Emerging Treatments and Technologies

ORIGINAL ARTICLE

Hyperbaric Oxygenation Accelerates the

Healing Rate of Nonischemic Chronic
Diabetic Foot Ulcers
A prospective randomized study
1 1
LAURENCE KESSLER, MD, PHD RAPHAEL PASSEMARD, MD, PHD velop a foot ulcer each year (2). Moreover,
2 3
PASCAL BILBAULT, MD DOMINIQUE STEPHAN, MD, PHD duration of hospitalization attests to the
FRANCOISE ORTEGA´, MD1 MICHEL PINGET, MD, PHD1
1 2 high morbidity of this condition (3), which
CLAIRE GRASSO, MD, PHD FRANCIS SCHNEIDER, MD, PHD has been shown to require as long as 26
weeks for full recovery (4) despite a
multidisciplinary approach (associating
glycemia control, daily local care, foot off-
loading antibiotic therapy, and surgical
OBJECTIVE — To study the effect of systemic hyperbaric oxygenation (HBO) therapy on
revascularization).
the healing course of nonischemic chronic diabetic foot ulcers.
The diabetic foot is characterized by
RESEARCH DESIGN AND METHODS — From 1999 to 2000, 28 patients (average age sensory, motor, and autonomic neuropa-
60.2 9.7 years, diabetes duration 18.2 6.6 years), of whom 87% had type 2 diabetes, thies leading to alteration of pressure
demonstrating chronic Wagner grades I–III foot ulcers without clinical symptoms of distribution, foot deformities, and ulcer-
arteriopa-thy, were studied. They were randomized to undergo HBO because their ulcers did ations. Metabolic control and infection
not improve over 3 months of full standard treatment. All the patients demonstrated signs of treatments are of primary importance to
neuropathy. HBO was applied twice a day, 5 days a week for 2 weeks; each session lasted 90 control the evolution of the diabetic foot.
min at 2.5 ATA (absolute temperature air). The main parameter studied was the size of the
foot ulcer measured on tracing graphs with a computer. It was evaluated before HBO and at Hyperbaric oxygenation (HBO) has pre-
day 15 and 30 after the baseline. viously been proposed as an adjunctive
treatment for the diabetic foot because it
RESULTS — HBO was well tolerated in all but one patient (barotraumatic otitis). The trans- improves in vitro the complex processes
cutaneous oxygen pressure (TcPO2) measured on the dorsum of the feet of the patients was underlying healing (5–7). It has also been
45.6 18.1 mmHg (room air). During HBO, the TcPO2 measured around the ulcer increased reported that HBO reduces the incidence
significantly from 21.9 12.1 to 454.2 128.1 mmHg (P 0.001). At day 15 (i.e., after completion of major amputation in diabetic patients
of HBO), the size of ulcers decreased significantly in the HBO group (41.8 25.5 vs. 21.7 with a gangrenous foot (8). The actual
16.9% in the control group [P 0.037]). Such a difference could no longer be observed at day
30 (48.1 30.3 vs. 41.7 27.3%). Four weeks later, complete healing was observed in two
value of HBO on diabetic foot healing is,
patients having undergone HBO and none in the control group. however, still a matter of discussion be-
cause conflicting data exist in the litera-
CONCLUSIONS — In addition to standard multidisciplinary management, HBO doubles ture (9 –13) on its true therapeutic effect.
the mean healing rate of nonischemic chronic foot ulcers in selected diabetic patients. The The difficulty in controlling the different
time dependence of the effect of HBO warrants further investigations. parameters (metabolic, vascular, infec-
tious, and foot off-loading) involved in the
Diabetes Care 26:2378 –2382, 2003 evolution of the diabetic foot and the lack
ower-extremity ulcers are responsi- (1). Foot ulcer represents one of the major of prospective randomized studies on the
effect of HBO on this pathophysi-ological
condition make it difficult to rec-ognize
ble for 20% of the hospital admis- causes of lower-extremity injuries in the HBO as an incontrovertible treatment.
Lsions of diabetic patients; the 220 million people suffering from diabe-
incidence of amputation is 6 per 1,000 tes worldwide, 2.5% of whom will de- Recently, Me´chine et al. (14) have
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
re-ported on the effect of HBO on the
From the 1Department of Endocrinology and Diabetology, University Hospital, Strasbourg, France; the accel-eration of angiogenesis and on a
2
Medical Intensive Care and Regional Hyperbaric Oxygenation Center, University Hospital, Strasbourg,
stimulation of neovascularization in an
France; and the 3Department of Cardiovascular Disease, University Hospital, Strasbourg, France.
Address correspondence and reprint requests to Dr L. Kessler, Service d’Endocrinologie et de Diabe experimental model of wound healing in
´tolo-gie, Hoˆ pitaux Universitaires 1, Place de l’Hoˆ pital, 67091 Strausbourg Cedex, France. E-mail: the rat. On the other hand, Wattel et al.
[email protected]. (15) showed that the effectiveness of HBO
Received for publication 18 April 2002 and accepted in revised form 9 May 2003.
on healing in nondiabetic patients was de-
Abbreviations: HBO, hyperbaric oxygenation; TcPo2, transcutaneous oxygen tension.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and pendent on the peripheral arterial dises-ase.
conversion factors for many substances. Consequently, the purpose of this study was
© 2003 by the American Diabetes Association. to evaluate the effect of HBO on

2378 DIABETES CARE, VOLUME 26, NUMBER 8, AUGUST 2003

 Kessler and Associates

the healing of nonishemic chronic dia- Study protocol 4 weeks (day 15 and 30, respectively), the
betic foot ulcer in a prospective On inclusion, physical examination was aspect of ulcers (color, outline) was eval-
controlled and randomized study on the performed on patients, including palpa- uated by standardized photographs.
basis of the experimental protocol tion of the arterial pulses, evaluation of Weekly tracings of the surface area of the
proposed by Me´chine et al. pinprick, light touch, and vibratory sen- ulcer onto gridded transparent film were
sations in feet, and testing for Achilles’ performed by a physician blinded to the
tendon reflexes. Lower-limb vasculariza- patient’s group assignment. Tracings were
RESEARCH DESIGN AND tion was evaluated by Doppler scan, and digitally treated for measurement using a
METHODS baseline TcPO2 was simultaneously mea- computer program (Mouseyes version 1.1,
sured on the dorsum of the foot with a 1995, Dr. RJ Taylor, Salford, U.K.).
Patients modified Clark electrode (Kontron In- Baseline wound ulcer surface area was
The protocol was approved by our local struments, Watford, U.K.). The sensori- expressed in centimeters squared, and its
ethics committee, and written consent motor neuropathy of lower extremities was evolution was quoted as a percent-age of
was obtained from each patient. assessed by electromyography. In case of the reduction of the wound ulcer surface
From January 1999 to January 2000, abnormalities of the foot X-ray, magnetic area between baseline and day 15, between
28 type 1 and type 2 diabetic patients resonance imaging was per-formed to day 15 and 30, and between baseline and
consecutively admitted in our ward for evaluate chronic bone infec-tion. day 30.
chronic foot ulcers (Wagner grades I, II,
and III) were prospectively included in At the study outset, patients of both Statistical analysis
this study. Their ulcers (depth 2 mm) were groups were hospitalized for 2 weeks in Data were expressed as mean SD. For
characterized by the absence of fa-vorable the department of diabetology for con- the comparison between HBO and con-
evolution for at least 3 months despite the ventional treatment, regardless of their as- trol groups, P values were determined
stabilization of glycemia, the absence of sociation. They were then followed as 2
by a two-tailed Fisher’s exact test for
clinical local infection, and sat-isfactory outpatients for 2 weeks. During the hos-
dis-crete variables and by an unpaired
off-loading measures. In 17 pa-tients, the pitalization, the patients randomized for
Stu-dent’s t test for continuous
ulcers were located on the heels or soles HBO underwent two 90-min daily ses- variables. Comparison of wound ulcer
and were mainly due to an initial sions of 100% O2 breathing in a multi-
hyperkeratosis area complicated with cu-
area reduc-tion and TcPO2 between
place hyperbaric chamber (Comex Pro, HBO-treated and -untreated patients was
taneous fissures. When the ulcers were Comex, Marseille, France) pressurized at performed using the Student’s t test.
located on the toes, the initial provoking 2.5 ATA (absolute atmosphere air). This
causes were a traumatism or blister result- regimen lasted 5 days a week for 2 con-
ing from ill-fitting shoes (n 11). In 13 secutive weeks according to Me´chine et RESULTS — HBO was well tolerated
cases the ulcers were associated with an al. (14). In brief, HBO sessions included a in all but one patient, who demonstrated
aperture with chronic deep infection. The period of compression in air for 15 min a barotraumatic otitis, for which he was
initial size of ulcers was 2.56 1.83 cm .
2 followed by three 30-min breathing peri- dis-charged from the study.
Clinical signs of arteriopathy were absent ods, at FiO2 1, separated by 5-min in- As shown in Table 1, HBO patients
(the palpation of arterial pulses at lower and control patients did not differ in their
tervals of air breathing (Fi O2 0.21) and baseline characteristics (i.e., age, sex, type
extremities was normal). Doppler scans of then a decompression period of 15 min.
lower limbs were normal and the transcu- and duration of diabetes, micro- and ma-
The conventional additional treatment was crovascular complications, bone lysis, and
taneous oxygen tension (TcPO2) mea-sured applied to both groups of patients during
treatment). Of interest is the fact that ulcer
at the dorsum of the foot exhibiting the hospitalization and the ambula-tory period.
surface area was not statistically dif-ferent
ulcer was 30 mmHg. Each patient was Each patient was provided with an
between groups at the beginning of the
asked to keep weight off the affected foot. orthopedic device to remove me-chanical
stress and pressure at the site of the ulcer study.
The patients had a stabilized non-
proliferating retinopathy. During the study during walking (Barouk shoes)
period, 64 diabetic patients were admitted (2). In both groups, the optimization of Influence of HBO on the TcPO2
to our unit for foot ulcers. Of them, 34 metabolic control required subcutaneous As shown in Fig. 1, the TcP O2 measured
patients were excluded, 8 due to insulin administration (two or three injec- around the ulcer significantly increased
gangrenous ulcer with severe sepsis, 22 tions or bedtime treatment) for the major- from 21.9 12.2 in room air to 454.1 128.1
patients due to severe arteriopathy (TcPo2 ity of patients. In the case of chronic mmHg during the 1st session of HBO (P
30 mmHg), and 4 due exclusion criteria infection, patients were given antibiotics 0.001) and from 25.6 12.8 to 549.6 232.9
for HBO (emphysema, proliferat-ing according to microbiological tests. mmHg after the 20th session (P 0.001).
retinopathy, claustrophobia). Among the After the 1st and the 20th sessions of When the TcPO2 was measured in the
30 selected patients, 2 patients re-fused to HBO, TcPO2 was measured in room air second intercostal space, these values
participate. The 28 patients se-lected were and during the hyperbaric session in a significantly increased from 67.9 16.4 to
randomized to standard treatment or standardized fashion: first in noninflamed 1,119.6 180.2 mmHg and from 67.2 12.7
standard treatment plus HBO according to skin located 1 cm from the wound edges to 1,074 112.3 mmHg, respectively, after
a randomization table. The HBO and and second in the second intercostal space the 1st and the 20th sessions of HBO (P
control groups involved 15 and 13 diabetic as a reference (16,17). At baseline (i.e., 0.001). There was no significant difference
patients, respectively. before HBO was started), and 2 and between the

DIABETES CARE, VOLUME 26, NUMBER 8, AUGUST 2003 2379

Hyperbaric oxygen therapy for diabetic foot ulcers

Table 1—Clinical characteristics of control and HBO-treated patients

Control
HBO group group P
n 14 13
M/F 10/4 9/4
Age (years) 60.2 9.7 67.6 10.5 0.29
BMI (kg/m2) 29.9 3.1 29.1 5.9 0.68
Type 1 diabetes (%) 2/14 (14) 2/13 (15) 0.72
Type 2 diabetes (%) 12/14 (86) 11/13 (85) 0.72
Diabetes duration (years) 18.2 13.2 22.1 13.1 0.38
Ulcer surface area (cm2) 2.31 2.18 2.82 2.43 0.42
Insulin therapy (%) 13/14 (92.8) 12/13 (92.3) 0.62
Oral agent (%) 1/14 (7.2) 1/13 (7.7) 0.62
Stabilized retinopathy (%) 10/14 (71) 11/13 (84.6) 0.75
Renal impairment (%) 5/14 (35.7) 6/13 (46.1) 0.70
Coronary artery disease (%) 2/14 (14.2) 4/13 (30.8) 0.38 Figure 2—Reduction of ulcer size in
Carotid arteriopathy (%) 1/14 (7.1) 1/13 (7.6) 1.00 patients of HBO ( ) and control (f) group
TcPO2 (mmHg) foot dorsum 45.6 18.1 45.2 24.2 0.61 after 2 and 4 weeks. (*P 0.037)
Sensorimotor neuropathy (%) 14/14 (100) 13/13 (100) 1.00
HbA1c (%), normal range (4.4– 9.4 2.4 8.1 1.4 0.31 After 4 weeks, healing was
5.8) completed in two HBO patients but in
Bone lysis (%) 7/14 (50) 6/13 (46.1) 0.76 none of the control subjects.
Antibiotic therapy (%) 8/14 (57.1) 9/13 (69.2) 0.69
Data are means SD unless indicated otherwise. Renal impairment was defined as a creatinine clearance 60 CONCLUSIONS — This prospective
ml/min; coronary artery disease was confirmed by abnormalities at coronarography, carotid arteriopa-thy randomized study provides evidence that
by abnormalities at carotid echography; sensorimotor neuropathy was clinically defined by abnormalities HBO doubles the mean healing rate of
of pinprick, light touch, and a decrease in vibratory sensations and in the testing for Achille’s tendon
reflexes together with abnormalities in more than two nerves at electromyography (velocity 45 m/s); bone nonischemic chronic foot ulcers in se-
lysis was determined by X-ray findings. lected diabetic patients. In addition, it
suggests the possibility of shortening
hos-pitalization time in these patients.
increase in TcPO2 at the beginning and patients (41.8 25.5 vs. 21.7 16.9%) (P The rationale for the use of HBO as an
end of the HBO treatment. 0.037). Two weeks later, the reduc-tion adjunctive treatment for the diabetic foot
of the ulcer size was comparable be- stems from its beneficial effects on the mi-
Wound ulcer surface area tween the groups (48.1 30.3 vs. 41.7 croenvironment of the wound. If high ox-
measurements 27.3%). After a 4-week period, there ygen pressure over a long time period
After 2 weeks of treatment, the reduction was no difference in the reduction of (several days) stimulates an abnormal an-
of the ulcer surface area in HBO patients ulcer surface area between groups (61.9 giogenesis (as demonstrated in the eyes of
was significantly greater than in control 23.3 vs. 55.1 21.5%). newborns), several studies have reported
that cycling high and low oxygen pressure
over a short period (1 or 2 h) stimulates a
physiological angiogenesis at the site of
the ulcer. This is due, in part, to the re-
lease of collagen from fibroblasts and vas-
cular growth factors by macrophages
(18,19). The vascular response to high O 2
tension is usually vasoconstriction. How-
ever, the promotion of new vessel growth
follows the withdrawal of the high oxygen
with relative hypoxia in the constricted
tissues area. Furthermore, hyperoxia can
trigger the onset of signal transduction
pathways of regulating the gene expres-
sion of growth factors or their receptors,
like platelet-derived growth factor (20).
Figure 1—TcPO2 MEASUREMENTS IN THE
SECOND INTERCOSTAL SPACE AND AROUND Moreover, oxygen is able to strengthen
THE ULCER IN PATIENTS UNDERGOING HBO microbiocidal capacity of endogenous de-
IN ROOM AIR (f) AND AFTER THE FIRST HYPER- fense mechanisms in addition to its direct
BARIC SESSION ( ). ***P 0.001. antianaerobic activity (21). HBO cannot

2380 DIABETES CARE, VOLUME 26, NUMBER 8, AUGUST 2003

 Kessler and Associates

dramatically increase the O2 transported local O2 pressure. Only two randomized healing process, which begins slowly and
by hemoglobin, but it significantly in- controlled clinical trials evaluating HBO then increases (5). In a nonrandomized
creases the fraction of O2 dissolved in in the diabetic foot (11,12) are available. study, Baroni et al. (25) showed that HBO
plasma (22) and delivered throughout the In these studies, the authors have demon- accelerates the healing of diabetic chronic
organism, as demonstrated by TcPO2 strated that HBO is effective in decreasing foot ulcer. However, since 18 of the 28
measurements. In our patients, in ambi-ent major amputations in diabetic patients patients were hospitalized, and since 23
air, the TcPO2 of the foot dorsum was 30 with severely prevalent ischemic foot ul- had gangrene of the foot and 5 presented
mmHg, which is the threshold value cers. Recently, in a prospective nonran- neuropathic ulcers, the study population
usually accepted as the cutoff point, be- domized study, Zamboni et al. (11) was too heterogenous to draw any reliable
yond which the wound can heal without evaluated the influence of HBO on the conclusions.
adjuvant surgical treatment (23). healing of lower-extremity wounds in 10 A long-lasting effectiveness of HBO
It is important to note that the type 2 type 1 diabetic patients. The HBO group has been suggested in some pathophysio-
diabetic patients included in our study underwent 30 sessions over a period of 7 logical conditions involving irradiated tis-
were patients in their late fifties with a weeks. This study shows a greater reduc- sues (26). It is noteworthy that the effect
long diabetes duration (average 20 years). tion of the wound surface area in the HBO of HBO could no longer be observed in
All of these patients had neuropathy, as group together with a complete healing in our patients once the treatment had been
shown by clinical and electromyographic 80% of the patients over the entire 7-week discontinued. This is in keeping with the
data, but they demonstrated a mild pe- experimental model of Me´chine et al. (14)
period. In our study, a significant acceler-
ripheral lower-limb arteriopathy accord- and raises questions about the mecha-
ation of the healing was observed in the
ing to their TcPO2 values of 45 mmHg HBO group. However, among the 14 pa- nisms involved in such a phenomenon.
(normal values 60 mmHg). Before HBO tients who underwent the 20 sessions of Whether longer periods of HBO sessions
the TcPO2 around the ulcer was only 22 HBO, only two patients had their ulcers would result in better healing remains to
mmHg, which indicates that the wound healed after 4 weeks. The smaller number be established. In the rat, the effect of
ulcer tissues were unlikely to be supplied of HBO sessions could explain these dif- HBO is suggested to be less effective after
with enough O2 to undergo a correct heal- ferences. In both studies, no amputations 2 weeks of treatment, possibly as a dele-
ing. In our study, the TcP O2 value is re- were reported in either control or HBO terious consequence of pressure itself.
duced around the ulcer when compared patients. In our study, the matched pa- The tolerance of HBO was fairly ac-
with the values measured on the dorsum of tients were comparable regarding the sta- ceptable; of the 14 patients of the HBO
the foot. This difference can be ex-plained tus of diabetes, the presence of chronic group, only 1 was discharged due to a
by the existence in these patients of a bone infection, the size of wound ulcers, mild barotraumatic otitis, from which he
peripheral arteriopathy reaching the small and the follow-up. Indeed, during the ini- recovered without sequelae. The costs of
arteries associated with a reduction of the tial period of treatment, each and every the technique must, of course, also be
capillary vascularization and a patient was hospitalized and then fol- taken into account. Data reported by
modification of the tissues around the lowed in ambulatory care. During the 3 Mar-roni et al. (27) suggest that the cost
lesion. In agreement with others, we ob- months preceding the study, the absence of of HBO is equivalent to other new treat-
served a 20-fold increase of ulcer tissue O 2 favorable evolution observed in pa-tients ments (local topic of human growth fac-
tension under hyperbaric conditions (24); of both groups was observed in am- tor) in the diabetic foot and may be more
this effect can be explained by the bulatory care. After randomization, the effective.
selection of patients who did not dem- acceleration of the healing in the control HBO seems effective in accelerating
onstrate clinical and Doppler signs of group is probably due to the conditions of the healing rate of nonischemic chronic
macroangiopathy. In such conditions, hospitalization, during which the meta- diabetic foot ulcers. In humans, its effect
Wattel et al. (15) have already shown that bolic control, the local cares, and the re- is observed only during the treatment,
the effectiveness of HBO on healing is moval of metabolic stress are better. After which suggests a similar mechanism of
dependent on the TcPO2 increase dur-ing the 2 weeks of hospitalization, the im- action to that in the experimental model
the session. provement observed in ambulatory care of Me´chine et al. This result reinforces
Elevation of O2 tension in hypoxic can be explained by the intensive fol-low- the interest of HBO in selected diabetic
wound ulcers enhances neutrophil oxida- up of patients. During the first 2 weeks of pa-tients with chronic foot ulcers
tive killing of bacteria and stimulates the study, the healing rate was improved associated with neuropathy but without
fibroblast proliferation, collagen produc- only in patients undergoing HBO severe mac-roangiopathy.
tion, neovascularization, and epithelial- treatment. For a further 2 weeks, patients
ization (20). In addition, O2 is directly of both groups followed as out-patients
received similar conventional treatment. In Acknowledgments — This study was sup-
toxic to anaerobic organisms (13). De- ported by grant from The Centre europe´en
spite these findings, few controlled pro- this time, the healing rate was comparable
d’e´-tude du Diabe`te (CeeD).
spective clinical studies have been able to between the two groups, further
support the use of HBO for chronic non- supporting the effect of HBO since its
healing wound ulcers. HBO has probably suspension resulted in the absence of References
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DIABETES CARE, VOLUME 26, NUMBER 8, AUGUST 2003 2381

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