ANALYTIC REVIEWS
Hyperbaric Oxygen Therapy
Stephen R. Thom, MD, PhD
The physiological effects of hyperbaric oxygen extend
beyond the elevation of oxygen concentration in body
tissues, and clinical data is available
to support its use in
more than gas bubble diseases. Hyperbaric medicine is
discussed within the context of its recognized mecha-
nisms of action. The experimental data and clinical ex-
perience for hyperbaric oxygen therapy are reviewed
for the following conditions: clostridial myonecrosis,
necrotizing soft-tissue infections, chronic refractory os-
teomyelitis, radiation necrosis, refractory cutaneous ul-
cerations, compromised skin grafts and flaps, crush in-
jury and acute peripheral ischemia, carbon monoxide
poisoning, arterial gas embolism, decompression sick-
ness, and thermal burns. Risks associated with hyper-
baric oxygen therapy are discussed, and cost analysis
data are noted for specific conditions.
From the Institute for Environmental Medicine, University of
Pennsylvania, 1 John Morgan Bldg, Philadelphia, PA 19104-
6068.
Received Oct 19, 1988. Accepted for publication
1988.
Address correspondence to Dr Thom.
58
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The use of hyperbaric oxygen (HBO) therapy in
critical care is increasing world wide. Within the
United States, HBO treatments for some conditions
now number in the thousands each year (Table 1)
[1]. Perhaps for this reason alone, a review of the
subject has merit. There is, however, an equally
important issue: There have been a number of de-
velopments over the past several years in basic re-
search on the mechanisms of action of HBO. The
biochemical and physiological effects of this treat-
ment go beyond merely raising arterial oxygen ten-
sion (Po2) to exaggerated levels; the mechanisms
identified deserve more detailed research, both in
terms of a therapeutic perspective and to more
clearly elucidate pathophysiological mechanisms of
disease states.
Hyperbaric oxygen therapy is defined as the
treatment of a patient entirely enclosed within a
pressure vessel who is breathing oxygen (02) at a
pressure greater than sea level (1 atmosphere abso-
lute [ATA]). Hyperbaric oxygen therapy is viewed
by many clinicians with disdain, largely because of
its past use for an array of conditions and diseases
without benefit of scientific validation. To be sure,
abuses with HBO still occur today. In contrast to the
past, however, there is a growing understanding of
the mechanisms of action of HBO, and there are a
number of disease states for which research has
indicated therapeutic benefit.
The resurgence of interest and scientific study of
HBO therapy began in 1961 [2]. Controlled, ran-
domized clinical studies have been performed in
some areas, and there are a number of conditions
for which HBO treatment has been advocated
based on animal studies and clinical experience.
The available basic research on the mechanisms of
action has improved confidence, but more con-
trolled clinical studies are required. In some areas
these studies are underway. A practical question
therefore becomes whether the apparent benefit
versus risk and cost is favorable to the patient based
on the available data, until the results of further
studies become available. It is perhaps notable that
there are no controlled studies of any therapeutic
method for several conditions discussed in this re-
view. Recommendations for the use of HBO are
Nov 15, reviewed regularly by an international committee
of scientists and physicians under the auspices of
the Undersea and Hyperbaric Medical Society. It is

Table l. Number of Patients Treated with
Hyperbaric Oxygen in 1987 ’
From [1]. Used with permission.
the aim of this review to outline conditions that
may be considered for treatment with HBO and
to discuss the available literature. The conditions
listed by the Undersea and Hyperbaric Medical So-
ciety as experimental (i.e., for which HBO use can-
not be recommended) will not be discussed, but a
synopsis of the available literature is available [3].
Mechanisms of Action
Primary mechanisms of HBO action include a re-
duction in volume of gas-filled spaces and hyperox-
ygenation of all perfused tissue beds. Hyperbaric
oxygen is used to treat bubble-related diseases, de-
compression sickness, and air embolism, based on
an understanding of the pathophysiology of these
disorders. Efficacy is based partially on Boyle’s law:
as pressure is increased there is a diminution of
tissue distortion and vascular compromise. Hyper-
oxygenation of tissues occurs because of a mark-
edly increased arterial O2 content, which is related
Table 2. Tissue Oxygen Tension with Increasing Inspired Oxygen Pressure
ATA =
1 atmosphere absolute; O2 =
oxygen.
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59
principally to 02 physically dissolving in plasma.
The oxyhemoglobin dissociation curve is un-
changed. The highest P02 used in clinical practice is
3 ATA, and atthis pressure, arterial Po2 may reach
1,900 to 2,100 mm Hg. Dissolved 02 content
reaches as high as 6.8 volumes percent (6.8 ml 02/
100 ml blood).
Mechanisms Secondary to
Hyperoxygenation
An elevation in arterial02 content increases tissue
Po2, but the elevations in animals and humans ex-
posed to different 02 pressures are found to be
considerably less than the arterial P02 (Table 2).
This is largely due to arteriolar vasoconstriction,
which increases as arterial 02 content rises [4,5]. It
is well known that there is no single value for the
Po2 in a tissue, but rather a gradient between the
arterial and venous 02 levels. When C~2 electrodes,
or mass spectrometer probes, are placed in tissues
a &dquo;mean&dquo; Po2 is recorded. Given that hemoglobin
concentration does not change and cardiopulmo-
nary function is stable, this value may be affected by
arterial 02 content, the rate of local blood flow,
capillary density, cellular metabolic rate, and pH.
Ventilation with 100% 02 (1 ATA) versus air (0.2
ATA) causes a relatively small increase in plasma
02 content (about 2 volumes %), because 02 is only
poorly soluble in aqueous solutions. In the absence
of major cardiopulmonary disease, hemoglobin sat-
uration changes negligibly and there is little change
in tissue Po2. A marked increase in tissue P02 oc-
curs only with HBO [6-9].
Vasoconstriction. Arteriolar vasoconstriction caused
by HBO diminishes local perfusion, but perfiision
is still sufficient to cause super-normal tissue Po2
[6-9]. In animal experiments involving compart-
ment syndrome, reperfusion of ischemic limbs, and
60
burns, HBO caused a reduction in edema forma-
tion that rather closely approximates the degree of
vasoconstriction [10-13].
The systemic cardiovascular effects associated
with HBO are surprisingly nominal, probably be-
cause of offsetting effects. Systemic peripheral vas-
cular resistance increases, but because of a vagal-
mediated bradycardia, blood pressure changes very
little [14]. Coronary artery vasoconstriction also oc-
curs as a result of the same local effects that are
seen in the peripheral circulation [15]. This phe-
nomenon is, however, rarely of clinical signifi-
cance. Vasoconstriction is proportional to
pressure that is used, and both pressure and the
duration of exposure are carefully controlled.
There is also a concomitant tissue hyperoxygena-
tion effect. It is notable that on very rare occasions
angina can occur in patients who will later be found
to have severe (left main or triple-vessel) coronary
artery disease.
Direct Antibacterial Effects. Oxygen is toxic to all
organisms [ 1 C]. The rate of development of toxic
effects is determined by the Po2, the duration of
exposure, and the inherent susceptibility of the or-
ganism. Anaerobic bacteria are especially sensitive
to 0,, largely because of a relative lack of antioxi-
dant enzymatic defenses [17]. Oxygen also alters
the local oxidation-reduction potential, which can
adversely effect bacterial growth, but seems to be of
lesser importance than Oz radicals [18].
Most clinical anaerobic isolates are relatively
aerotolerant, and fresh isolates have been shown to
survive 8 hours exposure to 160 mm Hg 02 [19].
Hyperbaric oxygen can kill a wide variety of bacte-
ria in in vitro experiments, but the relevant clinical
issue is the amount of 02 delivered to organisms
sequestered in the body (see Table 2). Although a
bacteriocidal effect might occur with strict anaer-
obes, the P02 levels achievable are likely to have no
direct effect, or at most a bacteriostatic effect,
against facultative and aerobic organisms [20,21].].
The adverse effects of 02 on microorganisms in-
clude an added dimension when considering exo-
toxin production by Clostridium species. In the re-
gion of the clostridial phlegmon P02 has been
found to increase to approximately 330 mm Hg
during exposure to 3 ATA 02 [8]. This pressure is
sufficient to block production of the lethal alpha
toxin, although the bacteria may remain viable [22].].
Because the systemic manifestations of clostridial
myonecrosis are more attributable to toxemia than
septicemia, the impact on toxin production is likely
to represent a major portion of the benefit seen
with HBO when used in conjunction with antibi-
otics and surgery [23].
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Phagocytic Function. Polymorphonuclear leuko-
cyte (PMN) bacteriocidal efficiency is impeded in
hypoxic conditions [24]. Oxygen-halide radicals
generated by the myeloperoxidase enzyme system
appear to be the principal bacteriocidal agents
within phagocytic vacuoles in PMN; whereas hydro-
gen peroxide (H202) and superoxide radicals are
the major bacteriocidal agents in macrophages.
Infection distorts the local microvasculature and
can destroy capillary arcades that cause ischemic,
hypoxic zones in necrotizing processes. Improve-
ment of subnormal Po2 can improve white blood
the 02 cell (WBC) function in these zones, and bacterio-
cidal efficiency is further improved under short-
term hyperoxia. These observations have been
made in animal experiments with normobaric hy-
peroxia (0.45 ATA) for soft tissue infections with
Pseudomonas aerugenosa or Staphylococcus au-
reus [25,26] and with HBO in osteomyelitis caused
by P. aerugenosa or S. aureus [7,27]. In both forms
of infection, brief (1.5 h) exposures to elevated Po?
caused significant changes in the outcome. In the
osteomyelitis model, HBO, but not 1 ATA 0, venti-
lation, improved tissue P02- In the soft tissue model
in which vascular integrity was apparently less se-
verely compromised, tissue Po, increased from near-
ly zero (infected, air breathing animal) to approx-
imately 60 mm Hg when breathing 40% O2 [25].
Why brief exposures to increased Po, should
have long-lasting benefits is problematic. The an-
swer lies most likely with an assessment of tissue
responses to infection. Regarding the soft tissue in-
fection model, it was hypothesized that Oz im-
proved WBC response so that bacteria were re-
moved before there was irreversible damage to
capillary endothelium (caused by both bacteria and
metabolic products of PMN). Regarding osteomy-
elitis and HBO, the effect may relate to improved
PMN bacteriocidal efficiency and possibly to a con-
comitant benefit related to capillary ingrowth (neo-
vascularization) that can be precipitated by HBO in
hypovascular tissue.
Hyperbaric oxygen’s ability to alter host re-
sponses to infection also extends to rather fulmi-
nate processes, such as sepsis [28,29]. It.has been
shown experimentally that intermittent HBO, if ad-
ministered quickly, can significantly improve out-
come [30-32]. However, the mechanisms have not
been identified, and at this juncture observations
are of theoretical interest. In a relatively recent re-
port on HBO in sepsis, benefit was shown in 2
separate rat models, and the effects could not be
related to a direct antibacterial action [32].
Wound Healing. Zones of hypoxia occur in virtually
all wounds, and the P02 may be only 3 mm Hg 120

,....m from the nearest capillary [33]. There is a well-
recognized paradox associated with 02 and wound
healing: Although 02 is required by regenerating
cells, hypoxic conditions and a high lactate concen-
tration (anaerobic metabolism) are also required
for healing [34]. The macrophage secretes an an-
giogenesis factor when hypoxic, as well as when an
environment of high lactate concentration exists
[35].
Intermittent exposure to HBO has been shown
to enhance the rate of healing in animal models
[36-38]. The condition of the compromised wound
(e.g., poor peripheral vasculature) is most perti-
nent to clinical situations when healing has not oc-
curred with aggressive, standard measures. There is
evidence that these wounds are often hypoxic
[39,40]. Ventilation with 100% 0, at 1 ATA causes a
negligible increase in the tissue 02 concentration,
whereas HBO raises Oz concentrations to several
hundred mm Hg [39,40]. Studies have been con-
ducted with patients who received HBO daily for
1.5 to 2 hours. Progressive improvements that per-
sist after the hyperoxic exposure have been noted
when wound P02 is monitored on a daily basis.
These changes have been shown to reflect angio-
genesis [39,41].].
The biochemical mechanism for this effect is not
entirely clear. It is known that only intermittent
HBO exposure, with lapses of time to breathe air, is
effective. Hypoxic conditions must exist in the
wound for intervals of time. Intermittent HBO does
not markedly change wound lactate concentration
(approximately 5-15 mM), which is fortuitous be-
cause collagen synthesis by fibroblasts is improved
at these relatively high lactate levels [42]. Increasing
P02 in the tissues, however, improves collagen syn-
thesis by fibroblasts [34,43].
Hyperbaric oxygen has been shown to induce
angiogenesis in irradiated tissues in humans over a
course of 20
daily treatments. This change has led
to meaningful improvements in the treatment of
radiation necrosis [41,44-49]. The mechanism for
this benefit is thought to involve 02 stimulation of
fibroblast collagen synthesis leading to improved
capillary ingrowth. In a recent animal study (Marx
RE. Unpublished observations), soft and bony tis-
sue was shown to be hypovascular six months after
irradiation (6,000 rads) because of the obliterative
radiation endarteritis. After the injury was estab-
lished, animals were randomly assigned to either a
control group or a group treated with 1 ATA 02 or
2.4 ATA 02 for 90 minutes 20 times over 4 weeks.
After completion of treatment, angiogenesis could
be clearly documented in the HBO group but not
in either the control or the 1 ATA 02 group.
Clinical studies have demonstrated what may be
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61
an additional part of the mechanism for this phe-
nomenon. The pattern, or gradient, of tissue Po2 in
irradiated wounds has been found to change from
being relatively shallow across the radius of the
irradiated bed (approximately 10-20 mm Hg differ-
ence from center to periphery) to a steep gradient
of about 230 mm Hg while under HBO [50]. Al-
though the physiological impact associated with
this change has not been fully elucidated, it is rec-
ognized that &dquo;normal&dquo; wounds have a steep 02 gra-
dient that in some way mediates the release of mac-
rophage angiogenic factor [51,52].
Clinical Use of Hyperbaric Oxygen
Clostridial Myonecrosis. Boerema and Brummel-
kamp introduced HBO for the treatment of gas gan-
grene in 1960, and the group in Amsterdam con-
tinues to lead the world in experience with this
condition [2,53]. The risk of death or major tissue
loss from clostridial myonecrosis depends on a
number of variables. Elderly, debilitated, or com-
promised patients are at greater risk, as are those in
whom the diagnosis is delayed. Patients with trun-
cal involvement who present already manifesting
evidence of severe systemic toxemia (e.g., shock,
hemolysis, severe alterations in mental status) also
have a worse prognosis [54-56].
Clostridial myonecrosis is relatively uncommon;
there may be 1,200 cases each year in the United
States [57]. This fact, coupled with the variables that
influence prognosis, has made an assessment of ef-
ficacy of therapeutic measures difficult. Several case
reports largely discount the clinical experiences
with HBO [58,59]. The only treatment protocol that
has been examined in any detail, however, has
been the triple approach: combined use of surgical
procedures, antibiotics, and HBO, which when
combined result in greater survival in animal ex-
perimentation than the use of any 2 methods [23].
Because the clinical outcome is so heavily influ-
enced by incubation time before diagnosis, this
animal study seems particularly valuable. Clinical
reports involving all 3 methods describe improved
tissue salvage and an overall mortality of 16 % (1211
of 744 patients). Deaths were almost exclusively
among those who presented in extremis and with
truncal involvement [53,57,60-67]. When attempt-
ing to assess the therapeutic efficacy of HBO from
these reports, the proportion of high risk patients is
obviously important. Similarly low mortality (15%
or less) without the use of HBO has only been
reported with experiences principally involving ex-
tremity gas gangrene that is treated promptly and in
the absence of severe toxemia [68-70].
 62
Once the diagnosis of clostridial myonecrosis is
suspected, the therapeutic approach that has most
often been advocated is to institute medical treat-
ment, including fluid resuscitation plus antibiotics
(penicillin, aminoglycoside, and clindamycin-in
50% of cases cultures grow other organisms in ad-
dition to clostridia) and to arrange for transport for
HBO therapy [64-67]. At the institution with the
hyperbaric chamber, a decision should be made as
to when surgery should be performed. The first
’ hyperbaric treatment (2.5 to 3 ATA 02 for 90 min-
utes) is often performed while the operating room
is being prepared. Once the operating room is
ready, even if the treatment is not over, the patient
can be decompressed and taken for a very limited
surgical debridement of nonviable tissue. Hyper-
baric oxygen treatments are typically performed at
8-hour intervals for the first 48 hours and then at
12-hour intervals. Usually only 3 to 4 days of treat-
ment are necessary. Throughout this period inten-
sive care should involve invasive monitoring; fluid,
antibiotics, and blood infusion; and careful obser-
vation of electrolyte activity. Hyperkalemia is a
common problem early in the clinical course when
hemolysis is present.
There is no published account of an
experience using therapeutic regimens other than
that described [64-67]. The only com-
previously
parisons of treatment protocols has been in several
that describe clinical results in medical cen-
reports
ters before and after HBO was available; tissue loss
and mortality are described as being decreased
with adjunctive HBO therapy [56,71,72].].
Soft Tissue Infections. Infections typi-
Necrotizing
cally lead to local hvpoxia [73], and in the case of
necrotizing infections this is exaggerated by what
seems to be an infection-induced occlusive endar-
teritis [74]. Because bacteriocidal efficiency of PMN
is diminished in this setting, a cycle of advancing
infection, ischemia, and further compromise in
host defenses is established. Hyperbaric oxygen has
been considered to possibly block this cycle.
The flora found in most necrotizing infections
include facultative and anaerobic bacteria. Al-
though it is difficult to prove rigorously, it is be-
lieved that the clinical condition arises because of a
synergistic action among these organisms. Specific
combinations of bacteria were described in some
early reports (e.g., in Meleney’s ulcer, anaerobic
streptococci with Staphylococcus aureus), but this
is no longer seen [75,76]. Animal models of syner-
gistic, mixed infections are lacking, and hence
neither pathophysiology nor therapy have been rig-
orously studied. These infections are usually ag-
gressively treated with antibiotics and surgery. A
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characteristic among the reports involving HBO is
that this treatment is adjunctive only. Until more
definitive study is done, the only justifiable motive
for considering HBO for mixed infections relates to
the relatively high morbidity and mortality that is
associated with these disease states.
There is some confusion regarding the clinical
classification of mixed soft-tissue infections, and
this has caused difficulty in assessing patient risk
and appropriate treatment. Hyperbaric oxygen
therapy has been used in a number of cases that
seem to fit the diagnoses of acute dermal gangrene,
necrotizing fasciitis, or anaerobic myonecrosis.
ACUTE DERMAL GANGRENE. Mixed flora infection lead-
ing to cutaneous ulceration (but sparing the deep
fascia) will for the sake of this review be described
as acute dermal gangrene. Several reports provide
full descriptions of the condition [77,78]. Generally
the infection involves a centrifugal advancement of
skin and subcutaneous tissue necrosis at the site of
an injury or spontaneous skin ulcer. The condition
of the patient on presentation can be quite variable
and may largely depend on the severity of the un-
derlying immunocompromise or systemic disease.
Predisposing disorders, most commonly diabetes
extensive
mellitus, are described in up to 75% of patients
[77]. The infection may remain indolent for an un-
determined time and then flair with a fulminate
systemic manifestation (e.g., sepsis). It is difficult to
obtain a clear assessment of a patient’s risk, how-
ever, because not all series have made distinctions
pertaining to the presence of underlying illness.
Mortality rates as high as 76% have been reported
[77-79].
The first organized description of treatment for
dermal gangrene in 1975, when
acute was Leding-
ham [78] reported on 8 patients. Five patients sur-
vived, and it was the author’s opinion that clinical
improvement could be correlated with the initia-
tion of HBO therapy [78]. There were three reports
involving HBO prior to 1975. In one report of 2
patients, HBO was felt to be beneficial; in two re-
ports, each of a single patient, benefit was consid-
ered equivocal [80-82]. The most recent and larg-
est experience reported with HBO treatment of
acute dermal gangrene has been by Bakker [83].
Hyperbaric oxygen was believed to improve clini-
cal status in all 19 patients, but 2 ultimately died.
The author was careful to point out that HBO was
an adjunctive treatment and did not replace other
treatment measures. In patients with slowly pro-
gressing infection for which standard measures had
failed, however, treatment was recommended.
NECROTIZING FASCims. Necrotizing fasciitis is charac-
terized by widespread fascial necrosis that, at least

initially, spares the overlying skin and underlying
muscle. Infections typically follow some form of
local trauma, and there is no specific bacteriolog-
ical characterization [75]. Mortality averages ap-
proximately 38% among reported series, and risk is
directly related to a delay in diagnosis. Risk is also
greater among patients over age 50 who have pre-
existing disease and when the trunk (versus ex-
tremities) is involved [78,79,84-87].
The relative rarity of necrotizing fasciitis, in addi-
tion to the clinical variables that alter patient risk,
has made the assessment of any single therapeutic
intervention difficult. Again, reports involving HBO
all show that patients were treated first with antibi-
otics and surgery, and benefit with HBO was based
on a failure to respond to conventional measures.
There has been a general view that HBO is benefi-
cial [83,88-90], although this was not shared among
all investigators [53,78]. The benefit of HBO was
viewed as more obvious in acute dermal gangrene
than in necrotizing fasciitis among reports describ-
ing experiences with both conditions [78-83].
Fournier’s gangrene is a form of necrotizing fas-
ciitis that arises in the penoscrotal or vulvar region;
there have been a number of recent reports that
suggest benefit with the adjunctive use of HBO [91-
93].].
ANAEROBIC MYONECROSIS, The form of anaerobic
myonecrosis that frequently is clostri-
occurs most
dial gas gangrene, which has already been dis-
cussed. Experience with myonecrosis arising from
mixed flora with anaerobes other than clostridia is
very To our knowledge, only 2 cases involving
rare.
HBO therapy have been discussed in the literature
[94]. Although the opinion was favorable regarding
the use of HBO, clearly the experience with this
condition is so small that no assessment of a spe-
cific therapeutic regimen can be made.
Chronic Refractory Osteomyelitis. There is consid-
erable variation of opinion regarding the treatment
of refractory osteomyelitis that is separate from any
specific discussion concerning HBO. The patients
in whom HBO has been recommended are those
who have failed standard surgical and antibiotic
therapy [3]. The clinical reality among this sub-
group, however, is the difficulty in assessing the
adequacy of standard treatment in each particular
case (e.g., duration of parenteral antibiotics, failure
to remove all sequestra). Surgical debridement,
with extirpation of all involved bone as well as dead
space obliteration, plus antibiotic treatment is con-
sidered to be the standard treatment.
There has been no prospective, randomized
study performed to assess the efficacy of any treat-
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63
ment in osteomyelitis. Therefore, an assessment of
the benefit of any form of treatment for refractory
osteomyelitis must be based on &dquo;open&dquo; reports, in
which efficacy has been assessed based on resolu-
tion of disease with a particular intervention when
previous therapies have failed. To assess the rela-
tive merits of HBO, reports on other forms of treat-
ment must be considered. Animal studies have
been used to evaluate treatment with vessel bearing
flaps [95,96], several antibiotic regimens [97-100],
and HBO [7,101,102].
Most typically, patients who can be considered to
be suffering from chronic refractory osteomyelitis
are those who have had persistent infection for
more than 6 weeks that have failed to heal despite
at least one surgical procedure to remove grossly
infected bone, and at least initial treatment with
parenteral antibiotics. This description is decep-
tively simple. For the most part, the definition of
chronic osteomyelitis extends beyond any specific
time interval and is more accurately a pathological
classification of infected bone within a fibrous en-
velope. As the vascular supply to the infected bone
becomes compromised over time, necrosis occurs
and a sequestrum forms. Appropriate treatment
must be based on an assessment of these character-
istics, the overall health of a patient, and the func-
tional significance of the infection [103].
Treatment of chronic osteomyelitis with surgical
procedures and antibiotics is extremely effective.
Damholt [104] reported a 98% success rate in 55
patients treated with &dquo;aggressive&dquo; operations and
antibiotics. Sacks and associates [105) reported 97%
success among 13 patients treated with the Papi-
neau protocol. May and co-workers [106] reported
100% success among 35 patients using a microvas-
cular free-muscle flap, with a 46% incidence of rela-
tively minor operative complications. Ruttle and
colleagues [107] and Fitzgerald and associates [108]]
reported on the same 42 patients treated with mus-
cle flaps and described a 93% success rate. How-
ever, 26 of the 42 patients suffered some form of
postoperative complication, which is evidence of
the difficulties sometimes associated with treating
these complex cases. Because surgical and antibi-
otic therapy result in high rates of resolution, HBO
use is not advocated in patients with chronic os-
teomyelitis [3]. This view is reinforced in a recent
article by Esterhai and colleagues [109]. In this ret-
rospective report, 13 of 14 patients (93%) treated
with antibiotics and surgery exhibited resolution of
their infection, a finding consistent with other se-
ries on chronic osteomyelitis; 11 of 14 patients
(79%) treated with HBO, antibiotics, and surgery
showed healing. The patients in both groups that
failed to respond were described by the authors as
64
having had inadequate surgery during which
crotic, infected bone was, for various reasons,
fully debrided.
In refractory osteomyelitis, when surgical and an-
tibiotic therapy fail to resolve the infection, the suc-
cess rate with further operation and antibiotic treat-
ment is relatively low. Several of the reports in this
category reflect a substantial clinical experience. In
1970, West and co-workers [110] reported a 65%
success rate among 186 patients treated at the Mayo
Clinic. In that same year, Kelly and associates [ 111 ]
reported on 42 patients; 80% of the infections were
resolved with multiple operations, antibiotics, and
closed drainage and suction. In a report that re-
flects the risk associated with mixed flora chronic
refractory osteomyelitis, Hall and colleagues [112]
described an overall success rate of 80% among
182 patients, but only 38.5% success when consid-
ering patients with mixed infections. Ger [113] and
Weiland and co-workers [114] described the effi-
cacy of muscle flap treatment as being 66% (6 of 9)
and 76% (25 of 33), respectively. Complications in
these series were rather severe: In one report [1131]
8 of 9 patients had postoperative complications,
and in the other study [114], 44% of flaps failed
and were associated with sepsis. Complications oc-
curred almost exclusively among patients with seg-
mental bone defects.
Success rates with the use of HBO in chronic
refractory osteomyelitis have varied somewhat
since the first reported use in 1966 [115]. Not all
patients in early series received surgical debride-
ments, and success was reported in 63 and 71%
[116,117]. Higher success rates (85% or better)
have been reported with appropriate surgical de-
bridements, antibiotics, and adjunctive HBO ther-
apy [118,119]. Long-term follow-up (mean, 8.4
years) of the patients in one of these series has
revealed 75% resolution [120]. A 90% success rate
has recently been reported among 38 patients who
were followed for 24 to 59 months [121]. In this
series, 18 patients received bone grafts, all of which
healed, and the patients suffered no postoperative
complications. Muscle flaps were used in 4 patients;
all did well initially, but two ultimately suffered re-
currences. The authors outlined the subgroup of
patients for whom HBO may be considered, as well
as a therapeutic regimen involving, on average, 48
HBO treatments [121].].
It is believed, based on animal studies, that the
benefit of HBO therapy lies in its ability to improve
white blood cell function in the relatively hypoxic
areas of residual infected bone, and possibly to im-
prove angiogenesis based on mechanisms outlined
for wound healing. Current clinical data suggest
that the odds of success with adjunctive HBO ther-
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ne- apy are at least as good as those found among re-
not ports of chronic refractory osteomyelitis treatment
using ablative operations and flaps. Because of the
relatively high incidence of complications associ-
ated with these aggressive techniques, further con-
sideration of HBO is merited. Enthusiasm for HBO
must be tempered, of course, by the knowledge
that its use does not abrogate the need for antibi-
otics, surgical debridement, and management of
any dead space. Therefore, issues of cost-effective-
ness must also be a factor. Some reports suggest
that with HBO hospitalizations are shorter, which
would very favorably influence costs. Several brief
assessments of these issues have been presented
[120,122,123].].
Compromised Wound Treatment. Hyperbaric oxy-
gen has been suggested as a therapy for patients
with radiation necrosis and for some patients with a
variety of refractory wounds associated with small
vessel, peripheral vascular disease [3]. There is a
considerable body of data on the efficacy of HBO in
irradiated tissue and a small amount of data in
other conditions.
RADIATION INJURY. After radiation exposure and im-
mediate cell damage, a late tissue injury evolves
that can be related to a progressive loss of micro-
vasculature. In a subset of patients that undergo
radiation therapy, the extent of this late injury can
cause either spontaneous or postoperative soft-
tissue breakdown and bone fractures [124]. The in-
cidence of these complications is dependent on a
number of variables. Radiation therapy for all can-
cers has been estimated to lead to osteoradionecro-
sis in approximately 3 to 10% of patients [125-127].
There are now numerous reports that describe
the benefit of HBO in the treatment of osteoradio-
necrosis of the mandible (41,44-48,127-129). Marx
and associates [124] have studied the pathophysiol-
ogy of the disease extensively, and they recently
published a review of their clinical findings in
which they describe a standardized protocol for
treatment involving surgery, antibiotics, and HBO.
The most recent study using this protocol reported
100% success in the treatment of 268 patients [50],
which contrasts sharply with the 20 to 65% success
rate reported without adjunctive HBO therapy
[130,131]. Improved healing and a reduction in
posttraumatic osteoradionecrosis has been con-
firmed in a prospective randomized study [49]. The
cost-effectiveness of prophylactic HBO in high-risk
patients has been shown, with a savings of nearly
$40,000 for each patient [49]. Success with HBO
treatment has also been reported anecdotally with

other forms of radiation injury that were refractory
to surgical and medical treatment [127,132-135].
REFRACTORY CUTANEOUS ULCERATION CAUSED BY SMALL
VESSEL DISEASE. A small prospective study reported
benefit with HBO therapy in treating severe foot
wounds in diabetic patients [136]. Encouraging,
anecdotal information has been reported in several
refractory ulcer conditions (e.g., diabetic feet, auto-
immune-vasculitis, pyoderma gangrenosum [137-
142]. Further research in these areas is necessary.
Treatment of Compromised Flaps and Grafts.
When there is a clinical assessment that a skin graft
or flap is at risk of failing, adjunctive HBO treatment
has been recommended [3]. Flaps in which per-
fusion is compromised have been shown to be
hypoxic [143] and at greater risk of developing
necrotizing infection [95,144]. Improved tissue
oxygenation and increased flap capillary density oc-
curs in response to HBO [145,146], and improved
survival has been reported in a number of animal
studies of compromised flaps and grafts [147-154].
Several experimental studies failed to document a
benefit, but there were obvious procedural flaws.
In [155], HBO had no benefit when circulation
one
had ceased completely. The most recent study re-
ported no benefit using a toxic HBO protocol in a
small group of pigs (4 control, 3 experimental) in
which multiple flaps had been raised (not indepen-
dent samples) [156].
A beneficial effect of HBO has been described in
a number of clinical reports, although no ran-
domized study has been performed [157-160]. A
randomized analysis attempt involving HBO in skin
grafts was published in 1967 [161]. In this report,
patients were randomly assigned to receive HBO
after grafting. A statistically significant benefit was
described, but the failure rate in the control group
was extraordinarily high. Additionally, the use of
HBO in what may be considered a &dquo;normal&dquo; skin
grafting situation (e.g., no evidence of compro-
mised healing) is not supported by the available
literature.
There is a need for a controlled study of treat-
ment of compromised flaps and grafts. The assess-
ment that a skin graft or myocutaneous flap is
&dquo;compromised&dquo; is a qualitative clinical judgment,
which adds to the difficulty in establishing properly
controlled studies and tends to increase the reli-
ance on animal research using models of flaps or
grafts designed to have a high failure rate.
Crush and Acute Peripheral Ischemia. From
mechanistic perspective, it has been considered
that by using HBO to improve 02 delivery through
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65
compromised vasculature, cell viability may be in-
creased in areas of marginal perfusion. The obvious
problem with this view is that although 02 may be
delivered for the 90 minutes to 2 hours that a pa-
tient is receiving HBO therapy, there are many
hours between treatments during which the tissues
would become hypoxic. Nonetheless, favorable re-
ports involving HBO have appeared [162-168]. Re-
sults of several animal models indicate that the bio-
chemical effects of HBO may extend considerably
beyond a short-term improvement in 02 supply
[10-12,169,170].
Clinical experience with HBO in crush injuries
has recently been reviewed by Strauss and Hart
[171]. A review of the literature offers two principal
insights: First, clinical experience is generally favor-
able, with the opinion that HBO may benefit 57%
(53 of 93) of patients reported in English language
articles; and second, there is an extensive experi-
ence involving HBO outside of English-speaking
countries, with a reported experience with 634
crush injuries as of 1984.
Two animal models have been used to assess the
effects of HBO in peripheral ischemia. Strauss and
colleagues [10] and Skyhar and co-workers [11]
have published several papers using a model of the
compartment syndrome in the dog hind limb. They
demonstrated that the timely use of HBO can sig-
nificantly reduce muscle necrosis and edema, and
can improve muscle viability. They also demon-
strated that the intracompartmental pressures re-
quired to induce muscle necrosis are markedly re-
duced in the face of hemorrhagic hypotension, and
that HBO could be shown to significantly improve
muscle viability.
In a model of temporary limb ischemia in the
rat (e.g., ischemia-reperfusion injury), HBO was
shown to reduce postischemic edema [12]. In fol-
low-up studies [169,170] of the metabolic effects
associated with HBO, the use of a single treatment
resulted in significantly improved cellular adeno-
sine triphosphate and phosphocreatine levels and a
lower concentration of lactate. When the study was
extended 12 hours following the standard 3-hour
ischemic insult, the benefit with 3 interspersed
HBO exposures was found to persist for at least 4
hours after the last treatment. The indication, there-
fore, is that the benefit of HBO is not merely due to
02 delivery through compromised vasculature.
The nature of theunderlying insult in postisch-
emic injury is currently under extensive study. With
the view that 02 radical generation and oxidative
injury are the basis of reperfusion phenomena
a [172], one would predict that HBO may exacerbate
the postischemic injury. Recent biochemical evi-
dence indicates, however, that there are situations
66
where O2 can paradoxically antagonize oxidative
injury [173; Thom SR. Unpublished observation,
1988]. Further research is necessary to both eluci-
date the in vivo biochemical effects of HBO and
verify the benefits noted in clinical reports.
Carbon Monoxide Poisoning. It is estimated that
carbon monoxide (CO) is the leading cause of
death by poisoning in the United States. The actual
number of cases is very difficult to ascertain, how-
ever, because the diagnosis can be difficult unless
the index of suspicion is high. It has been shown
that up to 30% of cases may be undiagnosed [174].
Approximately 40% of smoke inhalation victims
die as a result of CO poisoning (approximately
4,800 people), and there are 3,800 or more persons
who die because of faulty indoor heaters or auto-
mobile exhaust [175,176].J.
The morbidity associated with carbon monoxide
poisoning can be quite serious. Neurological dete-
rioration can occur after any form of ischemic-
hypoxic brain insult, but the incidence following
CO poisoning seems to be particularly high. Ani-
mal studies suggest that this may be due to the
propensity of CO to produce a dual cerebral insult:
hypoxia from carboxyhemoglobin (COHgb) and a
concomitant ischemic insult (probably due to
carboxymyoglobin mediated cardiac dysfunction)
[177-179]. Sequelae may manifest from 3 days to 4
weeks after apparent recovery from acute poison-
ing. In a large retrospective survey, Shillito and as-
sociates [180] reported an 0.8% incidence of de-
layed neurological sequelae. More recent studies
involving quantitative estimations of neurological
function have indicated that the incidence may be
10 to 40% among patients who suffer more than
nominal exposure [181-184]. Risk is greatest
among patients over the age of 60, those who have
prior cardiovascular disease, and individuals who
have suffered an interval of unconsciousness. It ap-
pears that the longer the coma, the greater the risk,
but any history of unconsciousness is associated
with an increased risk. It is important to stress that
while the COHgb level may be loosely associated
with symptomatology, this association has only
been demonstrated with nominal symptoms such
as nausea, vomiting, and headache [185-187].
Supplemental oxygen inhalation is a cornerstone
in the treatment of CO poisoning. Carboxyhemo-
globin dissociation is hastened by an elevation in
the oxygen partial pressure (Table 3). Although re-
cent reports [188; Thom SR. Unpublished observa-
tions, 1988] suggest that the mechanism of HBO
may extend beyond its effect on COHgb, it is due to
the reduction in COHgb half-life that HBO has been
recommended and used to treat severe CO poison-
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Table 3. Carboxyhemoglobin Half-life with
Increasing Oxygen Pressure
to
ing for more than 25 years. Controlled clinical stud-
ies are lacking, but there are a number of reports
that describe a reversal of severe neurological and
cardiovascular depression in temporal relationship
with institution of HBO [189-192]. The results of a
relatively large retrospective study indicate that
prompt administration of HBO can reduce mortal-
ity (13% when HBO is administered within 6 hours
of patient discovery versus 30% if administered
’ later) [189]. Several recent reports have indicated
that prompt administration of HBO may reduce the
incidence of delayed neurological sequelae to 0 to
4% [193-195].
It has been hypothesized that some aspects of CO
poisoning may be due to an &dquo;ischemia-reperfu-
sion&dquo; injury, and brain lipid peroxidation has been
described in a recent animal study [188]. Oxygen
treatment was studied in this model and HBO (3
ATA) but not 100% oxygen treatment (1 ATA) was
shown to be effective in preventing lipid peroxida-
tion. The effect of the HBO was not caused by a
hastened COHgb dissociation. Although the effect
is paradoxical on initial consideration, it appears
that the biochemical mechanism may be related to
an 02, or more specifically H202, mediated antago-
nism of the propagation of lipid peroxidation [188;
Thom SR Unpublished observation, 1988]. Antago-
nism of lipid peroxidation by H202 has been noted
in a number of earlier reports [196-199].
Arterial Gas Embolism. Arterial gas embolism can
affect any organ. By virtue of brain blood flow and
function, and possibly because of the buoyancy of
bubbles, most clinical reports and experimental
studies have been devoted to cerebral gas embo-
lism. Although cerebral embolism will be specifi-
cally discussed, aspects of pathophysiology and
treatment can be applied to other organs. The clini-
cal presentation of cerebral gas embolism is pro-
tean, and many attempts have been made to classify
the varied presentations [200]. Coma and unilateral
motor and sensory changes are most common. It is
not uncommon for patients to show some degree
of spontaneous improvement following emboliza-
tion. These improvements are not always sustained,
however, and should never delay the institution
of definitive, recompression therapy. Cerebral gas

embolism can arise from pulmonary over-pressuri-
zation injuries associated with compressed air ven-
tilation (e.g., scuba diving) and when the integrity
of the vasculature, venous or arterial, is violated
(e.g., as a result of trauma and iatrogenic methods).
The efficacy of HBO in cerebral gas embolism
has been assessed in animal studies, and the major-
ity of clinical experience has been reported in asso-
ciation with military activities such as submarine
escape training [201-207]. The mechanism of ac-
tion relates to several effects, the first of which is
based on Boyle’s law. Vascular occlusion can be
reduced by decreasing the volume of the offending
bubbles with increased pressure. The increased P02
associated with HBO therapy may improve 02 de-
livery to hypoperfused tissue as a result of in-
creased diffusion of 02 from functional capillaries.
There may also be some benefit because of HBO-
associated vasoconstriction, which may decrease
the cerebral edema that sometimes accompanies
these vascular insults [208-210]. Treatment that
must be stressed, because it is a component of ini-
tial management, is ventilation with 100% O2,
which reduces inert gas concentration in plasma.
Bubble size will then decrease as a result of the
enhanced diffusion of inert gas from the bubble to
the plasma.
Delay in between embolization and HBO treat-
ment worsens prognosis, because of the ongoing
ischemic process and also because over time, sev-
eral processes tend to stabilize bubbles and cause
a solid, fixed intravasculature occlusion. Bubbles
tend to coalesce and become encased in a deposit
of platelets, plasma-derived lipid material, and
fibrin [211]. These secondary events may begin
within 5 minutes of embolization [212]. Despite lo-
gistical issues that delay initiation of HBO, success
may still occur when recompression is carried out.
Published experience in this setting is not exten-
sive, but it appears that prognosis remains rather
good if therapy is instituted within 5 hours of em-
bolization. Rare reports of success have been de-
scribed even with delays of 24 hours or more [213].
Decompression Sickness. Decompression sickness
is a multisystem disorder that is caused by a rapid
reduction in environmental pressure; the condition
occurs among deep sea divers and high altitude
aviators. Pathogenesis is due to liberation of dis-
solved inert gas on decompression and the forma-
tion of bubbles in blood and body tissues. Symp-
toms arise because of both local ischemia and
inflammation triggered at the blood-bubble inter-
phase [214]. Musculoskeletal pain and neurological
dysfunction (most often related to the spinal cord)
are the common complaints. The pattern and sever-
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67
ity of symptoms is highly variable. The most impor-
tant clue is recent decompression. Ninety percent
of patients will suffer an onset of symptoms within
12 hours of decompression, although in 1 to 2% of
patients, symptoms may not be manifested until af-
ter 24 hours [215,216].
The mechanism for HBO benefit in decompres-
sion sickness is analogous to that described for gas
embolism. Again, the greatest clinical experience
has been reported in association with military activ-
ities [217]. Animal experimentation has focused on
aspects of pathophysiology, with some research on
comparisons of HBO protocols [218]. Emergency
treatment includes intravenous hydration, ventila-
tion with 100% O2, and rapid transport for HBO
therapy. As with gas embolism, the odds for suc-
cessful treatment diminish with time. On rare occa-
sions, however, recompression therapy has been
effective even if delayed 7 to 9 days [219,220J.
Thermal Burns. An investigation of the effects of
HBO on burns followed the clinical observations of
Wada and associates [221] on the faster healing
among burned miners who were actually treated
for CO poisoning. Since then there have been a
number of animal studies that have shown that
HBO leads to a reduction in fluid requirements,
improved microcirculation, reduction in edema
and inflammatory reaction, less conversion of par-
tial to full-thickness injury, and faster epitheliali-
zation [222-224]. Clinical experiences include a
small randomized, double-blinded study that doc-
umented a reduction in fluid requirement, faster
healing, fewer complications, and improved sur-
vival [225]. Clinical experiences reported in uncon-
trolled series also indicate benefit with HBO treat-
ment [226-228]. Waisbren and colleagues [229]
failed to document a salutary effect on survival with
HBO, but did report a reduction in the need for
grafting. In a recent study with matched popula-
tions, reduction in surgical procedures when HBO
was administered was noted in patients with 40 to
80% total body surface area burns [230]. A signifi-
cant reduction in length of hospital stay has been
identified in patients with smaller burn areas (i.e.,
18 to 39% ) [231].
Adverse Effects of HBO
The inherent toxicity of 02 must be addressed
when HBO is used therapeutically. Because of care-
ful administration the incidence of toxicity is re-
markably low, however, what must not be over-
looked when considering the use of HBO is the
ability of the clinical facility to also deliver proper
68
medical care. The sophistication present in many of
the hyperbaric chamber facilities today is largely
analogous to that of an intensive care unit. Equip-
ment is available for invasive cardiovascular moni-
toring, mechanical ventilation, cardiac pacing, and
intravenous infusion. It is perhaps worth stating
that HBO should never be considered unless
proper supportive medical care can be delivered.
The structural, fire, and operational safety of a
hyperbaric facility requires constant maintenance
but can be ensured with proper steps. Physical,
pressure-related effects onpatients are nominal,
and the risk of pulmonary overexpansion injuries is
minimized with controlled, slow rates of decom-
pression. Patients are not at risk of suffering decom-
pression sickness following standard treatment
protocols, because they breathe only pure 02. Sinus
and otic barotrauma are minimized with decon-
gestants ; on rare occasions myringotomies are re-
quired.
The human organ systems most susceptible to
the toxic effects of 02 are the lungs, brain, and eyes.
Pulmonary 02 toxicity has been studied extensively.
It is known that HBO (2 to 3 ATA) can impair
pulmonary mechanics (e.g., elasticity), vital capac-
ity, and gas exchange [232-235]. These changes are
observed, however, only when the duration of ex-
posure is well in excess of that used clinically. Al-
terations in pulmonary function in association with
standard, clinical use of HBO have not been ob-
served [236,237].
The most pronounced manifestation of central
nervous system 02 toxicity is a grand mal seizure.
Although unpredictable, some patients may exhibit
a prodrome, which includes muscle fasciculations,
narrowing of visual fields, nausea, vomiting, and
vertigo. Pathological changes in association with
isolated, 02-mediated seizures have not been found
in studies with guinea pigs, rabbits, or humans
[238]. The incidence of seizures caused by 02 toxic-
ity with use of current clinical HBO protocols is
approximately 1 in 10,000 patients [239,240].
The toxic effects of 02 on the eyes are most typi-
cally thought of in the context of retrolental fibro-
plasia (RLF). There is no report of RLF following
HBO treatment in young children, which may
merely reflect that this practice is uncommon. In-
termittent HBO treatments can cause myopia, usu-
ally among older patients treated for several weeks
(e.g., more than 30 treatments). This change has
been hypothesized to occur due to an alteration in
lens structure. HBO-induced myopia is virtually al-
ways temporary, and reversal occurs in approxi-
mately 6 weeks after termination of treatment [241].].
Full reversal may take 6 months or more in patients
undergoing protracted HBO treatments. Extraordi-
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narily prolonged treatment with HBO (more than
200 hours) has been linked with nuclear cataract
formation [242]. The mechanism for this effect has
not been identified. The risk associated with typical
exposures to HBO (virtually always less than 120
hours) appears to be quite low. A 6-month to 8-
year follow-up of 563 patients who received more
than 20 HBO treatments has been conducted by the
United States Air Force [239]. No chronic or late
effects were noted, and cataracts occurred in only 2
patients (an elderly patient on high-dose steroids
and a poorly controlled diabetic) [239].
Retinal changes have not been noted in associa-
tion with the therapeutic use of HBO. There are,
however, reports of retinal atrophy and retinal de-
tachment among patients exposed to prolonged
normobaric hyperoxia [243-245]. Retinal changes
have been noted in animal experiments involving
prolonged exposure to high pressure 02 (3 ATA
for 4 hours). The only report of severe visual im-
pairment in association with exposure to HBO has
been a temporary loss of vision in a volunteer for a
research project with a past history of retrobulbar
neuritis [246].
Conclusion
The fund of knowledge regarding HBO therapy is
growing. HBO treatment in air embolism and de-
compression sickness is accepted largely because
of an understanding of the therapeutic mechanism
of action. Improved clinical outcome with HBO has
been shown in controlled clinical studies involving
radiation necrosis and burns, and animal and other
basic research has elucidated therapeutic mecha-
nisms of action in a number of additional disease
states. Based on this research and comparative,
so-called externally controlled clinical data, HBO
treatment has been advocated for clostridial myo-
necrosis, some mixed infections, CO poisoning,
compromised grafts and flaps, a small subset of re-
fractory cutaneous ulcerations, crush injuries, and
chronic refractory osteomyelitis. The incidence of
many of these conditions is low in the population,
either because of intrinsic pathophysiological fac-
tors (e.g., gas gangrene), or because the conditions
only arise in a minority of patients for whom stan-
dard treatments fail (e.g., compromised grafts or
flaps, refractory osteomyelitis). More clinical and
basic research is necessary, and some controlled
trials are currently underway that will more clearly
determine the benefit of HBO treatment, as well as
allow a closer assessment of the pathophysiology of
the diseases being treated.
Many of the conditions treated with HBO lead to

lethal or disabled states. A pragmatic issue to be
confronted by clinicians, ’especially among practi-
tioners of intensive care who deal more regularly
with high risk states, is how to assess the data on
HBO that is available today. Bailar and co-workers
[247] have offered useful guidelines for assessing
the validity of conclusions drawn from externally
controlled trials. Five questions should be posed,
and an affirmative answer indicates stronger sup-
port for the conclusions. (1) Was the intervention
applied with the primary intent of affecting a pa-
tient’s outcome? (2) Is it clear that the authors in-
tended to analyze and report their findings before
generating the data? (3) Was there a plausible ra-
tionale for the interpretation of data before the re-
sults were analyzed? (4) Would the results be of
interest if they were different from the actual find-
Do the authors pre-
ings (e.g., negative results)? (5)
sent reasonable grounds for generalizing their re-
sults ? Answers to these questions in the context of
this review are obviously subjective. Nonetheless, it
appears that for of the reports examined, the
most
answers to questions 1, 3, 4, and 5 are yes. As for
question 2, the affirmative answer applies to some
but perhaps not all reports.
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