Pie diabetico y Oxigeno hiperbarico

MEDICINA HIPERBARICA
OXYMEDDIABETES CARE, VOLUME 23, NUMBER 10, OCTOBER 2000 1551
Although the clinical history of hyperbaric
medicine dates back to the 17th
century, reports of the beneficial
effects of increased oxygen pressure on
wound healing and infection did not appear
in the medical literature until the 1960s.
The most recent report by the Hyperbaric
Oxygen Therapy Committee of the Undersea
and Hyperbaric Medical Society (1) lists
several indications for hyperbaric oxygen
(HBO) therapy that are directly applicable
to lower-extremity pathology. These include
clostridial myonecrosis, acute traumatic
ischemia, enhancement of healing in problem
wounds, necrotizing soft tissue infections,
refractory osteomyelitis, compromised
skin grafts and flaps, and thermal
burns. Interestingly, there are relatively few
controlled clinical trials in human subjects
involving HBO for the treatment of these
conditions. In fact, the majority of published
reports on this topic consists of
review articles, case reports, uncontrolled
studies, and animal or in vitro studies.
Based on our experiences, we believe
that many clinicians routinely incorporate
HBO sessions into their treatment protocols
without full knowledge of the evidencebased
data that support this therapy. Anecdotally,
we have observed a tendency
among physicians to view HBO therapy as
a panacea for all types of nonhealing
wounds, particularly diabetic foot wounds.
This practice has been further complicated
by patient-oriented television and print
media campaigns that laud the benefits of
HBO therapy for nonhealing wounds.
Therefore, the purpose of this article is to
document peer-reviewed medical publications
that have reported on HBO therapy as
an adjunct to standard lower-extremity
wound care regimens in diabetic patients.
RESEARCH DESIGN AND
METHODS— A review of the medical
literature was conducted using PubMed,
the National Library of Medicine’s World
Wide Web–based MEDLINE search engine.
The following key phrases were entered in
the search engine to identify relevant articles:
“hyperbaric oxygen,” “wound healing,”
“diabetic foot,” “gas gangrene,” “chronic
osteomyelitis,” “necrotizing fasciitis,” and
“thermal burns.” In addition, the references
cited in the articles collected through the
MEDLINE search were reviewed to identify
other relevant publications.
Inclusion criteria for articles were as
follows: articles published in English, articles
from journals listed in Index Medicus,
articles describing scientific research of systemic
HBO as adjuvant therapy for either
wound healing or infection, review articles
describing the use of systemic HBO as
adjuvant therapy for either wound healing
or infection, and case reports describing the
use of systemic HBO for either wound healing
or infection. Articles were excluded if
they were not published in English or if
they were not directly applicable to lowerextremity
pathology.
Articles meeting the inclusion and
exclusion criteria were reviewed and placed
into one of three categories: reviews and
case reports, experimental animal or in
vitro studies, or human studies. A table
was constructed for the latter category to
list relevant data from each article. Furthermore,
research articles involving HBO
treatment and the diabetic foot were cri-
From the Diabetex Foot Care Center (R.P.W., L.A.L.), San Antonio, Texas; and the Vrieje University (E.J.G.P.),
Amsterdam, the Netherlands.
Address correspondence and reprint requests to Robert P. Wunderlich, Diabetex Foot Care Center, 1222
N. Main St., Suite 100, San Antonio, TX 78212. E-mail: robert@wunderlich.com.
Received for publication 7 April 2000 and accepted in revised form 6 July 2000.
Abbreviations: HBO, hyperbaric oxygen; TcPO2, transcutaneous partial pressure of oxygen.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion
factors for many substances.
Systemic Hyperbaric Oxygen Therapy
Lower-extremity wound healing and the diabetic foot
R E V I E W A R T I C L E
OBJECTIVE— To document peer-reviewed medical publications that have reported on
hyperbaric oxygen (HBO) therapy as an adjunct to standard lower-extremity wound care,
focusing on publications dealing with the diabetic foot.
RESEARCH DESIGN AND METHODS— A review of the medical literature was conducted
using MEDLINE. Research articles involving HBO treatment and the diabetic foot were
critiqued to identify factors that may have been a source of bias.
RESULTS— Of the published reports on human studies, seven involved diabetes-related foot
pathology. Five of these studies, two of which were randomized, included a control group that
did not receive HBO therapy. The controlled diabetic foot studies included an average of 28 subjects
in the HBO therapy group (range 10–62) and an average of 16.2 subjects in the non-HBO
control group (range 5–33). Most of the published reports have several potential sources of bias,
including, but not limited to, inadequate evaluation of comorbid conditions relevant to
wound healing, small sample size, and poor documentation of wound size or severity. Four of
the seven reports involving the diabetic foot were published by a group of researchers at the
University of Milan between 1987 and 1996.
CONCLUSIONS— Additional randomized placebo-controlled clinical trials in large diabetic
populations would further lend credence to the presumption that HBO therapy improves
clinical outcomes. Given the relatively high cost of this treatment modality, perhaps a more
acute awareness of the medical literature would reduce the economic burden that HBO therapy
imposes on care providers that are financially at risk.
Diabetes Care 23:1551–1555, 2000
ROBERT P. WUNDERLICH, DPM
EDGAR J.G. PETERS, MD
LAWRENCE A. LAVERY, DPM, MPH
R e v i e w s / C o m m e n t a r i e s / P o s i t i o n S t a t e m e n t s
1552 DIABETES CARE, VOLUME 23, NUMBER 10, OCTOBER 2000
Systemic HBO therapy
tiqued to identify factors that may have
been a source of bias. These factors
included, but were not limited to, lack of a
control group, inadequate sample size,
insufficient evaluation of comorbid conditions,
and poorly defined methods of retrospective
analysis.
RESULTS— A total of 76 articles were
identified that met the inclusion and exclusion
criteria. There were 21 studies involving
human subjects (2–22) (Table 1), 27
animal or in vitro studies (23–49), and 28
reviews and/or case reports (50–77). Of
the studies involving human subjects, 62%
(13 of 21 articles) included a control group.
Of the published reports of human studies,
seven involved diabetes-related foot pathology.
Five of these studies, two of which
were randomized, included a control group
that did not receive HBO therapy. The controlled
diabetic foot studies included an
average of 28 subjects in the HBO therapy
group (range 10–62) and 16.2 subjects in
the non-HBO control group (range 5–33).
Interestingly, four of the seven reports
involving the diabetic foot were published
by the same group of researchers at the
University of Milan between 1987 and
1996 (8,9,13,14).
CONCLUSIONS — Although HBO
therapy has gained popularity as an
adjunctive treatment for diabetic foot
wounds, there are surprisingly few published
reports that support its efficacy. Furthermore,
there seem to be no objective
measures to assist clinicians in appropriately
selecting patients for HBO therapy.
Our literature search revealed only two
reports of randomized controlled clinical
trials that evaluated HBO therapy in the
diabetic foot. Given the substantial cost
associated with these treatments, a more
thorough analysis of human studies dealing
with HBO therapy for the diabetic foot
is not only justified but necessary.
As previously indicated, more than half
of the published research reports dealing
with HBO therapy for diabetic foot disease
originated from a group of researchers at
the Center of Diabetology and Metabolic
Diseases, Niguarda Hospital, and the
Department of Anesthesia and Hyperbaric
Medicine, Galeassi Institute, Milan, Italy
(8,9,13,14). The first report published by
this group appeared in Diabetes Care in
1987 (9). This nonrandomized study
included 18 hospitalized diabetic subjects
and 10 diabetic control subjects. Of the 28
study subjects, 23 had gangrene of the foot
and 5 had neuropathic ulcers. Both groups
were treated with strict metabolic control
and daily wound debridement. The HBO
group had an average of 34 ± 21.8 HBO
treatments of 90 min/day at a pressure of
2.5–2.8 atm. At the conclusion of the study,
16 patients in the HBO group had healed
compared with only 1 patient in the control
group. Additionally, 2 patients in the HBO
group required an amputation compared
with 4 patients in the control group (P =
0.001). The report does not discuss any differences
in outcomes relative to potentially
confounding variables, such as vascular
disease, ulcer size and depth, or the presence
of infection.
The same group of researchers from
Milan published a second and identically
titled report in the Journal of Hyperbaric
Medicine in 1990 (13). The period of time
during which the study patients were
recruited (1982–1990) overlaps with the
period of their first report (1982–1984),
but the authors do not discuss whether
any study subjects were included in both
reports. Therefore, although the HBO
group consisted of 62 diabetic subjects and
the control group had 18 diabetic subjects,
it is unclear whether this larger sample size
does in fact represent a separate and distinct
study population. The report indicates
that there were no significant differences
in major diabetic complications, such
as peripheral vascular disease and peripheral
neuropathy. The authors did not discuss
the criteria for the operational definition
of peripheral vascular disease and did
not provide data on wound severity or the
presence of infection among the study subjects.
The patients in the HBO group
underwent an average of 72 ± 29 sessions.
The authors indicated that a pressure of 2.5
atm was used “as a reparative stimulus”
and that 2.8 atm was used “as antibacterial
support,” but there is no information on
how many treatments were given at each
pressure. Of the 62 patients in the HBO
group, 59 recovered without the need for
an amputation (compared with 18 and 12,
respectively, for the control group; P 
0.001). Again, the authors do not discuss
the effects of wound size, wound depth,
infection, or peripheral vascular disease on
clinical outcomes. Additionally, the study
would have benefited from having a larger
control group for comparison.
Oriani et al. (14) published a third
report on HBO therapy and the diabetic
foot in 1992. Again, the retrospective study
period overlaps with that of both previously
published reports, and, therefore, it is likely
that data from nearly half of the patients
included in this report had been published
previously. The report gives no information
on comorbid conditions, such as peripheral
vascular disease, hyperglycemia, or other
conditions that could adversely affect wound
healing. Additionally, they provide no information
regarding the average size and depth
of the wounds or the presence of infection.
There is no control group presented for
comparison. During the study period, 151
diabetic patients with “major ulceronecrotic
lesions of the lower extremities” underwent
an average of 40 HBO treatments; the conditions
of 130 patients healed, whereas the
conditions of 21 patients deteriorated. The
authors did not report any statistical analysis
of their outcomes. Clearly, this report
leaves many questions unanswered.
The most recent published report from
the group of researchers at the University of
Milan appeared in Diabetes Care in 1996
(8). In this report, the authors presented the
results of a prospective randomized clinical
trial, which included 35 subjects in the
HBO group and 33 subjects in the control
group. The control group did not receive
placebo sessions in a hyperbaric chamber at
normal atmospheric pressure, so it is
unknown whether a placebo effect exists for
this treatment modality. The authors report
significantly fewer major amputations
(below the knee or above the knee) for the
HBO group, but only among patients with
Wagner grade IV ulcers. There was no statistical
difference in minor amputations
between the HBO and control groups. Likewise,
no intergroup variation in major
amputations existed among patients with
Wagner grade II or III wounds. The results
of this well-designed study suggest that
HBO therapy may be helpful in reducing
major amputations among diabetic patients
with Wagner grade IV foot ulcers.
In 1991, Wattel et al. (10) published
the results of a noncontrolled study of HBO
therapy for diabetic foot lesions. Their
study consisted of 59 diabetic patients with
neuropathic or ischemic wounds who
underwent an average of 29 ± 19 HBO sessions
at 2.5 atm. Although the abstract of
the report indicated that 52 patients healed
and 7 patients underwent an amputation,
the report itself stated that 48 patients
healed and 11 eventually required an
amputation. The authors did not discuss
this apparent discrepancy in outcomes.
Additionally, there is no mention of differences
in many important variables, including
the level of glucose control, wound size
and depth, infection, or local wound care.
The authors did note, however, that the
group of patients who healed had significantly
higher transcutaneous oxygen
(TcPO2) measurements at the level of the
wound than the group of patients who did
not heal (taken at 2.5 atm O2). Therefore,
the authors conclude that TcPO2 measurements
may be useful in selecting patients
for adjunctive HBO therapy. However, one
must consider the numerous key variables
that were not mentioned in this report as a
potential source of bias.
In 1992, Doctor et al. (11) published
the results of a prospective randomized
controlled study of HBO therapy for diabetic
subjects with chronic foot lesions.
Thirty patients were randomized into either
a study group, which received conventional
treatment plus HBO sessions, or a control
group, which received conventional treatment
alone. There were no significant differences
in age, sex, duration of diabetes,
neuropathy, or the presence of distal pulses.
The report does not indicate whether a
more extensive examination was performed
to rule out peripheral vascular disease.
Additionally, there is no mention of wound
size or depth in either the study or the control
group. The study group received four
sessions of HBO therapy at a pressure of 3
atm for 45 min per session. Clearly, the
number of HBO sessions is significantly
fewer than those reported by others in the
medical literature, and the benefit of such a
small number of treatments is questionable.
The authors reported significantly
fewer major amputations in the HBO group
than the standard treatment group. However,
the report also indicated that “uncontrolled
diabetes” indicated the need of a
major amputation in five of the seven
patients who required the procedure. There
was no difference in the length of hospital
stay or the number of minor amputations
between the groups.
The most recently published prospective
study of HBO for diabetic foot wounds
appeared in 1997. Zamboni et al. (12) evaluated
HBO therapy for a group of 10 consecutive
insulin-dependent diabetic patients
with lower-extremity wounds. Five of these
patients refused HBO therapy and thus
served as a control group. The authors did
not record several variables that may have
affected wound healing, such as wound
depth, serum albumin, degree of glycemic
control, and the presence of anemia or other
general medical conditions detrimental to
wound healing. The HBO group underwent
five sessions per week of HBO therapy at 2.0
atm for a total of 30 treatments. The authors
did not mention whether measures were
taken to off-load ulcers located on the plantar
aspect of the foot. The results of this small
study indicate a greater reduction in wound
surface area in the HBO group over the
entire 7-week study. Additionally, none of
the patients in either the HBO group or the
control group underwent an amputation.
These results are encouraging; however, a
much larger study population is needed to
make any meaningful conclusions.
After critiquing the medical literature
that supports HBO therapy as an adjunctive
treatment for diabetic foot wounds, we
DIABETES CARE, VOLUME 23, NUMBER 10, OCTOBER 2000 1553
Wunderlich, Peters, and Lavery
Table 1—Studies involving human subjects that met the inclusion criteria
Average Dive % Healed Better
Type of HBO: number duration in HBO than
Reference study Randomized Controlled n control Condition of dives atm (min) group control
2 Retrospective NA No 38 NA Osteomyelitis* 48 2.4 90 89.5 NA
3 Retrospective NA No 44 NA Osteomyelitis† 50 2 120 68.0 NA
5 Prospective No Yes 28 1:1 Osteomyelitis‡ NR 2 120 86.0 No
4 Retrospective NA No 198 NA Necrotizing ST infection 31.7 2.4 90 76.8 NA
6 Retrospective NA No 24 NA Necrotizing ST infection§ 3 2.8 120 NR NA
7 Retrospective No Yes 43 0.2:1 Clostridial myositis NR NR NR NR No¶
16 Prospective Yes Yes 16 1:1 Chronic leg ulcers# 30 2.5 90 NR Yes**
18 Prospective No No 19 NA Varicose leg ulcers 30.35 2 120 89.5 NA
19 Retrospective No No 20 NA Chronic wounds†† 46 2.5 90 75.0 NA
17 Prospective Yes Yes 36 1:1 Crush injury 12 2.5 90 94.4 Yes
15 Prospective Yes Yes 48 1:1 STSG 3 2 120 84.2 Yes
22 Retrospective NA Yes 72 1:1 Severe burns‡‡ NR NR NR 38.9§§ No
21 Retrospective NA Yes 49 1:1 Severe burns NR 2.5 90 NR¶¶ Yes
20 Prospective Yes Yes 16 1:1 Severe burns## NR 2 90 NR*** Yes
8 Prospective Yes Yes 68 0.9:1 Diabetic foot ulcers 38 2.5 90 NR Yes†††
11 Prospective Yes Yes 30 1:1 Diabetic foot ulcers 4 3 45 NR Yes‡‡‡
13 Retrospective No Yes 80 3.4:1 Diabetic foot ulcers 72 2.5–2.8 NR 95.2 Yes§§§
14 Retrospective NA No 151 NA Diabetic foot ulcers 40 2.5–2.8 90 86.1 NA
12 Prospective No Yes 10 1:1 Diabetic foot ulcers 30 2 120 80.0 No
9 Prospective No Yes 28 1.8:1 Diabetic ulcers/gangrene 34 2.5–2.8 90 88.9 Yes
10 Retrospective NA No 59 NA Diabetic ulcers/gangrene 29 2.5 90 81.4 NA
NA, not applicable; NR, not reported; ST, soft tissue; STSG, split-thickness skin graft. *Chronic and nonhematogenous; †spinal cord injury patients; ‡chronic and refractory;
§clostridial myonecrosis or necrotizing fasciitis; overall mortality 25%; ¶fewer deaths in HBO group; #nondiabetic and nonischemic; **mean decrease in wound area
at week 6; ††diabetic foot ulcers and ischemic ulcers; ‡‡mean total burn area 54.6%; §§survival % in HBO group; 50% or more body surface burned; ¶¶41.7% mortality
HBO group and 68.0% mortality in control group; ##10–50% body surface area burned; ***mean healing time less for HBO group; †††significantly less major amputations
among patients with Wagner Grade IV ulcers only; ‡‡‡significantly less major amputations and quicker control of infection; §§§significantly less amputations.
conclude that additional research is needed
to define the specific indications and benefits
of this treatment modality. Specifically,
randomized placebo-controlled clinical trials
in large diabetic populations would further
lend credence to the presumption that
HBO therapy improves clinical outcomes.
Clearly, it would be difficult to conduct a
perfectly controlled HBO study because of
the numerous clinical variables that affect
wound healing. The most convincing work
in the medical literature to date demonstrates
that HBO therapy can reduce the
number of major amputations in patients
with Wagner grade IV wounds (8). Even
these results should be reevaluated in a
larger multicenter trial that would allow
many of the potential confounding factors
to be controlled or evaluated in the model.
Interestingly, wound care centers often use
the TcPO2 response to 100% oxygen challenge
as a criterion to determine if the
wound would benefit from HBO therapy.
However, after reviewing the literature, we
found only one very small human study
that may support this practice (19).
The authors’ anecdotal experience is
that HBO therapy is commonly used as an
adjunct to standard wound care in many
types of wounds, both deep and superficial,
infected and noninfected, ischemic, and
well-perfused. It is reasonable to predict
that, in many cases, aggressive local wound
care and adequate off-loading would obviate
any need for HBO therapy. There does
not seem to be any evidence-based criteria
to select patients for HBO therapy or to
predict who will benefit and who will not.
Given the relatively high cost of this treatment
modality, perhaps a more acute
awareness of the medical literature would
reduce the economic burden that HBO
therapy places on care providers that are
financially at risk.
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Wunderlich, Peters, and Lavery