829939

research-article2019
IJLXXX10.1177/1534734619829939The International Journal of Lower Extremity WoundsSalama et al

Original Article
The International Journal of Lower

Adjuvant Hyperbaric Oxygen Therapy

Extremity Wounds
1­–6
© The Author(s) 2019
Enhances Healing of Nonischemic Article reuse guidelines:
sagepub.com/journals-permissions

Diabetic Foot Ulcers Compared With DOI: 10.1177/1534734619829939

https://doi.org/10.1177/1534734619829939
journals.sagepub.com/home/ijl

Standard Wound Care Alone

Shimaa Elhossieny Salama, MBBCH1, Ali Eid Eldeeb, MD1,

Ahmed Husseiny Elbarbary, MD2 , and Salwa Elmorsy Abdelghany, MD1

Abstract
Recent systematic reviews and meta-analyses have produced conflicting results about the efficacy of hyperbaric oxygen
therapy (HBOT) in improving the healing rate for chronic diabetic foot wounds. This study aimed to assess the efficacy
of systemic HBOT in healing of chronic nonischemic diabetic foot ulcer. Thirty adult patients having Wagner’s grade 2
or 3 chronic diabetic foot ulcers, in whom the response to 30 days of standard wound care was not favorable, were
prospectively randomized to have either HBOT (20-40 sessions) plus conventional treatment (n = 15) or conventional
treatment alone (n = 15). Ischemic wounds and patients with contraindications to systemic HBOT were excluded. The
primary end point was complete healing of the target ulcer. Secondary endpoints included the following: rate of ulcer
healing at the end of treatment period and at 4 and 8 weeks thereafter as well as rate of amputation. A significantly
greater percentage of HBOT-treated wounds (33.3%, 5/15) achieved complete closure than conventional therapy–treated
wounds (0%, 0/15; P = .014) at the end of treatment. This significant difference was maintained throughout the 8 weeks
of follow-up. Complications frequency was nonsignificantly different between both groups. Our study showed that HBOT
plus conventional therapy appears as safe as and probably more effective than conventional therapy alone for the healing
of chronic nonischemic diabetic foot wounds. Larger studies are required to confirm its specific indications.

Keywords
hyperbaric oxygen, diabetic foot, ulcers, HBOT

Impaired wound healing in diabetics leads frequently to
chronic leg and foot ulcers, which are considered as a seri-
ous complication. The risk of developing a foot ulcer in dia-
betics is approximately 25% during the lifetime, and
approximately 84% of diabetes-related lower limb amputa-
tions are on top of ulceration.1,2
Peripheral macrovascular and microvascular disease,
peripheral neuropathy, and wound infection due to dimin-
ished resistance of the immune system in diabetics are all
implicated in the pathogenesis of diabetic foot ulcers
(DFUs). Moreover, anatomical foot deformities that lead to
disturbed plantar loading have a major role in DFUs’ occur-
rence and chronicity.3 These ulcers have been convention-
ally treated by blood sugar control, ulcer debridement, moist
dressing application, plantar off-loading through some tech-
niques such as total contact cast, and surgery in some cases.
Conventional methods alone sometimes fail to heal chronic
ulcers so that adjunctive methods may be necessary.4
Hyperbaric oxygen therapy (HBOT) has been proposed
to aid treatment of DFUs owing to its effects on the reversal
of wound tissue hypoxia.5 Administering 100% oxygen at 1
absolute atmospheric air (ATA) pressure for a period of
time increases the amount of oxygen dissolved in the plasma
5-fold; from 0.3 to 1.5 ml/L3, and at 2.5 ATA, the dissolved
oxygen content is approximately 5.5 ml/L3. Dissolved oxy-
gen can reach areas where red blood cells cannot pass.6,7
Thus, HBOT is thought to assist wound healing, due to
much increase in the dissolved oxygen in the plasma and
tissue oxygen delivery.8
However, recent systematic reviews, meta-analyses, and
randomized controlled trials have produced conflicting
results about efficacy of HBOT—as an adjuvant to standard
wound care—in improving the healing rate and reducing
the amputation rate for chronic diabetic foot wounds.9-11
1
Physical Medicine, Rheumatology and Rehabilitation Department, Tanta
University Hospitals, Tanta, Egypt
2
Vascular Surgery Department, Tanta University Hospitals, Tanta, Egypt
Corresponding Author:
Ahmed Hussieny Elbarbary, Department of Vascular Surgery, Faculty of
Medicine, Tanta University, PO Box 31527, Tanta, Egypt.
Email: albarbary73@gmail.com
2 The International Journal of Lower Extremity Wounds 00(0)
These evidence-based guidelines recommended further
studies to identify the indications and subgroups that may
benefit from HBOT.
Hence, we conducted this study to assess the efficacy of
systemic HBOT in the healing of chronic nonischemic DFUs.
Patients and Methods
Study Design
This prospective study was conducted during the period
from June 2017 to June 2018 in the Vascular Surgery
Department and the Physical Medicine, Rheumatology and
Rehabilitation Department, Tanta University Hospitals. It
included adults having chronic diabetic foot wounds (grade
2 or 3 on Wagner Ulcer Classification System)12 dating since
3 months or more, and have been treated with standard
wound care for at least 30 days with no favorable outcome.
Patients must have adequate perfusion of the lower limb as
evidenced by presence of pedal pulse, triphasic Doppler sig-
nals, and/or Ankle Brachial Index (ABI) of 0.8 or more.
Patients were randomized to receive either HBOT plus
conventional treatment (study group; number = 15 patients)
or 2 months of conventional treatment alone (control group;
number = 15 patients). Patients were excluded from the
study if they were previously treated with other methods dur-
ing the past 30 days prior to presentation, for example, VAC
(vacuum assisted closure), growth factor products, or enzy-
matic debridement. Furthermore, patients who are contrain-
dicated or unsuitable for systemic HBOT due to malignancy,
pregnancy, seizures, middle ear problems, pacemaker, claus-
trophobia, congenital spherocytosis, or obstructive pulmo-
nary disease, for example, emphysema or expected poor
compliance to HBOT, were also excluded.
Randomization was done using a computer-generated
randomization table with 1:1 ratio. The study was in accor-
dance with the Declaration of Helsinki (revised 2013). An
informed written consent was obtained from all patients
participating in the study. The Local Faculty Ethical
Committee approved this study under No. 31374/02/17.
Study Protocol
Before inclusion in the study, evaluation of patient history,
including duration, type, and control of diabetes mellitus,
was carried out. Assessments were performed for cardio-
vascular and pulmonary risk factors together with vascular
and neurological clinical assessments. Lower limb vascu-
larity was evaluated by palpation of peripheral pulses, ABI,
and Doppler or duplex scan when needed. Clinical assess-
ment of neuropathy included testing of pinprick, light touch,
and vibratory sensations in feet and evaluation of Achilles’
tendon reflexes. In case of abnormalities of the foot, X-ray
and/or magnetic resonance imaging were performed to dis-
cover chronic osteomyelitis.
Ulcer Assessment.  The ulcer was assessed regarding its site,
measurements, presence of exudates, and type of granula-
tion tissue coverage. The ulcer surface area was calculated
by obtaining the impression of the ulcer on a sheet of cel-
lophane paper then transferring the imprint on a grid paper
to calculate numbers of squares.
HBOT Protocol.  HBOT patients received once daily sessions
for 5 days a week with 2 days off, for a total number of 20
to 40 sessions according to the ulcer response. We used the
Sechrist 3600H monoplace hyperbaric oxygen chamber
(Sechrist Industries, Inc, Anaheim, CA). The session began
with a gradual pressure increase to the designated treatment
pressure of approximately 2.5 ATA over about 10 to 15 min-
utes in a 100% oxygen environment (compression phase).
The treatment period “at pressure” lasted for 1 hour. Then,
gradual decompression over about 10 to 15 minutes was
made.
Conventional Treatment Method.  Initial surgical debridement
was performed, and then antibiotic was used according to
culture and sensitivity results together with metabolic con-
trol. Topical daily moist saline dressing with antiseptic was
applied. Repeated debridement and appropriate plantar off-
loading was done in selected cases.
Follow-up
At each follow-up visit, 4 and 8 weeks after the last HBOT
session or after conventional treatment for 2 months, the
surface area of the ulcer was measured, the type and pro-
gression of granulation tissue coverage was recorded, as
well as the presence of infection or any other complication
as infection or amputation.
Study Endpoints
The primary endpoint was complete healing of the target
ulcer. Complete healing was defined as an ulcer becomes
completely covered by epithelium.
The target ulcer was the one having the criteria of inclu-
sion, that is, Wagner grade 2 or 3, dated since not less than
3 months, large enough to draw follow-up results. Secondary
endpoints were rate of ulcer healing measured at the end of
treatment period and at 4 and 8 weeks thereafter and fre-
quency of minor amputation (toe or forefoot amputation) or
major amputation (above ankle amputation).
Statistical Analysis
Statistical presentation and analysis of the present study was
conducted by GraphPad Prism version 6. Continuous vari-
ables were expressed as mean ± standard deviation when
normally distributed and were analyzed using standard
Student’s test (t test), while they were expressed as median
Salama et al 3

Table.1.  Baseline Characteristics in Both Groupsa.

Variable HBOT (n = 15) Conventional (n = 15) P

Age (years) 55.1 ± 7.5 57.7 ± 6.7 .51
Male sex 12 (80%) 10 (66.7%) .41
Type 2 diabetes mellitus 14 (93.3%) 13 (86.6%) .54
Diabetes duration (years) 20 ± 7.4 18 ± 8 .45
Smoking 7 (46.7%) 8 (53.3%) .72
Hypertension 11 (73.3%) 9 (60%) .44
Congestive heart failure 2 (13.3%) 3 (20%) .42
Baseline ulcer duration (weeks) 16.5 ± 1.5 15.5 ± 1.4 .64
Baseline ulcer surface area (cm2) 7.5 (1.5-15.5) 8 (2-16.5) .61
Wagner grade
  Grade 2 6 (40%) 7 (46.7%) .71
  Grade 3 9 (60%) 8 (53.3%)
Ulcer location
  Foot dorsum 4 (26.7%) 6 (40%) .723
 Sole 9 (60%) 7 (46.7%)
 Leg 2 (13.3%) 2 (13.3%)

Abbreviations: HBOT, hyperbaric oxygen therapy; SD, standard deviation.

a
Data are expressed as mean ± SD, or number and percentage. A 2-sided P < .05 was considered statistically significant.

and range and were analyzed using Mann-Whitney’s test

when nonnormally distributed. Categorical variables were
expressed as median and range and were analyzed with con-
tingency tables using χ2 test. Comparison of the wound sur-
face area reduction between groups was performed using the
standard Student’s t test. A 2-sided P value < .05 was con-
sidered statistically significant. Bivariate analysis for corre-
lation between session number and wound area reduction
was performed using Pearson’s test.

Results
The baseline characteristics and baseline wound measurements
did not differ significantly between both groups (Table 1).
At the end of all HBOT sessions and 2 months of con-
ventional treatment, the median ulcer surface area was sig-
nificantly reduced in the HBOT group but not in the
control group (Figure 1). The median pretreatment ulcer
surface area in the HBOT group was 7.5 cm2, with a range
of 1.5 to 15.5 cm2, which was reduced to 2 cm2, with a
range of 0 to 4.5 cm2, P = .0001*, at the end of treatment
Figure 1.  (A) Plantar ulcer, Wagner grade 2, had been present
period. In the control group, the median pretreatment ulcer
since 3 months, after debridement and before hyperbaric oxygen
surface area was 8 cm2, with a range of 2 to 16.5 cm2, therapy (HBOT). (B) The same ulcer after 30 HBOT sessions
which was reduced to 7.5 cm2, with a range of 1.8 to 10.5 cm2, showing significant ulcer area reduction.
P = .126.
This significant ulcer size reduction in the HBOT group
was maintained at 4 and 8 weeks of follow-up (Table 2 and 10 cases versus 2 and 3 cases in the HBOT group versus the
Figure 2). control group, P = .046*, .025*, respectively, Table 2.
Complete healing of the target ulcer, at the end of the On bivariate analysis, it was found that a significantly
treatment, was observed in 5 cases in the HBOT group ver- higher wound healing rate was associated with more HBOT
sus no case in the control group, P = .014*. At 4 and 8 sessions completed (r = 0.888, P = .0001, 95% confidence
weeks of follow-up, these numbers were increased to 7 and interval = 0.6904-0.9626; Figure 3).
4 The International Journal of Lower Extremity Wounds 00(0)

Table 2.  Ulcer Surface Area and Complete Healing in Both Groupsa.

Variable HBOT Control P

Pretreatment ulcer area 7.5 (1.5-15.5) 8 (2-16.5) .61
Ulcer area at end of treatment 2 (0-4.5) 7.5 (1.8-10.5) .0001*
Ulcer area after 4 weeks 1.5 (0-2.5) 4 (0-8.5) .0001*
Ulcer area after 8 weeks 0 (0-2) 3.5 (0-4) .0001*
Change at end of treatment (cm2) 5.5 (1.5-12) 1.6 (0-6.5) .0001*
Change at end of treatment (%) 75 (35.7-100) 20 (0-57)
Complete ulcer healing
 Posttreatment 5 (33.3%) 0 (0%) .014*
  After 4 weeks 7 (46.7%) 2 (13.3%) .046*
  After 8 weeks 10 (66.7%) 3 (20%) .025*

Abbreviation: HBOT, hyperbaric oxygen therapy.

a
Data are presented as median and range or number and percentage.
*A 2-sided P < .05 was considered statistically significant.

Figure 2.  Wound area changes at different time points in the

study.

Mild to moderate wound infections were observed in 3

(20%) versus 5 (33.3%) cases of the HBOT group versus
control group, respectively, during the period of treatment.
This was cleared after surgical debridement, and culture
and sensitivity with appropriate antibiotics administrated
accordingly. There was no major amputation in both groups
while minor (toes) amputations were done to one patient in
each group.
Discussion
Currently, there is low- to moderate-quality evidence for the
effectiveness of HBOT, as adjuvant therapy, for healing of
chronic nonischemic DFUs and preventing amputation.10
Our study proved that HBOT addition to conventional
therapy resulted in significantly higher rates of ulcer size
reduction as well as number of complete ulcer healing
than conventional therapy used alone. These results were
maintained at 4 and 8 weeks of HBOT discontinuation.
Amputation frequency was not significantly different
between groups.
Figure 3.  Significant positive correlation between the
hyperbaric oxygen therapy sessions numbers and ulcer size
reduction rate.
Abbreviation: r, correlation coefficient.
A P value <.05 was considered statistically significant.
These results correlated well with those obtained by sev-
eral authors who reported improved healing of DFUs on
using HBOT; Duzgun et al13 found that HBOT was associ-
ated with significantly higher rates of wound healing than
standard wound care (66% vs 0%), respectively. Similarly,
Chen et al14 conducted a study on 38 patients with nonheal-
ing DFUs; the study group was treated with standard care
plus HBOT, n = 20, while the control group was treated
with standard care alone, n = 18. Complete DFU closure
was achieved in 5 patients (25%) in the HBOT group versus
1 patient (5.5%) in the standard care group, P = .001.
Kessler et al15 included nonischemic ulcers only and
reported complete ulcer healing in 2/14 patients (14.3%)
Salama et al 5
after 20 (twice daily) HBOT sessions and in 0/13 patients in
the standard care group. However, they found no difference
in wound size reduction after 4 weeks (62% vs 55%).
In our study, there was a significant positive correlation
between the number of HBOT sessions and the rate of ulcer
healing. Hence, more reduction in wound surface area was
associated with increasing the number of HBOT sessions.
Patients who completed 35 sessions or more had 100%
ulcer area reduction (Figure 3). This was in agreement with
the findings reported by Löndahl et al,16 who performed a
study on 94 patients with Wagner grades 2 to 4 ulcers, and
they observed complete ulcer healing in 23/38 patients
(61%) of those who completed >35 HBOT sessions versus
10/37 (27%) complete healing in the placebo group, P =
.009.
The beneficial effects of HBOT may be explained on the
following grounds: HBOT can hyperoxygenate the rela-
tively ischemic tissues by 10- to 20-fold. It stimulates pro-
duction of growth factors and inhibits cytokine release. This
helps improve collagen production, neovascularization, and
wound healing. In addition, HBOT has an antibacterial
activity through production of oxygen free radicals.17
The probable protective effect of HBOT against amputa-
tion was a matter of great debate between studies, possibly
due to the heterogeneous inclusion of ischemic patients
together with nonischemic ones and of Wagner grade 4
DFU (forefoot gangrene) in which minor amputation is
inevitable and does not reflect a treatment effect. Some
authors defined healing of Wagner grade 4 DFU as closure
of the resulting wound after separation or surgical removal
of the gangrenous part.13,18 However, the resultant wound is
an acute one, in most cases, having a different response for
HBOT treatment than the chronic wound, which is the tar-
get in most of these studies. Therefore, it appears that
although HBOT is indicated in Wagner grade 3 or higher, in
randomized trials it would be better to compare lower
grades with no gangrene or inevitable amputation.
In the present study, we excluded Wagner 4 or higher
grades for proper evaluation of the effect of HBOT on
chronic wounds only. There was no significant difference in
amputation frequency between both groups. Similarly,
Kessler et al15 and Ma et al19 reported no difference in
amputation frequencies in their trials that only included
patients with nonischemic ulcers. Also, Abidia et al20 and
Löndahl et al16 observed no effect on amputation frequen-
cies in their trials, which included ischemic ulcers. On the
other hand, in a study by Faglia et al18 that included some
patients with ischemic ulcers and gangrenous lesions,
HBOT was associated with a significant decrease in major
amputations, and significant increase in minor amputation,
while Duzgun et al,13 who did not mention the state of per-
fusion of their treated limbs, found a significant reduction
in the number of major as well as minor amputations.
The results of a meta-analysis by Liu et al21 that included
624 patients supported the use of HBOT to reduce healing
times and amputation in DFUs. Similarly, the 2015
Cochrane review22 of HBOT for chronic wounds examined
10 randomized controlled trials of patients with DFUs; low-
to moderate-grade evidence from 5 trials found that HBOT
improved the short-term wound healing and might lower
the rate of major amputation.15,16,19,20,23 A more recent meta-
analysis concluded that HBOT patients had significantly
greater ulcer area reduction compared with standard treat-
ment, but no significant effect on amputation reduction or
proportion of ulcer closure was detected.24
Finally, although HBOT has mixed evidence supporting
its use as an adjunctive treatment to enhance DFU healing
and prevent amputation, HBOT can generally be considered
a safe treatment modality in treatment of DFU that improves
the progress of healing.25
Limitations of the Study
Despite the small sample size, this study would be a valu-
able addition regarding the management of this problem.
Further studies with larger numbers and longer follow-up
are recommended.
Conclusion
HBOT plus conventional therapy appears as safe as and
probably more effective than conventional therapy alone
for the healing of chronic diabetic nonischemic foot wounds.
Larger studies with longer periods of follow-up are recom-
mended to establish its role and its long-term effect.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Ahmed Husseiny Elbarbary https://orcid.org/0000-0001-5328
-018X
Note
*indicates statistical significance values.
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