Hyperbaric Oxygen Therapy in Ischaemic Foot Ulcers in Type 2 Diabetes: A Clinical Trial

Sarah Perren1, Alfred Gatt1, *, Nikolaos Papanas2, Cynthia Formosa1
1 Faculty of Health Sciences, University of Malta, Msida, Malta
2 Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece

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© 2018 Perren et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Faculty of Health Sciences, University of Malta, Tal-Qroqq, Msida, MSD 2080, Malta; Tel: 00356 99497886; Fax: 00356 2340 2342; E-mail: alfred.gatt@um.edu.mt


Background and Aims:

Several treatment modalities and protocols for ischaemic foot ulcers are available. However, little consensus exists on optimal treatment. The aim of this study was to compare Standard Wound Care (SWC) alone vs. SWC with adjunct hyperbaric oxygen therapy (HBOT) in the treatment of ischaemic Diabetic Foot Ulcers (DFUs).

Patients and Methods:

Twenty-six patients with Type 2 Diabetes Mellitus (T2DM) presenting with a newly diagnosed ischaemic foot ulcer were included. These were divided into group A (SWC with adjunct HBOT) and group B (SWC only). Participants were followed every week for 4 weeks and their ulcers were measured for their surface area and depth to assess any change in wound size.


Both treatment arms succeeded in reducing ulcer area and depth (p<0.001). However, ulcer area (p<0.001) and depth (p<0.001) exhibited superior improvement in group A.

Conclusion :

Adjunctive HBOT appears to improve wound healing in ischaemic DFUs and merits further study.

Keywords: Hyperbaric oxygen therapy, Diabetic foot ulcer, Ischaemia, Peripheral arterial disease, Standard wound care, HBOT.


Lower-extremity complications in patients with diabetes mellitus (DM) have become an increasingly significant public health concern [1]. The global diabetic foot ulcer (DFU) prevalence was 6.3% (95% confidence interval (CI): 5.4-7.3%), which was higher in males (4.5%, 95%CI: 3.7-5.2%) than in females (3.5%, 95%CI: 2.8-4.2%), and higher in patients with type 2 (6.4%, 95%CI: 4.6-8.1%) than those with type 1 DM (5.5%, 95%CI: 3.2-7.7%) [2]. DFUs precede 84% of lower extremity amputations, are associated with increased mortality (by 2.4%) [3-5] and have a high recurrence rate [6], with essentially a poor prognosis [7].

Different local wound management options exist, ranging from a number of dressings to a vast range of advanced treatments used in adjunct to standard treatment of wound care [8]. However, to date, there is no unequivocal evidence for the best local treatment of DFUs [9, 10].

Current Standard Wound Care (SWC) protocols include wound cleansing, optimised glycaemic control, treating infection, improving blood supply and relieving pressure on the wound site [10, 11]. Ideally, all natural phases of wound healing, i.e. inflammatory, proliferative phase and maturation phase, which are all oxygen-dependent, should be supported, but this fails to be the case in clinical reality [12]. In an endeavour to improve healing rates, Hyperbaric Oxygen Therapy (HBOT) has been used [13]. However, its use remains debated, and the evidence for its effectiveness, at least in non-ischaemic diabetic ulcers, is limited [14, 15]. Therefore, the aim of this study was to compare the efficacy of HBOT added to SWC vs. SWC alone in promoting healing of ischaemic DFUs.


This single-centre clinical trial included 26 subjects with Type 2 DM (T2DM) presenting to a tissue viability unit with a newly diagnosed ischaemic DFU. The study was approved by the institutional Ethics Committee and carried out in accordance with the Declaration of Helsinki, as revised in 2000. All patients gave their informed consent. Inclusion criteria were: adult T2DM and newly diagnosed ischaemic DFU. Exclusion criteria were: neuropathic DFU, infected DFU, severe ischaemia requiring urgent revascularisation, recent change of medication, chronic alcohol abuse, systemic disease or pernicious anaemia.

Patients were randomised into group A (n=13; SWC with adjunct HBOT) and group B (n=13; SWC only). Patients were matched for age, gender, DM duration, current medication, HbA1c, wound size and location (according to the angiosomes supplying the wound area with arterial blood) [16], using frequency distribution matching to ensure both groups were comparable at baseline. All examinations were carried out by the same investigator to ensure uniformity. Room temperature was kept at 21-23°C to avoid vasoconstriction of digital arteries. Screening process involved review of the patient’s medical history and a lower-extremity physical examination.

2.1. Peripheral Sensory Neuropathy

Semmes-Weinstein 10 g monofilaments were used to detect peripheral sensory neuropathy. Testing was performed on the plantar aspect of the hallux and third digit, as well as on the 1st, 3rd and 5th metatarsal heads.

2.2. Peripheral Arterial Disease

Vascular assessment was carried out by Spectral Waveform Doppler Analysis (SWDA) and Ankle Brachial Pressure Index (ABI). Peripheral arterial disease (PAD) was diagnosed by measurement of ankle brachial index (ABI) and quantitative pedal waveform analysis was obtained. A handheld continuous wave Doppler with an 8MHz probe (Huntleigh, Cardiff, UK) was used. Waveforms were classified as triphasic, biphasic, monophasic discontinuous, and monophasic continuous. Triphasic waveforms were considered as normal, whereas biphasic, monophasic discontinuous, and monophasic continuous waveforms were interpreted as abnormal [16]. Measurements were carried out after patients rested for 5 min in the supine position. ABI 0.9-1.29 was normal [16]. PAD was defined an ABI ≤ 0.89 in either foot. ABI ≥ 1.3 was considered indicative of vascular calcification [17].

DFUs were categorised according to their type, and only ischaemic ones were included. To ensure this, patients were recruited if they exhibited biphasic/monophasic waveforms and/or ABI was <0.9 [17, 18].

2.3. Procedure for Wound Measurement

Acetate tracing paper with a printed grid was used to calculate wound area. Sterile probes were used to calculate wound depth. A fine-tipped permanent marker was used to trace the wound outline. Minimal pressure was applied while tracing to prevent distorting the shape and border of the ulceration. A 0.2 cm2 grid was used to calculate the area of the ulcer to increase precision. The Wagner grading system was used to grade ulcerations [19]. In this study, ulcerations included were recorded as a grade 1, 2 or 3.

2.4. Treatment Procedure

In group A, 100% oxygen under increased atmospheric pressure was delivered to the lungs of participants through a mask in a multi-place chamber 5 days/week (from Monday to Friday) for approximately 2 h daily, for 40 sessions, as per standard practice [13, 14] and according to our hospital HBOT protocols, under qualified medical supervision. Dressings (calcium alginate) were changed 3 times/week at the HBOT unit.

In both groups, SWC was offered at the tissue viability unit. During each visit, the podiatrist cleansed the wound with sterile saline solution, and any superficial dead tissue or callus present at the lesion or in the surrounding areas was debrided with a sterile scalpel. After wound cleansing, calcium alginate was applied. In all patients, wound measurement was conducted after wound cleansing. Dressings were changed every 2 days in both groups.

2.5. Statistical Analysis

Analysis was carried out with Statistical Package for Social Sciences version 25 (SPSS; SPSS Inc, Chicago, IL). Data were normally distributed, as shown by the Shapiro Wilks test. The independent sample t-test was employed to compare differences between the 2 groups. Significance was defined at the 5% level (two-tailed p<0.05).


Patient characteristics are summarised in Table 1. All patients exhibited monophasic Doppler waveforms denoting severe arterial disease. Table 2 provides details on wound reductions for all participants.

Table 1. Participant characteristics.
Standard Wound Care with
Adjunctive Hyperbaric Oxygen Therapy
Standard Wound Care Only
Age Less than 70 years 7 26.9% 7 26.9%
70 years or more 6 23.1% 6 23.1%
Gender Male 10 38.5% 10 38.5%
Female 3 11.5% 3 11.5%
Weight ≤80 kg 5 19.2% 7 26.9%
>80 kg 8 30.8% 6 23.1%
Diabetes duration <5 years 6 23.1% 6 23.1%
≥5 years 7 26.9% 7 26.9%
Diabetes type Type 1 0 0% 0 0%
Type 2 13 50% 13 50%
Antidiabetic medication Metformin 10 38.5% 10 38.5%
Insulin 3 11.5% 3 11.5%
HbA1c <9% 6 23.1% 6 23.1%
≥9% 7 26.9% 7 26.9%
Waveforms Monophasic 13 50% 13 50%
Biphasic 0 0% 0 0%
Triphasic 0 0% 0 0%
Wagner classification Grade 1 2 7.7% 2 7.7%
Grade 2 2 7.7% 2 7.7%
Grade 3 9 34.6% 9 34.6%
Past ulcers Yes 11 42.3% 8 30.8%
No 2 7.7% 5 19.2%
Smoking history Never 7 26.9% 3 11.5%
Past smoker 5 19.2% 6 23.1%
Present smoker 1 3.8% 4 15.4%
Drinking History Never 10 38.5% 10 38.5%
Past drinker 3 11.5% 3 11.56%
Present drinker 0 0% 0 0%
Table 2. Wound reductions.
Week Range (cm2) Mean (cm2) Std. Dev. p
SWC with adjunctive HBOT 1 7.79 11.73 2.239 <0.001
2 7.54 10.14 2.219
3 6.64 8.96 1.881
4 6.50 7.98 1.951
SWC only 1 3.02 10.60 0.926 <0.001
2 3.17 10.14 0.891
3 2.86 9.78 0.857
4 2.80 9.55 0.835
SWC: standard wound care: HBOT: hyperbaric oxygen therapy.

Both groups demonstrated a significant improvement by the end of the trial; Tables 3-5. However, ulcer area (p<0.001) and depth (p<0.001) exhibited superior improvement in group A.

Table 3. Mean depth by weeks and groups.
Week Range (cm) Mean (cm) Std. Dev. p
SWC with adjunctive HBOT 1 1.50 1.59 0.388 <0.001
2 1.40 1.31 0.362
3 1.00 0.97 0.312
4 0.80 0.71 0.253
SWC only 1 1.10 1.53 0.335 <0.001
2 1.00 1.48 0.322
3 1.00 1.40 0.316
4 1.00 1.34 0.293
SWC: standard wound care: HBOT: hyperbaric oxygen therapy.
Table 4. Mean surface area by weeks and groups.
Group Range (cm2) Mean (cm2) Std. Dev. p
Week 1 SWC with adjunctive HBOT 7.79 11.73 2.239 0.112
SWC only 3.02 10.60 0.926
Week 2 SWC with adjunctive HBOT 7.54 10.14 2.219 0.996
SWC only 3.17 10.14 0.891
Week 3 SWC with adjunctive HBOT 6.64 8.96 1.881 0.173
SWC only 2.86 9.78 0.857
Week 4 SWC with adjunctive HBOT 6.50 7.98 1.951 0.013
SWC only 2.80 9.55 0.835
SWC: standard wound care: HBOT: hyperbaric oxygen therapy.
Table 5. Mean depth clustered by groups and weeks.
Group Range (cm) Mean (cm) Std. Dev. p
Week 1 SWC with adjunctive HBOT 1.50 1.59 0.388 0.669
SWC only 1.10 1.53 0.335
Week 2 SWC with adjunctive HBOT 1.40 1.31 0.362 0.220
SWC only 1.00 1.48 0.322
Week 3 SWC with adjunctive HBOT 1.00 0.97 0.312 0.002
SWC only 1.00 1.40 0.316
Week 4 SWC with adjunctive HBOT 0.80 0.71 0.253 <0.001
SWC only 1.00 1.34 0.293
SWC: standard wound care: HBOT: hyperbaric oxygen therapy.

In group A, mean ulcer area (p=0.013) and depth (p<0.001) were significantly smaller than in group B at week 4. There was also a significant difference in mean ulcer depth between the two groups at week 3 (p=0.002). Reduction of wound area (3.75 cm2 in group A vs. 1.05 cm2 in group B, p<0.001) and ulcer depth (0.89 cm in group A vs. 0.19 cm in group B, p<0.001) were more pronounced in group A.


The present study has demonstrated that adjunct HBOT enhances the reduction of ulcer area and depth at 4 weeks in T2DM patients with ischaemic DFUs. HBOT is known to ensure hyperoxygenation of ischaemic tissue and restoration from hypoxia [13]. Indeed, fibroblasts, endothelial cells, and keratinocytes are replicated at higher rates in an oxygen-rich environment [20]. Moreover, leukocytes kill bacteria more effectively when supplied with oxygen [21]. Furthermore, it has been postulated that HBOT also improves long-term health related quality of life in patients with chronic diabetic foot ulcers possibly attributed to better ulcer healing [22, 23] as has been reported in this study.

New in this study, when compared with previous works, is the elimination of confounding variables known to affect healing by tight control matching of the 2 groups. This represents the main strength of the study, and the authors are confident that the improvement in wound healing was indeed due to the inclusion of HBOT as an adjunct treatment to SWC. Indeed, different wound types, including non-ischaemic ulcers [21] and chronic wound ulcers [24], have been included in prior studies. Conversely, we exclusively evaluated HBOT in newly-diagnosed DFUs.

The limitations of the study include the small number of patients and the absence of sham HBOT. Thus, caution is needed in the interpretation of results.


In conclusion, adjunct HBOT promotes healing of ischaemic DFUs in T2DM patients. Our results add to the growing evidence on the utility of HBOT in the management of DFUs. Nevertheless, optimal patient selection and long-term results with this treatment modality are still needed before its wider use can be advocated.


The study was approved by the institutional Ethics Committee.


No animals were used in this research. All research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2008.


Written informed consent has been obtained for this study.


The authors declare no conflict of interest, financial or otherwise.


Declared none.


[1] Shojaiefard A, Khorgami Z, Larijani B. Independent risk factors for amputation in diabetic foot. Int J Diabetes Dev Ctries 2008; 28(2): 32-7.
[2] Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of diabetic foot ulceration: A systematic review and meta-analysis †. Ann Med 2017; 49(2): 106-16.
[3] Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of diabetic foot: The economic case for the limb salvage team. J Vasc Surg 2010; 52(3)(Suppl.): 17S-22S.
[4] Jeffcoate WJ, Price P, Harding KG. Wound healing and treatments for people with diabetic foot ulcers. Diabetes Metab Res Rev 2004; 20(Suppl. 1): S78-89.
[5] Armstrong DG, Wrobel J, Robbins JM. Guest Editorial: Are diabetes-related wounds and amputations worse than cancer? Int Wound J 2007; 4(4): 286-7.
[6] Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med 2017; 376(24): 2367-75.
[7] Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet 2003; 361(9368): 1545-51.
[8] Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes 2015; 6(1): 37-53.
[9] Sood A, Granick MS, Tomaselli NL. Wound dressings and comparative effectiveness data. Adv Wound Care (New Rochelle) 2014; 3(8): 511-29.
[10] Papanas N, Eleftheriadou I, Tentolouris N, Maltezos E. Advances in the topical treatment of diabetic foot ulcers. Curr Diabetes Rev 2012; 8(3): 209-18.
[11] Corbett LQ, Ennis WJ. What do patients want? Patient preference in wound care. Adv Wound Care (New Rochelle) 2014; 3(8): 537-43.
[12] Bowler PG, Duerden BI, Armstrong DG. Wound microbiology and associated approaches to wound management. Clin Microbiol Rev 2001; 14(2): 244-69.
[13] Tiaka EK, Papanas N, Manolakis AC, Maltezos E. The role of hyperbaric oxygen in the treatment of diabetic foot ulcers. Angiology 2012; 63(4): 302-14.
[14] Löndahl M. Hyperbaric oxygen therapy as treatment of diabetic foot ulcers. Diabetes Metab Res Rev 2012; 28(Suppl. 1): 78-84.
[15] Game FL, Hinchliffe RJ, Apelqvist J, et al. A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev 2012; 28(Suppl. 1): 119-41.
[16] Georgakarakos E, Papanas N, Papadaki E, Georgiadis GS, Maltezos E, Lazarides MK. Endovascular treatment of critical ischemia in the diabetic foot: New thresholds, new anatomies. Angiology 2013; 64(8): 583-91.
[17] Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR. Inter-society consensus for the management of peripheral arterial disease (TASC II) J Vasc Surg 2017; 45: S5-S67.
[18] Huang JY. Doppler ultrasonography of the lower extremity arteries: anatomy and scanning guidelines. Ultrasonography 2017; 36(2): 111-9.
[19] Wagner FW Jr. The dysvascular foot: a system for diagnosis and treatment. Foot Ankle 1981; 2(2): 64-122.
[20] Broussard CL. Hyperbaric oxygenation and wound healing. J Vasc Nurs 2004; 22(2): 42-8.
[21] Kessler L, Bilbault P, Ortéga F, et al. Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: A prospective randomized study. Diabetes Care 2003; 26(8): 2378-82.
[22] Löndahl M, Landin-Olsson M, Katzman P. Hyperbaric oxygen therapy improves health-related quality of life in patients with diabetes and chronic foot ulcer. Diabet Med 2011; 28(2): 186-90.
[23] Löndahl M, Katzman P, Nilsson A, Hammarlund C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care 2010; 33(5): 998-1003.
[24] Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev 2004; (2): CD004123.