Citation: JAMA, The Journal
of the American Medical Association, April 25, 1990 v263 n16 p2216(5)
Title: Hyperbaric oxygen therapy.
Authors: Grim, Pamela S.; Gottlieb, Lawrence J.; Boddie, Allyn; Batson,
Subjects: Hyperbaric oxygenation Evaluation
Oxygen therapy Complications
Hyperbaric oxygenation Complications
Reference #: A8988013
Abstract: Hyperbaric oxygen
(HBO) therapy involves intermittent inhalation of pure oxygen under a
pressure greater than one atmosphere. During the 1960s, HBO was proposed
as a treatment for cancer, heart attack, senility, and other conditions,
but research studies did not obtain reproducible results. The skepticism
engendered among medical personnel by these failures extended to HBO's
use for treating clinical conditions that it had been shown to help. A
review of these conditions is provided. HBO acts both mechanically, due
to its pressure component, and physiologically, due to its oxygen
component. HBO therapy has been effective in treating decompression
sickness (the illness resulting from too-rapid changes in pressure by
divers or aviators), and air embolism (introduction of air into the
circulatory system, often unintentionally by medical personnel) by
mechanically reducing the size of gas bubbles, and increasing oxygen
levels in the blood. Oxygen is essential for proper function of certain
cells of the immune system and, in certain injuries, such as burns and
crush injuries, HBO treatment can increase the supply of oxygen to
tissues otherwise deprived of it. Complications of HBO treatment include
trauma to or rupture of cavities, neurotoxicity resulting from exposure
to 100 percent oxygen for long periods, and other sequelae. HBO therapy
is indicated for decompression sickness, air embolism, carbon monoxide
poisoning, acute traumatic ischemia (crush injuries that deprive tissues
of oxygen), and bacterial invasion of a necrotic wound (in which tissue
has died). HBO may also stimulate regrowth of blood vessels in damaged
tissue adjacent to areas treated by radiation therapy and may promote
bone formation in cases of osteomyelitis (bone infection) that have not
responded to other treatments. This therapy also shows promise for
treating a variety of 'problem wounds', but randomized, prospective
studies are lacking. Overall, HBO therapy is safe and effective for
certain conditions, and well-formulated clinical trials could help
extend its use to others. (Consumer Summary produced by Reliance Medical
Full Text COPYRIGHT American Medical Association 1990
Hyperbaric Oxygen Therapy
Hyperbaric oxygen therapy involves intermittent inhalation of 100%
oxygen under a pressure greater than 1 atm. Despite over a century of
use in medical settings, hyperbaric oxygen remains a controversial
therapy. The last 20 years have seen a clarification of the mechanism of
action of hyperbaric therapy and a greater understanding of its
potential benefit. However, despite the substantial evidence that
hyperbaric oxygen may have a therapeutic effect in certain carefully
defined disease states, many practitioners remain unaware of these
findings or are concerned about using hyperbaric therapy because of the
controversy it has engendered. This review examines the indications
currently considered appropriate for hyperbaric oxygen and briefly
evaluates animal and clinical data substantiating these indications.
Areas in which the mechanism of action of hyperbaric oxygen is still not
well understood, as well as possible new areas of applications, are
Hyperbaric oxygen (HBO)
therapy involves intermittent inhalation of 100% oxygen under a pressure
greater than 1 atm.  Both therapeutic and toxic effects result from
two features of treatment: mechanical effects of increased pressure and
physiologic effects of hyperoxia.
Hyperbaric oxygen therapy
has long been accepted as a primary treatment for decompression sickness
; however, other proposed indications have been controversial. During
the 1960s there was widespread enthusiasm for hyperbaric treatment of
myocardial infarction, stroke, senility, and cancer. Enthusiasm waned
after results of clinical trials (and direct experience) showed little
benefit for these diseases.
The overzealous claims about
the effectiveness of HBO therapy have left a legacy of skepticism among
physicians.  However, animal studies, clinical trials, and greater
clinical experience over the last two decades have produced a set of
indications for which HBO therapy appears beneficial. These clinical
conditions are substantially different from those in the 1960s. However,
there has been no recent interdisciplinary review of HBO therapy
delineating these current indications, despite their broad applications.
Thus, while substantial evidence supports use of HBO therapy in certain
carefully defined settings, many patients who might benefit go untreated
because of their physician's unfamiliarity with recent research and
overall uncertainty about the legitimacy of HBO as therapy.
We discuss the mechanism of
action of HBO therapy and the commonly accepted clinical indications
(Table 1) as delineated by the Undersea and Hyperbaric Medical Society,
 the professional association of physicians administering HBO
therapy, and we briefly review the data supporting current indications.
MECHANISMS OF ACTION
In disease such as air
embolism and decompression sickness, the therapeutic effect of HBO
therapy is achieved through the mechanical reduction in bubble size
brought on by an increase in ambient pressure. A 5 atm a bubble is
reduced to 20% of its original volume and 60% of its original diameter.
Increasing pressure in HBO
therapy is often expressed in multiples of atmospheric pressure absolute
(ATA); 1 ATA equals 1 kg/c[m.sup.2] or 735.5 mm Hg. Most HBO treatments
are performed at 2 to 3 ATA. In air embolism and decompression sickness,
where pressure is crucial to therapeutic effect, treatments frequently
start at 6 ATA.
This additional pressure,
when associated with inspiration of high levels of oxygen, substantially
increases the level of oxygen dissolved into blood plasma. This state of
serum hyperoxia is the second beneficial effect of hyperbaric oxygen
Hyperoxia: Life Without
At sea level in room air,
hemoglobin is approximately 97% saturated with oxygen (19.5 vol% oxygen,
of which approximately 5.8 vol% is extracted by tissue). The amount of
oxygen dissolved into plasma is 0.32 vol%. An increase in P[O.sub.2] has
a negligible impact on total hemoglobin oxygen content; however, it does
result in an increase in the amount of oxygen dissolve directly into
plasma. With 100% inspired oxygen the amount of plasma oxygen increases
to 2.09 vol%. At 3 ATA plasma contains 6.8 vol% oxygen, a level
equivalent to the average tissue requirements for oxygen. Thus, HBO
treatment could and has sustained life without hemoglobin. 
The immune system, wound
healing, and vascular tone are all affected by oxygen supply. Oxygen
alone has little direct antimicrobial effect, even for most anaerobes
; it is, however, a crucial factor in immune function. Neutrophils
require molecular oxygen as a substrate for microbial killing. The
oxidative burst seen in neutrophils after phagocytosis of bacteria
involves a 10-to 15-fold increase in oxygen consumption.  Here oxygen
serves as a substrate in the formation of free radicals, which directly
or indirectly initiate phagocytic killing.  This endogenous
antimicrobial system virtually ceases functioning under conditions of
hypoxia. A tissue [PO.sub.2] of at least 30 mm Hg of oxygen is
considered necessary for normal oxidative function to occur. 
Oxygen partial pressures
below this are often seen in damaged and infected tissues. Increasing
the oxygen level in this tissue can allow restoration of white blood
cell function and return of adequate antimicrobial action.  The
cardiovascular effects of hyperbaric oxygen include a generalized
vasoconstriction and a small reduction in cardiac output.  This
ultimately may decrease the overall blood supply to a region, but the
increase in serum oxygen content results in an overall gain in delivered
oxygen. In conditions such as burns, cerebral edema, and crush injuries,
this vasoconstriction may be beneficial, reducing edema and tissue
swelling while maintaining tissue oxygenation. 
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.  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 disease. Air embolism, presumably resulting from a small
tear in the pulmonary vasculature, is another rare complication. 
One hundred percent oxygen under high pressure is neurotoxic and can
lower the seizure threshold and affect central nervous system control of
respiration. However, neurotoxicity is rare with the low-pressure,
short-duration treatments used clinically in HBO therapy. In one series
the incidence was reported as 1.3 seizures per 10 000 treatments. 
Pulmonary oxygen toxic
reactions can occur with 100% inspired oxygen at less than 1 ATA with
prolonged exposure. Almost all patients will show pulmonary toxicity
after 6 continuous hours of inspired oxygen at 2 ATA.  No clinical
HBO protocol requires this length of continuous exposure to 100% oxygen.
However, HBO treatments may contribute to the pulmonary oxygen toxicity
seen in critically ill patients who receive high concentrations of
inspired oxygen between hyperbaric treatments.
Although a concern in
premature newborns, retrolental fibroplasia has not been noted in
infants, children, or adults undergoing HBO therapy.  Development of
cataracts has been reported in patients receiving more than 150 HBO
Hyperbaric oxygen can be
administered in either a multiplace or a monoplace chamber. Multiplace
Chamber. Multiplace chambers are large tanks accommodating 2 to 14
people (Fig 1). They are usually built to achieve pressures 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.  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
Monoplace chambers (Fig 2)
are far less costly than their larger counterparts and have allowed
hospitals to institute HBO programs without prohibitive capital outlays.
Most chambers are sized to allow a single patient to lie supine under a
transparent acrylic dome or viewing port. The internal environment of a
monoplace chamber is maintained at 100% oxygen; thus, the patient does
not wear a mask. This high concentration of oxygen precludes the use of
any electronic equipment in the chamber. However, specially adapted
ventilators and monitoring systems do allow treatment of critically ill
Sickness.—Although occasionally seen in aviators, decompression sickness
is generally a disease 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 exhaled. With rapid ascent a
steep pressure gradient develops and intravascular nitrogen gas bubbles
form.  These can be detected in asymptomatic divers. 
With greater pressure
gradients, the nitrogen bubbles become large enough and prevalent enough
to mechanically 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. 
Decompression 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 embolization of bubbles into the cardiac
or central nervous system.
Hyperbaric oxygen therapy
mechanically decreases the size of the bubbles, oxygenates ischemic
tissue, and reduces the nitrogen gradient. Any patient with
decompression sickness should be transferred immediately to the nearest
HBO facility with the capacity to decompress to 3 to 6 ATA, as this has
been shown in numerous series to be the most reliable and effective
treatment. [22,23] The Duke University Divers Alert Network maintains a
24-hour emergency consultation telephone number, (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 severe
neurologic symptoms or sudden death. Hyperbaric oxygen therapy has been
part of successful treatment of air embolism due to cardiovascular
procedures, [24,25] lung biopsies,  hemodialysis,  and central
line placement.  Presumably, HBO therapy decreases the volume of the
embolism and oxygenates local tissues. Treatment involves immediate
descent to 6 ATA for 15 to 30 minutes on air, followed by decompression
to 2.8 ATA, where the patient receives prolonged oxygen treatment.
Poisoning.—Carbon monoxide poisoning accounts for half of all fatal
poisonings in the United States. Multiple series have shown that
patients with carbon monoxide poisoning improve markedly following
treatment with HBO. [29-31] However, both the mechanism of carbon
monoxide toxicity and the therapeutic effect of HBO are poorly
understood. Carbon monoxide toxicity was long thought to be due to
anoxia alone;  however, there is evidence that the pathophysiologic
effects occur with carbon monoxide binding to the cytochrome-oxidase
system, causing anoxia at the mitochondrial level.  In either case,
HBO therapy is the most rapid way of displacing carbon monoxide bound to
hemoglobin and cytochromes. The serum half-life of carboxyhemoglobin 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.  In treating
patients with carbon monoxide poisoning, it is important to remember
that serum carboxyhemoglobin 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 carboxyhemoglobin level.  Although HBO therapy
remains the preferred treatment for significant exposure (Table 3), only
a few controlled human studies with inconclusive results have compared
HBO with 100% oxygen at 1 atm. [36,37] Clostridial Myonecrosis.—Clostridial
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 tissue [PO.sub.2] of 250 mm Hg inhibits the production
of alpha toxin by Clostridium. 
Hyperbaric oxygen is
commonly used as an adjunct therapy in clostridial infections. In vivo
studies have demonstrated decreased mortality rates and diminished
tissue loss in infected mice. [39,40] In a study by DeMello et al, 
using a dog model of clinical Clostridium infection, 100% of infected
control dogs and dogs randomized to either HBO therapy or surgery died.
Fifty percent of the dogs that received antibiotics survived, 70% of the
dogs that received antibiotics and underwent surgery survived, and 95%
of the dogs that received antibiotics and HBO therapy and underwent
Multiple series have
evaluated the effect of HBO therapy on clostridial infections in humans.
[42,43] Surgeons experienced 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 demarcation of viable and nonviable tissue. There have, however,
been no randomized, controlled studies.
Hyperbaric oxygen therapy
has been recommended for treatment of necrotizing fasciitis, since
anaerobic bacteria play a role in the disease. [44,45] The diversity 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 necrotizing fasciitis is
an accepted indication for HBO, the benefit HBO therapy may provide is
still poorly understood, and surgery remains the cornerstone of therapy.
 Acute Traumatic Ischemia.—Acute crush injury to an extremity may
cause severe edema and ischemia in tissue and capillary beds not
relieved by restoration 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 plasma
flow.  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 syndrome. 
therapy, in addition to its therapeutic effects, can damage normal
adjacent tissue. The initial pathologic process is a progressive
obliterative endarteritis, resulting in areas of tissue hypoxia and
eventual cell death.  Large areas of hypocellular, hypovascular, and
hypoxic tissue are created that are devoid of functioning fibroblasts
and osteoblasts.  Hyperbaric oxygen therapy appears to assist in
salvaging such tissue by stimulating angioneogenesis in marginally
viable tissue.  Marx and Johnson  emphasize that, in
reconstructive surgery involving recently 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
presurgical and postsurgical treatments, they demonstrated a
satisfactory surgical outcome in 92% of their patients and a
complication rate of 9%.
tissue destruction progresses to breakdown of overlying tissues and
symptomatic destruction of bone. Prior to the introduction of HBO
therapy, only 5% to 30% of patients who developed osteoradionecrosis
could expect remission with conservative therapy.  In a protocol
developed by Marx,  a series of 58 patients received an initial
series of HBO treatments, followed by debridement 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 impressive results have been corroborated by
others. [57,58] Successful results have also been demonstrated for
radiation-induced cystitis  and other radiation-damaged soft tissue.
 Hyperbaric oxygen therapy is beneficial for patients at risk for
the development of osteoradionecrosis, such as irradiated patients
requiring tooth extraction. In a randomized trial comparing HBO and
penicillin therapy in 74 previously irradiated patients, 30% of the
patients who received penicillin developed osteoradionecrosis, while
5.4% of the patients who received HBO developed osteoradionecrosis. 
Similar results have been reported elsewhere. 
oxygen is currently being used as an adjunctive therapy with debridement
and antibiotics in osteomyelitis that has remained refractory to
standard therapy. Animal studies have demonstrated that HBO therapy used
in experimental models of osteomyelitis has increased osseous repair
 and promoted callus formation,  possibly by promoting
osteoclast activity.  Human studies involve series of patients in
whom standard treatment regimens have failed. Multiple clinical series
demonstrate substantial success with HBO therapy in these patients.
[66-68] However, to date there have been no randomized trials.
rationale for HBO therapy in problem wounds is to intermittently
increase the tissue oxygen tension to optimize fibroblast proliferation
 and white blood cell killing capacity  during periods of
hyperoxia and to stimulate angioneogenesis during periods of relative
hypoxia.  Series have been published showing improved healing with
HBO therapy in problem wounds refractory to standard therapy. [72,73]
Patients in whom increased oxygenation of wounds can be demonstrated
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 standardized patient populations
or treatment schedules.
Hyperbaric oxygen therapy
cannot substitute for surgical revascularization in advanced arterial
insufficiency and cannot reverse inadequate microvascular circulation.
 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.
Certain animal data indicate
that HBO therapy may improve the outcome of moderate and severe burns.
 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.
Hyperbaric oxygen therapy is
a safe and effective primary therapy when administered 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 contribution to the treatment of clostridial myonecrosis
has been substantiated by both animal models and clinical experience.
The role of HBO therapy in recovery from carbon monoxide poisoning,
while probably significant, is poorly understood 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 indications. Successful extension
of its use in other situations will be predicated on in vitro and in
vivo experimental evidence and appropriate well-controlled clinical
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