or inhibitors of
are replete with oxygen.75,76 Whether hypoxic or metalloproteases is as yet unclear.92,93
normoxic conditions prevail, however, free radi- Before leaving the subject of wound healing,
cals are required for HIF expression.76 –78 Hyper- mention should be made of conflicting data and
baric oxygen elevates HIF-1 and HIF-2 levels in where further work is needed. The influence hy-
vasculogenic stem/progenitor cells because of in- perbaric oxygen has on HIF isoform expression
creases in reactive oxygen species. One conse- appears to vary with different tissues and possibly
quence of reactive oxygen species–mediated stress with chronology (e.g., looking early or late after
is augmented production of the antioxidant thi- wounding or an ischemic insult). One recent
oredoxin and one of its regulatory enzymes, thi- model showing accelerated wound healing by hy-
oredoxin reductase.74 Thioredoxin can act as a perbaric oxygen reported lower HIF-1 levels at
transcription factor and in stem/progenitor cells wound margins, along with reduced inflammation
appears to be the proximal species responsible for and fewer apoptotic cells.51 In contrast, higher
promoting the expression and activity of HIFs.79 – 81 levels of HIF-1 have been linked to elevated vas-
HIF-1 and HIF-2 then stimulate transcription of cular endothelial growth factor in wounds in re-
many genes involved with neovascularization. A sponse to hyperoxia.72,94 With regard to diabetes,
physiological oxidative stress that triggers the there is a complex interplay present between re-
same pathway is lactate metabolism.71 active oxygen species and reactive nitrogen
Pluripotent mesenchymal stem cells were species.22,59,60 Impairments in endothelial nitric
shown in vitro to be stimulated by hyperbaric ox- oxide synthase function are related to hypergly-
ygen to synthesize placental growth factor. This cemia, insulin resistance, impaired enzyme syn-
too is a reactive oxygen species– dependent phe- thesis, disordered caveolin associations, and en-
nomenon and will significantly increase cell mi- hanced protein kinase C activity.59,60,95 Production
gratory and tube formation functions.82 Microvas- of O2ថ is augmented in diabetes, and this will re-
cular endothelial cells exposed to hyperbaric duce bioavailability of nitric oxide because the two
oxygen in ex vivo studies up-regulate a variety of radicals react rapidly to generate alternative reac-
protein damage– control pathways that lead to en- tive nitrogen species.96,97 Disordered balance be-
hanced oxidative stress resistance, cell prolifera- tween O2ថ and nitric oxide is reflected by elevated
tion, and tube formation.83 Hyperbaric oxygen levels of nitrotyrosine in plasma of type II
does not alter circulating levels of insulin, insulin- diabetics.98 The reason for outlining these issues
like growth factors, or proinflammatory cytokines with regard to hyperbaric oxygen is because there
(e.g., tumor necrosis factor–␣, interleukin-6, and is a need for more investigations. Data from dia-

134S
Volume 127, Number 1S • Hyperbaric Oxygen

betic animals and humans indicate that hyper- before and for 3 days following skin grafting led to
baric oxygen can overcome some aspects of en- a significant 29 percent improvement in graft
dothelial nitric oxide synthase inhibition, but it is survival.105 A problem with this trial, however, is
doubtful that all issues have been resolved.66,67,99,100 that the success in the control arm of the study was
To summarize, hyperbaric oxygen can stimu- markedly less that one would expect in current
late healing in refractory wounds and irradiated practice. As was emphasized in the review, support
tissues. Therapy for refractory diabetic wounds is for use of hyperbaric oxygen in flap/graft com-
likely to reduce the risk of lower extremity ampu- promise comes from a very large number of ani-
tation by two to three times, with an absolute rate mal studies.104,106 Comparative clinical trials sup-
of major amputation reductions of about 20 per- port its use but more work is needed.107,108
cent (e.g., 11 versus 32 percent) and a number
needed to treat of about four. With respect to REPERFUSION INJURIES AND
cost-effectiveness, a study from Canada indicated HYPERBARIC OXYGEN
that over a 12-year period, the use of hyperbaric Clinical studies have documented signifi-
oxygen should save about $9000 in overall costs to cant survival enhancement with hyperbaric ox-
the care of a patient with diabetes.101,102 It is likely ygen for extremity reimplantation and free tis-
that these estimates can be honed further with sue transfer, and following crush injury.109,110 As
improved patient selection criteria and the ben- is the case with flaps and grafts, however, the
efits in radiation injury are not well elucidated. amount of controlled clinical data is small and
The common mechanistic theme for both indica- insufficient to perform an evidence-based as-
tions is that oxidative stress responses improve sessment of hyperbaric oxygen efficacy. None-
neovascularization events. Cells within the wound theless, the breadth of clinical experience across
exhibit increased collagen synthesis, growth fac- a variety of disorders should spur closer assess-
tors production, improved cell migration, and ment of its use. Clinical trials have shown that
tube-formation functions. A separate free radical– hyperbaric oxygen can reduce coronary artery re-
based mechanism for augmentation of neovascu- stenosis after balloon angioplasty/stenting,111,112
larization by hyperbaric oxygen is through stem/ decrease muscle loss after thrombolytic treatment
progenitor cells. Hyperoxia stimulates bone for myocardial infarction,113–115 improve hepatic
marrow stem/progenitor cells mobilization and survival after transplantation and lead to more
also improves their functions once they home to rapid return of donor liver function,116,117 and re-
peripheral sites. duce the incidence of encephalopathy seen after
cardiopulmonary bypass and following carbon
COMPROMISED FLAPS AND GRAFTS monoxide poisoning.118,119 In contrast to protocols
Hyperbaric oxygen is used on occasion to treat for wound healing, hyperbaric oxygen treatments
compromised flaps and grafts, a practice sup- for reperfusion injuries are done for just a few days
ported by Guidelines from the Undersea and Hy- rather than weeks; they are performed at higher
perbaric Medical Society.21 This discussion was O2 partial pressures (2.5 to 3.0 ATA) and may
placed between wound-healing and reperfusion occur multiple times in the same day.
injuries because, depending on the situation, An early event associated with postischemic
graft/flap treatment may be more or less related tissue reperfusion is the adherence of circulat-
to supporting tissues through either of these two ing neutrophils to vascular endothelium by ␤2
main mechanistic categories. For example, in clin- integrins. When animals or humans are exposed
ical practice, a wound may not be ready for cov- to hyperbaric oxygen at 2.8 to 3.0 ATA for at
erage by a graft and neovascularization/granula- least 45 minutes, the ability of circulating neu-
tion tissue formation can be hastened according trophils to adhere to target tissues is temporarily
to mechanisms outlined above. This was the focus inhibited.120 –123 In animal models, hyperbaric oxy-
for a recent clinical series.103 Alternatively, a major gen–mediated inhibition of neutrophil ␤2 integrin
flap may suffer an ischemic insult in the process of adhesion has been shown to ameliorate reperfu-
its creation and thus mechanisms described in the sion injuries of the brain, heart, lung, liver, skeletal
next section are pertinent. muscle, and intestine, as well as smoke-induced
A comprehensive review of hyperbaric oxygen lung injury and encephalopathy due to carbon
use for flaps and grafts was recently published.104 monoxide poisoning.123–131 It also appears that
There is no need to recapitulate the information benefits of hyperbaric oxygen in decompression
except to say that there is one prospective, blinded sickness are related to the temporary inhibition of
clinical trial. Administration of hyperbaric oxygen neutrophil ␤2 integrins, in addition to the Boyle’s

135S
Plastic and Reconstructive Surgery • January Supplement 2011

law–mediated reduction in bubble volume as dis- used in a prophylactic manner to induce isch-
cussed in the introduction.132 emic tolerance, however, its mechanism appears
Exposure to hyperbaric oxygen inhibits neu- related to up-regulation of HIF-1 and at least
trophil ␤2 integrin function because hyperoxia in- one of its target genes, erythropoietin.152
creases synthesis of reactive species derived from In review, oxidative stress responses triggered
inducible nitric oxide synthase and myeloperoxi- by hyperbaric oxygen improve outcome from a
dase, leading to excessive S-nitrosylation of cy- wide variety of postischemic/inflammatory in-
toskeletal ␤ actin.133 This modification increases sults. Hyperbaric oxygen also improves ischemic
the concentration of short, non– cross-linked fil- tolerance when used in a prophylactic manner.
amentous-actin, which alters filamentous-actin Augmented synthesis of reactive species tempo-
distribution within the cell. Hyperbaric oxygen rarily inhibits adherence/sequestration of neutro-
does not reduce neutrophil viability and func- phils by inhibiting ␤2 integrin function, and in
tions, such as degranulation, phagocytosis, and many tissues, hyperbaric oxygen will induce anti-
oxidative burst in response to chemoattractants, oxidant enzymes and anti-inflammatory proteins.
remain intact.134,135 Inhibiting ␤2 integrins with More trials to assess clinical efficacy are needed.
monoclonal antibodies will also ameliorate isch-
emia-reperfusion injuries, but in contrast to TREATMENT RISKS
hyperbaric oxygen, antibody therapy causes pro- This review has emphasized the positive as-
found immunocompromise.136,137 Hyperbaric ox- pects of hyperbaric oxygen–induced reactive spe-
ygen does not inhibit neutrophil antibacterial cies, but there is clearly a potential for negative
functions because the G-protein coupled “inside- effects. The risks for oxygen toxicity depend on
out” pathway for activation (such as that triggered the concentration and intracellular localization of
by endotoxin) remains intact and actin S-nitrosy- reactive species. Because exposure to hyperoxia in
lation is reversed as a component of this activation clinical hyperbaric oxygen protocols is rather
process.133,138 Probably the most compelling evi- brief, studies show that antioxidant defenses are
dence that hyperbaric oxygen does not cause im- adequate so that biochemical stresses related to
munocompromise comes from studies in sepsis increases in reactive species are reversible.8,10,153,154
models, in which hyperbaric oxygen has a bene- Treatments often include so-called air breaks, dur-
ficial effect.139 –141 ing which a patient breathes just air for 5 minutes
A separate anti-inflammatory pathway for hy- once or twice through the course of a treatment.
perbaric oxygen involves impaired proinflamma- This intervention has been demonstrated to en-
tory cytokine production by monocyte-macroph- hance pulmonary oxygen tolerance.1 Central ner-
ages. This action has been shown in animal models vous system oxygen toxicity is manifested as a
and human beings.142–144 The effect on monocyte/ grand mal seizure. This occurs at an incidence of
macrophages may be the basis for reduced levels approximately one to four in 10,000 patient
of circulating proinflammatory cytokines under treatments.155–157 Pathological changes in associa-
stress conditions.84 The molecular mechanism is tion with isolated hyperbaric oxygen-mediated sei-
unknown but could be related to hyperbaric oxy- zures have not been found in studies with guinea
gen–mediated enhancement of heme oxygen- pigs, rabbits, and humans.158 Progressive myopia
ase-1 and heat shock proteins (e.g., heat shock has been reported in patients who undergo pro-
protein 70).7,10 Hence, once again, an oxidative longed daily therapy, but this typically reverses
stress response seems to occur. within 6 weeks after termination of treatments.159
Finally, hyperbaric oxygen has been shown Development of nuclear cataracts has been re-
in numerous models to augment ischemic tol- ported with excessive treatments that exceed a
erance of brain, spinal cord, liver, heart, and total of 150 to 200 hours, and the change does not
skeletal muscle by mechanisms involving induc- spontaneously reverse.160
tion of antioxidant enzymes and anti-inflamma-
tory proteins.15,145–149 A common theme among SUMMARY
some studies is alterations in HIF-1 production; This brief review has highlighted some of the
but, as was the case in wound-healing models, beneficial actions of hyperbaric oxygen and the
the timing of hyperbaric oxygen application ap- data that indicate oxidative stress brought about
pears to influence cellular responses. In several by hyperoxia can have therapeutic effects. Figure
models, exposure to hyperbaric oxygen amelio- 1 provides a summary of mechanisms, all of which
rates postischemic injuries by decreasing HIF-1 appear to stem from elevations in reactive species.
expression.150,151 When hyperbaric oxygen is Although there has been substantial advancement

136S
Volume 127, Number 1S • Hyperbaric Oxygen

of the field in recent years, more work is required 13. Sampson J, Ye Y, Rosen H, et al. Myeloperoxidase and
to establish the place of hyperbaric oxygen in 21st horseradish peroxidase catalyze tyrosine nitration in pro-
teins from nitrite and hydrogen peroxide. Arch Biochem
century medicine. Investigations of fundamental Biophys. 1998;356:207–213.
mechanisms are still needed, and better patient 14. Abu-Soud HM, Rousseau DL, Stuehr DJ. Nitric oxide bind-
selection criteria would improve cost efficacy. An ing to the heme of neuronal nitric-oxide synthase links its
extended discussion on other indications for hy- activity to changes in oxygen tension. J Biol Chem. 1996;271:
perbaric oxygen can be found in recent texts.19 –21 32515–32518.
15. Cabigas BP, Su J, Hutchins W, et al. Hyperoxic and hyper-
Stephen R. Thom, M.D., Ph.D. baric-induced cardioprotection: Role of nitric oxide syn-
Institute for Environmental Medicine thase 3. Cardiovasc Res. 2006;72:143–151.
University of Pennsylvania 16. Hink J, Thom SR, Simonsen U, et al. Vascular reactivity and
1 John Morgan Building endothelial NOS activity in rat thoracic aorta during and
3620 Hamilton Walk after hyperbaric oxygen exposure. Am J Physiol Heart Circ
Philadelphia, Pa. 19104-6068 Physiol. 2006;291:H1988–H1998.
sthom@mail.med.upenn.edu 17. Thom SR, Bhopale V, Fisher D, et al. Stimulation of nitric
oxide synthase in cerebral cortex due to elevated partial
pressures of oxygen: An oxidative stress response. J Neuro-
biol. 2002;51:85–100.
ACKNOWLEDGMENTS
18. Thom SR, Fisher D, Zhang J, et al. Stimulation of perivas-
This work was supported by grants from the Office cular nitric oxide synthesis by oxygen. Am J Physiol Heart Circ
of Naval Research and from the National Institutes of Physiol. 2003;284:H1230–H1239.
Health (DK080376). 19. Mathieu D. Handbook on Hyperbaric Medicine. Dordrecht, The
Netherlands: Springer; 2006.
20. Neuman TS, Thom SR. Physiology and Medicine of Hyperbaric
REFERENCES Oxygen Therapy. Philadelphia: Saunders-Elsevier; 2008.
1. Hendricks P, Hall D, Hunter W, et al. Extension of pulmo- 21. Gesell L. Hyperbaric Oxygen Therapy Indications. 12th ed.
nary O2 tolerance in man at 2 ATA by intermittent O2 Durham, N.C.: Undersea and Hyperbaric Medical Society;
exposure. J Appl Physiol. 1977;42:593–599. 2008.
2. Thom SR. Hyperbaric oxygen therapy. J Intensive Care Med. 22. Brem H, Tomic-Canic M. Cellular and molecular basis of
1989;4:58–74. wound healing in diabetes. J Clin Invest. 2007;117:1219–
3. Kemp M, Go YM, Jones DP. Nonequilibrium thermody- 1222.
namics of thiol/disulfide redox systems: A perspective on 23. Denham JW, Hauer-Jensen M. The radiotherapeutic injury:
redox systems in biology. Free Radic Biol Med. 2008;44:921– A complex “wound.” Radiother Oncol. 2002;63:129–145.
937. 24. Falanga V. Wound healing and its impairment in the dia-
4. Circu ML, Aw TY. Glutathione and apoptosis. Free Radic Res. betic foot. Lancet 2005;366:1736–1743.
2008;42:689–706. 25. Martin M, Lefaix J, Delanian S. TGF-beta1 and radiation
5. Valko M, Leibfritz D, Moncol J, et al. Free radicals and fibrosis: A master switch and a specific therapeutic target?
antioxidants in normal physiological functions and human Int J Radiat Oncol Biol Phys. 2000;47:277–290.
disease. Int J Biochem Cell Biol. 2007;39:44–84. 26. Stojadinovic O, Brem H, Vouthounis C, et al. Molecular
6. Zhang Q, Piston DW, Goodman RH. Regulation of core- pathogenesis of chronic wounds: The role of beta-catenin
pressor function by nuclear NADH. Science 2002;295:1895– and c-myc in the inhibition of epithelialization and wound
1897. healing. Am J Pathol. 2005;167:59–69.
7. Dennog C, Radermacher P, Barnett YA, et al. Antioxidant 27. Ueno H, Ohya T, Ito H, et al. Chitosan application to X-ray
status in humans after exposure to hyperbaric oxygen. Mutat irradiated wound in dogs. J Plast Reconstr Asthet Surg. 2007;
Res. 1999;428:83–89. 60:304–310.
8. Dennog C, Hartmann A, Frey G, et al. Detection of DNA 28. Denham J, Hauer-Jensen M. The radiotherapeutic injury-a
damage after hyperbaric oxygen (HBO) therapy. Mutagen- complex “wound.” Radiother Oncol. 2002;63:129–145.
esis 1996;11:605–609. 29. Falanga V. Wound healing and its impairment in the dia-
9. Narkowicz CK, Vial JH, McCartney PW. The effect of betic foot. Lancet 2005;366:1736–1743.
human dendritic cells on the lectin-induced responsive- 30. Peppa M, Stavroulakis P, Raptis SA. Advanced glucoxida-
ness of CD4⫹T cells to IL-2 and IL-4. Adv Exp Med Biol. tion products and impaired diabetic wound healing. Wound
1993;329:75–80. Repair Regen. 2009;17:461–472.
10. Rothfuss A, Radermacher P, Speit G. Involvement of heme 31. Goldman RJ. Hyperbaric oxygen therapy for wound healing
oxygenase-1 (HO-1) in the adaptive protection of human and limb salvage: A systematic review. PMR. 2009;1:471–
lymphocytes after hyperbaric oxygen (HBO) treatment. 489.
Carcinogenesis 2001;22:1979–1985. 32. Abidia A, Laden G, Kuhan G, et al. The role of hyperbaric
11. Brennan ML, Wu W, Fu X, et al. A tale of two contro- oxygen therapy in ischaemic diabetic lower extremity ul-
versies: Defining both the role of peroxidases in nitro- cers: A double-blind randomised-controlled trial. Eur J Vasc
tyrosine formation in vivo using eosinophil peroxidase Endovasc Surg. 2003;25:513–518.
and myeloperoxidase-deficient mice, and the nature of 33. Kessler L, Bilbault P, Ortega F, et al. Hyperbaric oxygen-
peroxidase-generated reactive nitrogen species. J Biol ation accelerates the healing rate of nonischemic chronic
Chem. 2002;277:17415–17427. diabetic foot ulcers: A prospective randomized study. Dia-
12. Lakshmi V, Nauseef W, Zenser T. Myeloperoxidase poten- betes Care 2003;26:2378–2382.
tiates nitric oxide-mediated nitrosation. J Biol Chem. 2005; 34. Faglia E, Favales F, Aldeghi A, et al. Adjunctive systemic
280:1746–1753. hyperbaric oxygen therapy in treatment of severe preva-

137S
Plastic and Reconstructive Surgery • January Supplement 2011

lently ischemic diabetic foot ulcer. Diabetes Care 1996;19: matopoiesis by recruitment of vasculogenic and hemato-
1338–1343. poietic stem cells. J Exp Med. 2001;193:1005–1014.
35. Faglia E, Favales F, Aldeghi A, et al. Change in major am- 55. Tepper OM, Capla JM, Galiano RD, et al. Adult vasculo-
putation rate in a center dedicated to diabetic foot care genesis occurs through in situ recruitment, proliferation,
during the 1980s: Prognosis determinants for major ampu- and tubulization of circulating bone marrow-derived cells.
tation. J Diabetes Complications 1998;12:96. Blood 2005;105:1068–1077.
36. Doctor N, Pandya S, Supe A. Hyperbaric oxygen therapy in 56. Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role
diabetic foot. J Postgrad Med. 1991;38:112–114. of endothelial nitric oxide synthase for mobilization of stem
37. Kalani M, Jorneskog G, Naderi N, et al. Hyperbaric oxygen and progenitor cells. Nat Med. 2003;9:1370–1376.
therapy in treatment of diabetic foot ulcers. J Diabetes Com- 57. Bivalacqua TJ, Champion HC, Usta MF, et al. RhoA/Rho-
plications 2002;16:153–158. kinase suppresses endothelial nitric oxide synthase in the
38. Baroni G, Porro T, Faglia E, et al. Hyperbaric oxygen in penis: A mechanism for diabetes-associated erectile dys-
diabetic gangrene treatment. Diabetes Care 1987;10:81–86. function. Proc Natl Acad Sci U S A. 2004;101:9121–9126.
39. Oriani G, Meazza D, Favales F, et al. Hyperbaric oxygen 58. Bucci M, Roviezzo F, Brancaleone V, et al. Diabetic mouse
therapy in diabetic gangrene. J Hyperb Med. 1990;5:171–175. angiopathy is linked to progressive sympathetic receptor
40. Fife CE, Buyukcakir C, Otto G, et al. Factors influencing the deletion coupled to an enhanced caveolin-1 expression.
outcome of lower-extremity diabetic ulcers treated with hy- Arterioscler Thromb Vasc Biol. 2004;24:721–726.
perbaric oxygen therapy. Wound Repair Regen. 2007;15:322– 59. Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia
331. inhibits endothelial nitric oxide synthase activity by post-
41. Kranke P, Bennett M, Roeckl-Wiedmann I, et al. Hyperbaric translational modification at the Akt site. J Clin Invest. 2001;
oxygen therapy for chronic wounds. Cochrane Database Syst 108:1341–1348.
Rev. 2004;2:CD004123. 60. Du XL, Edelstein D, Obici S, et al. Insulin resistance reduces
42. Duzgun AP, Satir AZ, Ozozan O, et al. Effect of hyperbaric arterial prostacyclin synthase and eNOS activities by in-
oxygen therapy on healing of diabetic foot ulcers. J Foot creasing endothelial fatty acid oxidation. J Clin Invest. 2006;
Ankle Surg. 2008;47:515–519. 116:1071–1080.
43. Londahl M, Katzman P, Nilsson A, et al. Hyperbaric oxygen 61. Vasa M, Fichtlscherer S, Aicher A, et al. Number and mi-
therapy facilitates healing of chronic foot ulcers in patients gratory activity of circulating endothelial progenitor cells
inversely correlate with risk factors for coronary artery dis-
with diabetes. Diabetes Care. 2010;33:998–1003.
ease. Circ Res. 2001;89:E1–E7.
44. Bennett M, Feldmeier J, Hampson N, et al. Hyperbaric
62. Seggewiss R, Buss EC, Herrmann D, et al. Kinetics of pe-
oxygen therapy for late radiation tissue injury. 2005;3:
ripheral blood stem cell mobilization following G-CSF-sup-
CD005005.
ported chemotherapy. Stem Cells 2003;21:568–574.
45. Clarke R, Tenorio C, Hussey J, et al. Hyperbaric oxygen
63. Platzbecker U, Bornhauser M, Zimmer K, et al. Second
treatment of chronic radiation proctitis: A randomized and
donation of granulocyte-colony-stimulating factor-mobi-
controlled doouble blind crossover trial with long-term fol-
lized peripheral blood progenitor cells: Risk factors asso-
low-up. Int J Radiat Oncol Biol Phys. 2008;72:134–143.
ciated with a low yield of CD34⫹ cells. Transfusion 2005;
46. Marx RE, Johnson RP, Kline SN. Prevention of osteoradio-
45:11–15.
necrosis: A randomized prospective clinical trial of hyper-
64. Ikeda KTKMH. Factors for PBPC collection efficiency and
baric oxygen versus penicillin. J Am Dent Assoc. 1985;111: collection predictors. Transfus Apher Sci. 2004;31:245–259.
49–54. 65. Thom SR, Bhopale VM, Velazquez OC, et al. Stem cell
47. Annane D, Depondt J, Aubert P, et al. Hyperbaric oxygen mobilization by hyperbaric oxygen. Am J Physiol Heart Circ
therapy for radionecrosis of the jaw: A randomized, place- Physiol. 2006;290:H1378–H1386.
bo-controlled, double-blind trial from the ORN96 study 66. Thom SR, Milovanova TN, Yang M, et al. Vasculogenic stem
group. J Clin Oncol. 2004;22:4893–4900. cell mobilization and wound recruitment in diabetic pa-
48. Maier A, Gaggl A, Klemen H, et al. Review of severe osteo- tients: Increased cell number and intracellular regulatory
radionecrosis treated by surgery alone or surgery with post- protein content associated with hyperbaric oxygen therapy.
operative hyperbaric oxygenation. Br J Oral Maxillofac Surg. Wound Repair Regen. (in press).
2000;38:173–176. 67. Yang B, Milovanova T, Hardy K, et al. Stem cell mobilization
49. Marx RE, Ehler WJ, Tayapongsak P, et al. Relationship of in diabetics: Responses to hyperbaric oxygen. Undersea Hy-
oxygen dose to angiogenesis induction in irradiated tissue. perb Med. 2007;34(Suppl.):235–236.
Am J Surg. 1990;160:519–524. 68. Powell TM, Paul JD, Hill JM, et al. Granulocyte colony-
50. Gallagher KA, Liu ZJ, Xiao M, et al. Diabetic impairments stimulating factor mobilizes functional endothelial progen-
in NO-mediated endothelial progenitor cell mobilization itor cells in patients with coronary artery disease. Arterioscler
and homing are reversed by hyperoxia and SDF-1 alpha. Thromb Vasc Biol. 2005;25:296–301.
J Clin Invest. 2007;117:1249–1259. 69. Gu GJ, Li YP, Peng ZY, et al. Mechanism of ischemic tol-
51. Zhang Q, Chang Q, Cox RA, et al. Hyperbaric oxygen erance induced by hyperbaric oxygen preconditioning in-
attenuates apoptosis and decreases inflammation in an isch- volves upregulation of hypoxia-inducible factor-1alpha and
emic wound model. J Invest Dermatol. 2008;128:2102–2112. erythropoietin in rats. J Appl Physiol. 2008;104:1185–1191.
52. Goldstein LJ, Gallagher KA, Bauer SM, et al. Endothelial 70. Hunt T, Aslam R, Beckert S, et al. Aerobically derived lactate
progenitor cell release into circulation is triggered by hy- stimulates revascularization and tissue repair via redox
peroxia-induced increases in bone marrow nitric oxide. mechanisms. Antioxid Redox Signal. 2007;9:1115–1124.
Stem Cells 2006;24:2309–2318. 71. Milovanova T, Bhopale VM, Sorokina EM, et al. Lactate
53. Carmeliet P. Mechanisms of angiogenesis and arteriogen- stimulates vasculogenic stem cells via the thioredoxin
esis. Nat Med. 2000;6:389–395. system and engages an autocrine activation loop involv-
54. Hattori K, Dias S, Heissig B, et al. Vascular endothelial ing hypoxia inducible factor-1. Mol Cell Biol. 2008;28:
growth factor and angiopoietin-1 stimulate postnatal he- 6248–6261.

138S
Volume 127, Number 1S • Hyperbaric Oxygen

72. Sheikh AY, Gibson JJ, Rollins MD, et al. Effect of hyperoxia 89. Lin S, Shyu KG, Lee CC, et al. Hyperbaric oxygen selectively
on vascular endothelial growth factor levels in a wound induces angiopoietin-2 in human umbilical vein endothe-
model. Arch Surg. 2000;135:1293–1297. lial cells. Biochem Biophys Res Commun. 2002;296:710–715.
73. Milovanova TN, Bhopale VM, Sorokina EM, et al. Lactate 90. Asano T, Kaneko E, Shinozaki S, et al. Hyperbaric oxygen
stimulates vasculogenic stem cells via the thioredoxin induces basic fibroblast growth factor and hepatocyte
system and engages an autocrine activation loop involv- growth factor expression and enhances blood perfusion
ing hypoxia-inducible factor 1. Mol Cell Biol. 2008;28: and muscle regeneration in mouse ischemic hind limbs.
6248–6261. Circ J. 2007;71:405–411.
74. Milovanova T, Bhopale VM, Sorokina EM, et al. Hyperbaric 91. Bonomo SR, Davidson JD, Yu Y, et al. Hyperbaric oxygen as
oxygen stimulates vasculogenic stem cell growth and dif- a signal transducer: Upregulation of platelet derived growth
ferentiation in vivo. J Appl Physiol. 2009;106:711–728. factor-beta receptor in the presence of HBO2 and PDGF.
75. Salceda S, Caro J. Hypoxia-inducible factor 1 alpha protein Undersea Hyperb Med. 1998;25:211–216.
is rapidly degraded by the ubiquitin-proteasome system un- 92. Hopf HW, Gibson JJ, Angeles AP, et al. Hyperoxia and
der normoxic conditions: Its stabilization by hypoxia de- angiogenesis. Wound Repair Regen. 2005;13:558–564.
pends upon redox-induced changes. J Biol Chem. 1997;272: 93. Dinar S, Agir H, Sen C, et al. Effects of hyperbaric oxygen
22642–22647. therapy on fibrovascular ingrowth in porous polyethylene
76. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. blocks implanted under burn scar tissue: An experimental
Curr Opin Cell Biol. 2001;13:167–171. study. Burns 2008;34:467–473.
77. Dulak J, Jozkowicz A. Regulation of vascular endothelial 94. Hunt TK, Aslam RS, Beckert S, et al. Aerobically derived
growth factor synthesis by nitric oxide: Facts and contro- lactate stimulates revascularization and tissue repair via re-
versies. Antioxid Redox Signal. 2003;5:123–132. dox mechanisms. Antioxid Redox Signal. 2007;9:1115–1124.
78. Schroedl C, McClintock DS, Budinger GR, et al. Hypoxic 95. Peppa M, Stavroulakis P, Raptis SA. Advanced glycoxidation
but not anoxic stabilization of HIF-1alpha requires mito- products and impaired diabetic wound healing. Wound Re-
chondrial reactive oxygen species. Am J Physiol Lung Cell Mol pair Regen. 2009;17:461–472.
Physiol. 2002;283:L922–L931. 96. Koppenol WH, Moreno JJ, Pryor WA, et al. Peroxynitrite, a
79. Ema M, Hirota K, Mimura J, et al. Molecular mechanisms cloaked oxidant formed by nitric oxide and superoxide.
of transcription activation by HLF and HIF1alpha in re- Chem Res Toxicol. 1992;5:834–842.
sponse to hypoxia: Their stabilization and redox signal-
97. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and
induced interaction with CBP/p300. EMBO J. 1999;18:
peroxynitrite: The good, the bad, and ugly. Am J Physiol.
1905–1914.
1996;271:C1424–C1437.
80. Kaga S, Zhan L, Matusmoto M, et al. Resveratrol enhances
98. Ceriello A, Mercuri F, Quagliaro L, et al. Detection of ni-
neovascularization in the infarcted rat myocardium
trotyrosine in the diabetic plasma: Evidence of oxidative
through the induction of thioredoxin-1, heme oxygenase-1
stress. Diabetologia 2001;44:834–838.
and vascular endothelial growth factor. J Mol Cell Cardiol.
99. Gallagher KA, Goldstein LJ, Buerk DG, et al. Diabetic impair-
2005;38:813–822.
ments in NO-mediated endothelial progenitor-cell mobiliza-
81. Welsh S, Bellamy W, Briehl M, et al. The redox protein
tion and homing are reversed by hyperoxia and SDF-1a. J Clin
thioredoxin-1 (Trx-1) increases hypoxia-inducible factor-
Invest. 2007;117:1249–1259.
1alpha protein expression: Trx-1 overexpression results in
increased vascular endothelial growth factor production 100. Thom S, Milovanova T. Hyperbaric oxygen therapy in-
and enhanced tumor angiogenesis. Cancer Res. 2002;62: creases stem cell number and HIF-1 content in diabetics
5089–5095. (abstract). Undersea Hyperb Med. 2008;35:280.
82. Shyu KG, Hung HF, Wang BW, et al. Hyperbaric oxygen 101. Hailey D, Jacobs P, Perry D, et al. Technology report: Ad-
induces placental growth factor expression in bone marrow- junctive hyperbaric oxygen therapy for diabetic foot ulcer:
derived mesenchymal stem cells. Life Sci. 2008;83:65–73. An economic analysis. Canadian Agency for Drugs and Tech-
83. Godman CA, Chheda KP, Hightower LE, et al. Hyperbaric nologies in Health Report no. 75:1–32, 2007.
oxygen induces a cytoprotective and angiogenic response in 102. Chuck AW, Haily D, Jacobs P, et al. Cost-effectiveness and
human microvascular endothelial cells. Cell Stress Chaperones budget impact of adjunctive hyperbaric oxygen therapy for
2010;15:431–442. diabetic foot ulcers. Int J Technol Assess Health Care 2008;24:
84. Fildissis G, Venetsanou K, Myrianthefs P, et al. Whole blood 176–183.
pro-inflammatory cytokines and adhesion molecules post- 103. Snyder SM, Beshlian KM, Hampson NB. Hyperbaric oxygen
lipopolysaccharides exposure in hyperbaric conditions. Eur and reduction mammaplasty in the previously irradiated
Cytokine Netw. 2004;15:217–221. breast. Plast Reconstr Surg. 2010;125:255e–257e.
85. Chen SJ, Yu CT, Cheng YL, et al. Effects of hyperbaric 104. Friedman HIF, Fitzmaurice M, Lefaivre JF, et al. An evi-
oxygen therapy on circulating interleukin-8, nitric oxide, dence-based appraisal of the use of hyperbaric oxygen on
and insulin-like growth factors in patients with type 2 dia- flaps and grafts. Plast Reconstr Surg 2006;117(Suppl.):175S–
betes mellitus. Clin Biochem. 2007;40:30–36. 190S.
86. Hildbrand P, Cirulli V, Prinsen RC, et al. The role of an- 105. Perrins DJD, Cantab MB. Influence of hyperbaric oxygen
giopoietins in the development of endothelial cells from on the survival of split skin grafts. Lancet 1967;1:868–871.
cord blood CD34⫹ progenitors. Blood 2004;104:2010–2019. 106. Kindwall E, Gottlieb L, Larson D. Hyperbaric oxygen ther-
87. Peichev M, Naiyer AJ, Pereira D, et al. Expression of apy in plastic surgery: A review article. Plast Reconstr Surg.
VEGFR-2 and AC133 by circulating human CD34(⫹) cells 1991;88:898–908.
identifies a population of functional endothelial precur- 107. Roje Z, Roje Z, Eterovic D, et al. Influence of adjuvant
sors. Blood 2000;95:952–958. hyperbaric oxygen therapy on short-term complications
88. Kang TS, Gorti GK, Quan SY, et al. Effect of hyperbaric during surgical reconstruction of upper and lower extrem-
oxygen on the growth factor profile of fibroblasts. Arch ity war injuries: Retrospective cohort study. Croat Med J.
Facial Plast Surg. 2004;6:31–35. 2008;49:224–232.

139S
Plastic and Reconstructive Surgery • January Supplement 2011

108. Bowersox J, Strauss M, Hart G. Clinical experience with 126. Tahepold P, Valen G, Starkopf J, et al. Pretreating rats with
hyperbaric oxygen therapy in the salvage of ischemic skin hyperoxia attenuates inschemia-reperfusion injury of the
flaps and grafts. J Hyperb Med. 1986;1:141–149. heart. Life Sci. 2001;68:1629–1640.
109. Bouachour G, Cronier P, Gouello JP, et al. Hyperbaric 127. Thom S, Mendiguren I, Fisher D. Smoke inhalation-in-
oxygen therapy in the management of crush injuries: A duced alveolar lung injury is inhibited by hyperbaric oxy-
randomized double-blind placebo-controlled clinical trial. gen. Undersea Hyperb Med. 2002;28:175–180.
J Trauma 1996;41:333–339. 128. Ueno S, Tanabe G, Kihara K, et al. Early post-operative
110. Waterhouse M, Zamboni W, Brown R, et al. The use of HBO hyperbaric oxygen therapy modifies neutrophile activation.
in compromised free tissue transfer and replantation: A Hepatogastroenterology 1999;46:1798–1799.
clinical review. Undersea Hyperb Med. 20(Suppl):64, 1993. 129. Zamboni WA, Roth AC, Russell RC, Graham B, Suchy H,
111. Sharifi M, Fares W, Abdel-Karim I, et al. Usefulness of hy- Kucan JO. Morphologic analysis of the microcirculation
perbaric oxygen therapy to inhibit restenosis after percu- during reperfusion of ischemic skeletal muscle and the
taneous coronary intervention for acute myocardial infarc- effect of hyperbaric oxygen. Plast Reconstr Surg. 1993;91:
tion or unstable angina pectoris. Am J Cardiol. 2004;93: 1110–1123.
1533–1535. 130. Yang ZJ, Bosco G, Montante A, et al. Hyperbaric O2 reduces
112. Sharifi M, Fares W, Abdel-Karim I, et al. Inhibition of re- intestinal ischemia-reperfusion-induced TNF-alpha pro-
stenosis by hyperbaric oxygen: A novel indication for an old duction and lung neutrophil sequestration. Eur J Appl
modality. Cardiovasc Radiat Med. 2002;3:124–126. Physiol. 2001;85:96–103.
113. Dekleva M, Neskovic A, Vlahovic A, et al. Adjunctive effect 131. Thom SR. Functional inhibition of leukocyte B2 integrins
of hyperbaric oxygen treatment after thrombolysis on left by hyperbaric oxygen in carbon monoxide-mediated brain
ventricular function in patients with acute myocardial in- injury in rats. Toxicol Appl Pharmacol. 1993;123:248–256.
farction. Am Heart J. 2004;148:E14. 132. Martin JD, Thom SR. Vascular leukocyte sequestration in
114. Shandling AH, Ellestad MH, Hart GB, et al. Hyperbaric decompression sickness and prophylactic hyperbaric oxy-
oxygen and thrombolysis in myocardial infarction: The gen therapy in rats. Aviat Space Environ Med. 2002;73:565–
HOT MI pilot study. Am Heart J. 1997;134:544–550. 569.
115. Stavitsky Y, Shandling AH, Ellestad MH, et al. Hyperbaric 133. Thom SR, Bhopale VM, Mancini JD, et al. Actin S-nitrosy-
oxygen and thrombolysis in myocardial infarction: The lation inhibits neutrophil beta-2 integrin function. J Biol
Chem. 2008;283:10822–10834.
“HOT MI” randomized multicenter study. Cardiology 1998;
134. Juttner B, Scheinichen D, Bartsch S, et al. Lack of toxic side
90:131–136.
effects in neutrophils following hyperbaric oxygen. Undersea
116. Mazariegos G, O’Toole K, Mieles L, et al. Hyperbaric oxy-
Hyperb Med. 2003;30:305–311.
gen therapy for hepatic artery thrombosis after liver trans-
135. Thom SR, Mendiguren I, Hardy K, et al. Inhibition of
plantation in children. Liver Transpl Surg. 1999;5:429–436.
human neutrophil beta2-integrin-dependent adherence by
117. Suehiro T, Shimura T, Okamura K, et al. The effect of
hyperbaric O2. Am J Physiol. 1997;272:C770–C777.
hyperbaric oxygen treatment on postoperative morbidity of
136. Mileski WJ, Sikes P, Atiles L, et al. Inhibition of leukocyte
left lobe donor in living donor adult liver transplantation.
adherence and susceptibility to infection. J Surg Res. 1993;
Hepatogastroenterology 2008;55:1014–1019.
54:349–354.
118. Alex J, Laden G, Cale A, et al. Pretreatment with hyperbaric
137. Mileski WJ, Winn RK, Vedder NB, et al. Inhibition of CD18-
oxygen and its effect on neuropsychometric dysfunction
dependent neutrophil adherence reduces organ injury af-
and systemic inflammatory response after cardiopulmonary ter hemorrhagic shock in primates. Surgery 1990;108:206–
bypass: A prospective randomized double-blind trial. J Tho- 212.
rac Cardiovasc Surg. 2005;130:1623–1630. 138. Thom SR, Bhopale VM, Milovanova TN. Neutrophil beta-2
119. Weaver LK, Hopkins RO, Chan KJ, et al. Hyperbaric oxygen integrin inhibition by hyperoxia is due to actin S-nitrosy-
for acute carbon monoxide poisoning. N Engl J Med. 2002; lation and delocalized thioredoxin reductase. Undersea Hy-
347:1057–1067. perb Med. 2010;37:300 –301.
120. Kalns J, Lane J, Delgado A, et al. Hyperbaric oxygen expo- 139. Buras J, Holt D, Orlow D, et al. Hyperbaric oxygen protects
sure temporarily reduces Mac-1 mediated functions of hu- from sepsis mortality via an interleukin-10-dependent
man neutrophils. Immunol Lett. 2002;83:125–131. mechanism. Crit Care Med. 2006;34:2624–2629.
121. Labrouche S, Javorschi S, Leroy D, et al. Influence of hy- 140. Ross RM, McAllister TA. Protective action of hyperbaric
perbaric oxygen on leukocyte functions and haemostasis in oxygen in mice with pneumococcal sipticaemia. Lancet:
normal volunteer divers. Thromb Res. 1999;96:309–315. 1965;1:579–581.
122. Thom SR. Leukocytes in carbon monoxide-mediated brain 141. Thom SR, Lauermann MW, Hart GB. Intermittent hyper-
oxidative injury. Toxicol Appl Pharmacol. 1993;123:234–247. baric oxygen therapy for reduction of mortality in experi-
123. Zamboni WA, Roth AC, Russell RC, et al. Morphologic mental polymicrobial sepsis. J Infect Dis. 1986;154:504–510.
analysis of the microcirculation during reperfusion of isch- 142. Benson RM, Minter LM, Osborne BA, et al. Hyperbaric
emic skeletal muscle and the effect of hyperbaric oxygen. oxygen inhibits stimulus-induced proinflammatory cyto-
Plast Reconstr Surg. 1993;91:1110–1123. kine synthesis by human blood-derived monocyte-macroph-
124. Atochin D, Fisher D, Demchenko I, et al. Neutrophil ages. Clin Exp Immunol. 2003;134:57–62.
sequestration and the effect of hyperbaric oxygen in a rat 143. Lahat N, Bitterman H, Yaniv N, Kinarty A, Bitterman N.
model of temporary middle cerebral artery occlusion. Exposure to hyperbaric oxygen induces tumor necrosis fac-
Undersea Hyperb Med. 2000;27:185–190. tor-alpha (TNF-alpha) secretion from rat macrophages.
125. Kihara K, Ueno S, Sakoda M, et al. Effects of hyperbaric Clin Exp Immunol. 1995;102:655–659.
oxygen exposure on experimental hepatic ischemia reper- 144. Weisz G, Lavy A, Adir Y, et al. Modification of in vivo and
fusion injury: Relationship between its timing and neutro- in vitro TNF-alpha, IL-1, and IL-6 secretion by circulating
phil sequestration. Liver Transpl. 2005;11:1574–1580. monocytes during hyperbaric oxygen treatment in patients

140S
Volume 127, Number 1S • Hyperbaric Oxygen

with perianal Crohn’s disease. J Clin Immunol. 1997;17:154– involves upregulation of hypoxia-inducible factor-1a and
159. erythropoietin in rats. J Appl Physiol. 2008;104:1185–1191.
145. Gregorevic P, Lynch GS, Williams DA. Hyperbaric oxygen 153. Narkowicz CK, Vial JH, McCartney PW. Hyperbaric oxygen
modulates antioxidant enzyme activity in rat skeletal mus- therapy increases free radical levels in the blood of humans.
cles. Eur J Appl Physiol. 2001;86:24–27. Free Radic Res Commun. 1993;19:71–80.
146. Hirata T, Cui Y, Funakoshi T, et al. The temporal profile of 154. Dennog C, Gedik C, Wood S, et al. Analysis of oxidative
genomic responses and protein synthesis in ischemic tol- DNA damage and HPRT mutations in humans after hyper-
erance of the rat brain induced by repeated hyperbaric baric oxygen treatment. Mutat Res. 1999;431:351–359.
oxygen. Brain Res. 2007;1130:214–222. 155. Hart GB, Strauss MB. Central nervous system oxygen tox-
147. Kim C, Choi H, Chun Y, et al. Hyperbaric oxygenation pre- icity in a clinical setting. In: Bove AA, Bachrack AJ, Green-
treatment induces catalase and reduces infarct size in ischemic baum LJ, eds. Undersea and Hyperbaric Physiology IX. Be-
rat myocardium. Pflugers Arch. 2001;442:519–525. thesda, Md.: Undersea and Hyperbaric Medical Society,
148. Nie H, Xiong L, Lao N, et al. Hyperbaric oxygen precon-
1987:695–699.
ditioning induces tolerance against spinal cord ischemia by
156. Davis JC, Dunn JM, Heimbach RD. Hyperbaric medicine:
upregulation of antioxidant enzymes in rabbits. J Cereb Blood
Patient selection, treatment procedures, and side-effects.
Flow Metab. 2006;26:666–674.
In: Davis JC, Hunt TK, eds. Problem Wounds. New York:
149. Yu S, Chiu J, Yang S, et al. Preconditioned hyperbaric ox-
ygenation protects the liver against ischemia-reperfusion Elsevier; 1988:25–235.
injury in rats. J Surg Res. 2005;128:28–36. 157. Plafki C, Peters P, Almeling M, et al. Complications and side
150. Calvert J, Cahill J, Yamaguchi-Okada M, et al. Oxygen treat- effects of hyperbaric oxygen therapy. Aviat Space Environ
ment after experimental hypoxia-ischemia in neonatal rats Med. 2000;71:119–124.
alters the expression of HIF-1a and its downstream target 158. Clark J. Oxygen toxicity. In: Neuman TS, Thom SR, eds.
genes. J Appl Physiol. 2006;101:853–865. Physiology and Medicine of Hyperbaric Oxygen Therapy. Phila-
151. Li Y, Zhou C, Calvert J, et al. Multiple effects of hyperbaric delphia: Saunders; 2008:527–563.
oxygen on the expression of HIF-1a and apoptotic genes in 159. Lyne AJ. Ocular effects of hyperbaric oxygen. Trans Oph-
a global ischemia-hypotension rat model. Exp Neurol. 2005; thalmol Soc U K. 1978;98:66–68.
191:198–210. 160. Palmquist BM, Philipson BO, Barr PO. Nuclear cataract and
152. Gu G.-J, Li Y-P, Peng Z-Y, et al. Mechanism of ischemic myopia during hyperbaric oxygen therapy. Br J Ophthalmol.
tolerance induced by hyperbaric oxygen preconditioning 1984;68:113–117.

141S