Hyperbaric Oxygen Therapy

Pamela S. Grim, MD; Lawrence J. Gottlieb, MD; Allyn Boddie, RN; Eric Batson, MD

Hyperbaric oxygen therapy involves intermittent inhalation of 100% oxygen through the mechanical reduction in
under a pressure greater than 1 atm. Despite over a century of use in medical bubble size brought on by an increase in
settings, hyperbaric oxygen remains a controversial therapy. The last 20 years ambient pressure. At 5 atm a bubble is
have seen a clarification of the mechanism of action of hyperbaric therapy and a reduced to 20% of its original volume
greater understanding of its potential benefit. However, despite the substantial and 60% of its original diameter.
evidence that hyperbaric oxygen may have a therapeutic effect in certain careful- Increasing pressure in HBO therapy
is often expressed in multiples of at¬
ly defined disease states, many practitioners remain unaware of these findings or mospheric pressure absolute (ATA);
are concerned about using hyperbaric therapy because of the controversy it has 1 ATA equals 1 kg/cm2 or 735.5 mm Hg.
engendered. This review examines the indications currently considered appro- Most HBO treatments are performed at
priate for hyperbaric oxygen and briefly evaluates animal and clinical data 2 to 3 ATA. In air embolism and decom¬
substantiating these indications. Areas in which the mechanism of action of pression sickness, where pressure is
hyperbaric oxygen is still not well understood, as well as possible new areas of crucial to therapeutic effect, treatments
applications, are discussed. frequently start at 6 ATA.
(JAMA. 1990;263:2216-2220) This additional pressure, when asso¬
ciated with inspiration of high levels of
oxygen, substantially increases the lev¬
el of oxygen dissolved into blood plas¬
HYPERBARIC oxygen (HBO) thera¬ greater clinical experience over the last ma. This state of serum hyperoxia is the
py involves intermittent inhalation of two decades have produced a set of indi¬ second beneficial effect of hyperbaric
100% oxygen under a pressure greater cations for which HBO therapy appears oxygen therapy.
than 1 atm. ' Both therapeutic and toxic beneficial. These clinical conditions are
effects result from two features of treat¬ substantially different from those in the Hyperoxia: Life Without Blood
ment: mechanical effects of increased 1960s. However, there has been no re¬ At sea level in room air, hemoglobin is
pressure and physiologic effects of cent interdisciplinary review of HBO
approximately 97% saturated with oxy¬
hyperoxia. therapy delineating these current indi¬ gen (19.5 vol% oxygen, ofwhich approx¬
Hyperbaric oxygen therapy has long cations, despite their broad applica¬ imately 5.8 vol% is extracted by tissue).
been accepted as a primary treatment tions. Thus, while substantial evidence The amount of oxygen dissolved into
for decompression sickness2; however, supports use of HBO therapy in certain plasma is 0.32 vol%. An increase in Po2
other proposed indications have been carefully defined settings, many pa¬ has a negligible impact on total he¬
controversial. During the 1960s there tients who might benefit go untreated
was widespread enthusiasm for hyper¬ because of their physicians' unfamiliari-
moglobin oxygen content; however, it
does result in an increase in the amount
baric treatment of myocardial infarc¬ ty with recent research and overall un¬ of oxygen dissolved directly into plas¬
tion, stroke, senility, and cancer. En¬ certainty about the legitimacy of HBO ma. With 100% inspired oxygen the
thusiasm waned after results of clinical as therapy. amount of plasma oxygen increases to
trials (and direct experience) showed We discuss the mechanism of action of 2.09 vol%. At 3 ATA plasma contains
little benefit for these diseases. The HBO therapy and the commonly ac¬ 6.8 vol% oxygen, a level equivalent to
overzealous claims about the effective¬ cepted clinical indications (Table 1) as the average tissue requirements for ox¬
ness of HBO therapy have left a legacy delineated by the Undersea and Hyper¬ ygen. Thus, HBO treatment could and
of skepticism among physicians.3 How¬ baric Medical Society,1 the professional has sustained life without hemoglobin.4
ever, animal studies, clinical trials, and association of physicians administering The immune system, wound healing,
HBO therapy, and we briefly review the and vascular tone are all affected by
From the Section of Plastic and Reconstructive Sur-
data supporting current indications.
gery, University of Chicago Hospitals (Drs Grim and oxygen supply. Oxygen alone has little
Gottlieb and Ms Boddie), and the Division of Health direct antimicrobial effect, even for
Care Technology, American Medical Association (Drs MECHANISMS OF ACTION
Grim and Batson), Chicago, Ill. most anaerobes6; it is, however, a
Pressure crucial factor in immune function. Neu-
The opinions in this article do not necessarily reflect
the policies of the American Medical Association.
Reprint requests to Section of Plastic and Recon-
In diseases such as air embolism and trophils require molecular oxygen as a
structive Surgery, University of Chicago, 5841 S Mary- decompression sickness, the therapeu¬ substrate for microbial killing. The oxi-
land Ave, Box 269, Chicago, IL 60637 (Dr Grim). tic effect of HBO therapy is achieved dative burst seen in neutrophils after

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 phagocytosis of bacteria involves a 10-
to 15-fold increase in oxygen consump¬
tion.6 Here oxygen serves as a substrate
in the formation of free radicals, which
directly or indirectly initiate phagocytic
killing.7 This endogenous antimicrobial
system virtually ceases functioning un¬
der conditions of hypoxia. A tissue Po2
of at least 30 mm Hg of oxygen is consid¬
ered necessary for normal oxidative
function to occur.8 Oxygen partial pres¬
sures below this are often seen in dam¬
aged and infected tissues. Increasing
the oxygen level in this tissue can allow
restoration of white blood cell function
and return of adequate antimicrobial
action.9
The cardiovascular effects of hyper¬
baric oxygen include a generalized vaso¬
constriction and a small reduction in car¬
diac output.10 This ultimately may
decrease the overall blood supply to a
region, but the increase in serum oxy¬
gen content results in an overall gain in
delivered oxygen. In conditions such as
burns, cerebral edema, and crush inju¬
ries, this vasoconstriction may be be¬
neficial, reducing edema and tissue
swelling while maintaining tissue oxy¬
génation.11
COMPLICATIONS
Usual complications of HBO therapy
are listed in Table 2. They are a result of
either barometric pressure changes or
oxygen toxicity. The most common
complications involve cavity trauma
due to change in pressure.12 Any air-
filled cavity that cannot equilibrate with
ambient pressure, such as the middle
ear when the eustachian tube is blocked,
is subject to deformity and barotrauma
during pressure changes in HBO
therapy.
Pneumothorax is a rare complication
of HBO treatment, usually occurring
only in patients with severe lung dis¬
ease. Air embolism, presumably result¬
ing from a small tear in the pulmonary
vasculature, is another rare complica¬
tion.13
One hundred percent oxygen under
high pressure is neurotoxic and can low¬
er the seizure threshold and affect cen¬
tral nervous system control of respira¬
tion. However, neurotoxicity is rare
with the low-pressure, short-duration
treatments used clinically in HBO ther¬
apy. In one series the incidence was
reported as 1.3 seizures per 10 000
treatments.14
Pulmonary oxygen toxic reactions
can occur with 100% inspired oxygen at
less than 1 ATA with prolonged expo¬
sure. Almost all patients will show pul¬
monary toxicity after 6 continuous
hours of inspired oxygen at 2 ATA.15 No
clinical HBO protocol requires this
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Table 1. —Indications for Hyperbaric Oxygen Ther¬
apy_
Air gas embolism
or
Carbon monoxide and/or cyanide poisoning; smoke
inhalation
Acute traumatic Ischemias such as compartment syn¬
drome and crush injury
Decompression sickness
Enhancement of healing in selected
problem wounds
Exceptional blood loss
Clostridial gangrene
Necrotlzing soft-tissue Infection
Osteomyelitis (refractory)
Radiation necrosis
Osteoradionecrosis and soft-tissue radionecrosis
Caries in radiated bones
Skin grafts or flaps (compromised)
length of continuous exposure to 100%
oxygen. However, HBO treatments
may contribute to the pulmonary oxy¬
gen toxicity seen in critically ill patients
who receive high concentrations of in¬
spired oxygen between hyperbaric
treatments.
Although a concern in premature
newborns, retrolental fibroplasia has
not been noted in infants, children, or
adults undergoing HBO therapy.16 De¬
velopment of cataracts has been re¬
ported in patients receiving more than
150 HBO treatments."
HBO ADMINISTRATION
Hyperbaric oxygen can be adminis¬
tered in either a multiplace or a mono-
place chamber.
Multiplace Chamber
Multiplace chambers are large tanks
accommodating 2 to 14 people (Fig 1).
They are usually built to achieve pres¬
sures up to 6 atm and have a chamber
lock-entry system that allows personnel
to pass through without altering the
pressure of the inner chamber. Patients
can be directly cared for by medical staff
within the chamber. The chamber is
filled with compressed air; patients
breathe 100% oxygen through a face
mask, head hood, or endotracheal tube.
Although fire hazards restrict the use of
certain electronic equipment, some
monitors and ventilators with solid-
state circuitry can be used within the
chamber, allowing intensive care of
critically ill patients.18 The multiplace
chamber's ability to maintain pressures
of 6 atm or more, makes it the chamber
of choice for decompression sickness
and air embolism.
Monoplace Chamber
Monoplace chambers (Fig 2) are far
less costly than their larger counter¬
parts and have allowed hospitals to in¬
stitute HBO programs without prohibi¬
tive capital outlays. Most chambers are
sized to allow a single patient to lie su¬
pine under a transparent acrylic dome
or viewing port. The internal environ-
Table 2—Major Complications of Hyperbaric Ther¬
apy_
Barotrauma
Ear or sinus trauma
Tympanic membrane rupture
Pneumothorax
Air embolism
Oxygen toxicity
Central nervous system toxic reactions
Pulmonary toxic reactions
Other
Fire
Reversible visual changes
Claustrophobia
ment of a monoplace chamber is main¬
tained at 100% oxygen; thus, the patient
does not wear a mask. This high concen¬
tration of oxygen precludes the use of
any electronic equipment in the cham¬
ber. However, specially adapted venti¬
lators and monitoring systems do allow
treatment of critically ill patients.
CLINICAL INDICATIONS
Acute Conditions
Decompression Sickness. Al¬
though occasionally seen in aviators, de¬ —
compression sickness is generally a dis¬
ease of divers. During a dive, the diver
is exposed to pressures greater than
1 atm, and tissue uptake of nitrogen
increases according to the principles of
Henry's law. With ascent, a pressure
gradient develops, and nitrogen leaves
the tissue, dissolving into the blood and
passing to the lungs, where it is ex¬
haled. With rapid ascent a steep pres¬
sure gradient develops and intravascu-
lar nitrogen gas bubbles form.19 These
can be detected in asymptomatic
divers.20 With greater pressure gradi¬
ents, the nitrogen bubbles become large
enough and prevalent enough to me¬
chanically deform tissue and obstruct
blood vessels. The gas-fluid interface
also interacts with blood cells, platelets,
and proteins, causing disruption of the
intravascular coagulation system.21 De¬
compression sickness results.
Divers can experience decompression
sickness as pain only, usually as a "deep
and dull ache" in the extremities. More
serious cases can present as paraplegia
or cardiovascular collapse due to embo-
lization of bubbles into the cardiac or
central nervous system.
Hyperbaric oxygen therapy mechani¬
cally decreases the size of the bubbles,
oxygenates ischémie tissue, and re¬
duces the nitrogen gradient. Any
patient with decompression sickness
should be transferred immediately to
the nearest HBO facility with the capac¬
ity to decompress to 3 to 6 ATA, as this
has been shown in numerous series to be
the most reliable and effective treat¬
ment.2223 The Duke University Divers

Fig 1.—Multiplace hyperbaric chambers (courtesy of St Luke's Medical Center, Milwaukee, Wis).
Fig 2.—A monoplace hyperbaric chamber (photograph by David Tepllca,
Alert Network maintains a 24-hour
emergency consultation telephone num¬
ber, (919) 684-8111, and can identify the
closest available HBO facility.
Air Embolism.—Air embolism can
be a complication of uncontrolled ascent
in diving but more frequently is seen
medically in iatrogenic misadventures.
Bubbles can embolize to the cerebral or
cardiac circulation, producing either se¬
vere neurologic symptoms or sudden
death. Hyperbaric oxygen therapy has
been part of successful treatment of air
embolism due to cardiovascular proce¬
dures "•" lung biopsies,26 hemodialysis,27
, be due to anoxia alone32; however, there
and central line placement.28 Presum¬
ably, HBO therapy decreases the vol¬
ume of the embolism and oxygenates
local tissues. Treatment involves imme¬
diate descent to 6 ATA for 15 to
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MD).
30 minutes on air, followed by decom¬
pression to 2.8 ATA, where the patient
receives prolonged oxygen treatment.
Carbon Monoxide Poisoning.—
Carbon monoxide poisoning accounts
for half of all fatal poisonings in the
United States. Multiple series have
shown that patients with carbon monox¬
ide poisoning improve markedly follow¬
ing treatment with HBO.2*31 However,
both the mechanism of carbon monoxide
toxicity and the therapeutic effect of
HBO are poorly understood. Carbon
monoxide toxicity was long thought to
is evidence that the pathophysiologic ef¬
fects occur with carbon monoxide bind¬
ing to the cytochrome-oxidase system,
causing anoxia at the mitochondrial lev¬
el.33 In either case, HBO therapy is the
Table 3.—Suggested Guidelines for Treatment of
Carbon Monoxide Poisoning
History of unconsciousness
Presence of neuropsychiatrie abnormality
Presence of cardiac instability or cardiac ischemia
Carboxyhemoglobin level >25%,
lower levels In children and pregnant women
most rapid way of displacing carbon
monoxide bound to hemoglobin and cy-
tochromes. The serum half-life of car¬
boxyhemoglobin is decreased from
5 hours 20 minutes with room air to
80 minutes with 100% oxygen and 23
minutes with 100% oxygen at 3 ATA.34
In treating patients with carbon mon¬
oxide poisoning, it is important to
remember that serum carboxyhemoglo¬
bin levels do not reflect tissue levels of
carboxyhemoglobin and, therefore,
may not correlate with the degree of
toxicity. Accompanying signs and
symptoms are as important to guiding
therapy as the serum carboxyhemoglo¬
bin level.35
Although HBO therapy remains the
preferred treatment for significant ex¬
posure (Table 3), only a few controlled
human studies with inconclusive results
have compared HBO with 100% oxygen
at 1 atm.36'37
Clostridial Myonecrosis.—Clostrid-
ial myonecrosis occurs when a hypoxic
environment within a necrotic wound
allows clostridial spores to convert to
vegetative organisms. These organisms
produce exotoxins that destroy red
blood cells, cause tissue necrosis, and
abolish local host defenses. The most
important exotoxin is alpha toxin. A tis¬
sue Po2 of 250 mm Hg inhibits the pro¬
duction of alpha toxin by Clostridium.38
Hyperbaric oxygen is commonly used
as an adjunct therapy in clostridial in¬
fections. In vivo studies have demon¬
strated decreased mortality rates and
diminished tissue loss in infected
mice.39" In a study by DeMello et al,41
using a dog model of clinical Clostridi¬
um infection, 100% of infected control
dogs and dogs randomized to either
HBO therapy or surgery died. Fifty
percent of the dogs that received antibi¬
otics survived, 70% of the dogs that re¬
ceived antibiotics and underwent sur¬
gery survived, and 95% of the dogs that
received antibiotics and HBO therapy
and underwent surgery survived.
Multiple series have evaluated the ef¬
fect of HBO therapy on clostridial infec¬
tions in humans.42,43 Surgeons experi¬
enced with its use emphasize that early
HBO treatment reduces systemic toxic
reactions so that patients in shock seem
more stable and better able to tolerate
surgery, and there is clearer demarca¬
tion of viable and nonviable tissue.
 There have, however, been no random¬
ized, controlled studies.
Hyperbaric oxygen therapy has been
recommended for treatment of necrotiz-
ing fasciitis, since anaerobic bacteria
play a role in the disease.44'45 The diversi¬
ty of clinical states in retrospective
studies and the paucity of experimental
data make it difficult to demonstrate the
effect of HBO therapy on nonclostridial
soft-tissue infection. Although necrotiz-
ing fasciitis is an accepted indication for
HBO, the benefit HBO therapy may
provide is still poorly understood, and
surgery remains the cornerstone of
therapy.46
Acute Traumatic Ischemia.—Acute
crush injury to an extremity may cause
severe edema and ischemia in tissue and
capillary beds not relieved by restora¬
tion of arterial perfusion. Hyperbaric
oxygen therapy may aid salvage during
the acute stages of revascularization by
reducing edema via vasoconstriction
and increasing oxygen delivery via plas¬
ma flow.47 Investigators have used HBO
therapy successfully as an adjunct to
surgery in crush injuries.48,49 Additional
evidence has demonstrated that HBO
therapy may also serve as an adjunct
therapy in the compartment syn¬
drome.50
Chronic Conditions
Irradiated Tissue.—Radiation ther¬
apy, in adddition to its therapeutic ef¬
fects, can damage normal adjacent tis¬
sue. The initial pathologic process is a
progressive obliterative endarteritis,
resulting in areas of tissue hypoxia and
eventual cell death.51 Large areas of
hypocellular, hypovascular, and hypox-
ic tissue are created that are devoid of
functioning fibroblasts and osteo-
blasts.52 Hyperbaric oxygen therapy ap¬
pears to assist in salvaging such tissue
by stimulating angioneogenesis in mar¬
ginally viable tissue.53
Marx and Johnson54 emphasize that,
in reconstructive surgery involving re¬
cently irradiated tissue, presurgical
HBO treatment can help promote a
well-vascularized wound bed that will
enhance reconstruction and graft take.
Using a specific HBO protocol of presur¬
gical and postsurgical treatments, they
demonstrated a satisfactory surgical
outcome in 92% of their patients and a
complication rate of 9%.
In osteoradionecrosis, tissue destruc¬
tion progresses to breakdown of overly¬
ing tissues and symptomatic destruc¬
tion of bone. Prior to the introduction of
HBO therapy, only 5% to 30% of pa¬
tients who developed osteoradionecro¬
sis could expect remission with conser¬
vative therapy.55 In a protocol
developed by Marx,56 a series of 58 pa-
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tients received an initial series of HBO
treatments, followed by débridement
and further HBO treatment, as dictated
by their clinical course. All 58 patients
studied had resolution of symptoms of
osteoradionecrosis, with good results
on long-term follow up. These impres¬
sive results have been corroborated by
others.57'58 Successful results have also
been demonstrated for radiation-in¬
duced cystitis59 and other radiation-
damaged soft tissue.60
Hyperbaric oxygen therapy is benefi¬
cial for patients at risk for the develop¬
ment of osteoradionecrosis, such as
irradiated patients requiring tooth ex¬
traction. In a randomized trial compar¬
ing HBO and penicillin therapy in 74
previously irradiated patients, 30% of
the patients who received penicillin de¬
veloped osteoradionecrosis, while 5.4%
of the patients who received HBO de¬
veloped osteoradionecrosis.61 Similar
results have been reported elsewhere.62
Refractory Osteomyelitis.—Hyper¬
baric oxygen iscurrently being used as
an adjunctive therapy with débride¬
ment and antibiotics in osteomyelitis
that has remained refractory to stan¬
dard therapy. Animal studies have
demonstrated that HBO therapy used
in experimental models of osteomyelitis
has increased osseous repair63 and pro¬
moted callus formation,64 possibly by
promoting osteoclast activity.65 Human
studies involve series of patients in
whom standard treatment regimens
have failed. Multiple clinical series dem¬
onstrate substantial success with HBO
therapy in these patients.66"68 However,
to date there have been no randomized
trials.
Problem Wounds.—The rationale
for HBO therapy in problem wounds is
to intermittently increase the tissue ox¬
ygen tension to optimize fibroblast pro¬
liferation69 and white blood cell killing
capacity™ during periods of hyperoxia
and to stimulate angioneogenesis dur¬
ing periods of relative hypoxia.71 Series
have been published showing improved
healing with HBO therapy in problem
wounds refractory to standard thera¬
py.72,73 Patients in whom increased
oxygénation of wounds can be demon¬
strated following HBO therapy are the
most likely to benefit. However, unlike
osteoradionecrosis, where a well-
defined clinical problem has been shown
to improve with a carefully designed
protocol incorporating HBO therapy,
treatment of problem wounds remains
an ill-defined field, and HBO data often
consist of small series without standard¬
ized patient populations or treatment
schedules.
Hyperbaric oxygen therapy cannot
substitute for surgical revascularization
in advanced arterial insufficiency and
cannot reverse inadequate microvascu-
lar circulation.74 Hyperbaric oxygen
therapy may serve as an adjunct in the
treatment of certain problem wounds,
but it cannot replace meticulous local
care based on sound physiologic
principles.
Special Considerations
Certain animal data indicate that
HBO therapy may improve the outcome
of moderate and severe burns.75 Few
centers use HBO as standard therapy,
but recent publications of patient series
have demonstrated good response.76"78
Broad-based justification of the use of
HBO in burns, however, will depend on
favorable results of randomized clinical
trials.
SUMMARY
Hyperbaric oxygen therapy is a safe
and effective primary therapy when ad¬
ministered for decompression sickness
and air embolism. The role of HBO as an
adjunctive therapy in the treatment and
prevention of osteoradionecrosis has
been impressively documented. Its con¬
tribution to the treatment of clostridial
myonecrosis has been substantiated by
both animal models and clinical experi¬
ence. The role of HBO therapy in recov¬
ery from carbon monoxide poisoning,
while probably significant, is poorly un¬
derstood and awaits clarification of the
mechanism of action of both carbon
monoxide poisoning and the beneficial
effects of oxygen therapy.
Hyperbaric oxygen therapy is clearly
of value for carefully defined indica¬
tions. Successful extension of its use in
other situations will be predicated on in
vitro and in vivo experimental evidence
and appropriate well-controlled clinical
trials.
We thank Eric Kindwall, MD, Thomas Neuman,
MD, and William McGivney, PhD, for their
thoughtful review of the manuscript, and Thomas
Krizak, MD, for his unstinting support.
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