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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
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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
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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-
iZDnaRuQfErSd3RMaTDC2v6RSecRDcjiT26qZ2NPu1qZesjOeIPUV82GMNKtmkeCSXvWAux8ju1HdQdrooaz6mv5mrfN0ibPSllU
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
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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/
iZDnaRuQfErSd3RMaTDC2v6RSecRDcjiT26qZ2NPu1qZesjOeIPUV82GMNKtmkeCSXvWAux8ju1HdQdrooaz6mv5mrfN0ibPSllU
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
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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-
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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
iZDnaRuQfErSd3RMaTDC2v6RSecRDcjiT26qZ2NPu1qZesjOeIPUV82GMNKtmkeCSXvWAux8ju1HdQdrooaz6mv5mrfN0ibPSllU
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
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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
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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
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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
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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-
iZDnaRuQfErSd3RMaTDC2v6RSecRDcjiT26qZ2NPu1qZesjOeIPUV82GMNKtmkeCSXvWAux8ju1HdQdrooaz6mv5mrfN0ibPSllU
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:
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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
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system and engages an autocrine activation loop involv- growth factor expression and enhances blood perfusion
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108. Bowersox J, Strauss M, Hart G. Clinical experience with 126. Tahepold P, Valen G, Starkopf J, et al. Pretreating rats with
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