INTRODUCTION:

Diabetes mellitus patients who are hospitalized generally experience complications from diabetic foot ulcers (DFU). Based on Diabetic Federation Control, 20-30% of diabetic patients are hospitalized because of diabetic foot ulcers. Ulceration in the lower extremities causes infection of deep tissues followed by neurological disturbances^1,2. This condition can cause the skin barrier to be contaminated with germs and the epidermis layer gets damaged. New cases of diabetes increased by 5%, and 1% experienced leg amputation annually. Foot wounds occur in diabetes patients every 1.2 seconds and diabetes patients experience an amputation every 20 seconds^3–7. Approximately 50% of diabetic foot ulcer patients experience infection which increases the risk of visits to the ER, hospitalization, infection and amputation^8–14. The 5-year mortality rate for DFU patients is comparable to that of most cancers^15,16. The costs incurred by patients with DFU exceed the costs of treating most cancer patients^17,18. DFU patients are more likely to experience abnormal anxiety and depression compared to those with diabetes. Patients with diabetes need precise medication and lifestyle changes to enhance their quality of life^19-21.

Previous studies revealed that Hyperbaric Oxygen Therapy (HBOT) can accelerate wound healing through multiple pathways, including increased ROS, angiogenesis, fibroblast replication, osteoclast activation, plasma antioxidant status, resolution of inflammation, and upregulation of VEGF and platelet-derived growth factor (PDGF)^22–26. Hyperbaric oxygen treatment (HBOT) is a therapeutic method that involves exposing patients to pure quantities of oxygen (O2) under increased atmospheric pressure. The pressure, as defined by the Undersea and Hyperbaric Medical Society (UHMS), could reach 1.4 atmospheres or surpass it. Following the implementation of HBOT, there has been a surge in publications, particularly a growing quantity of RCTs, which have played a significant role in altering practices. This reviews have included randomised and non-randomised controlled trials; have considered all Wagner severity; not only discuss the effectivity and safety but also the quality of life patient with HBOT. The application of HBOT is still controversial because some studies conclude that the use of HBOT led to increased rates of fully healed DFUs and reduced rates of major amputation, meanwhile HBOT needs a massive time and financial commitment. Treatments of HBOT last around 2.5 hours daily and the typical course of therapy involves 30 sessions, lasting a total of 6 weeks. Therefore, this systematic review aims to confirm HBOT effectivity in wound healing and amputation in DFU patients.

METHODS:

Research Strategy:

A systematic review was conducted according to the PRISMA protocol (Figure 1). Databases used for literature searches include PUBMED, SCOPUS and COHCRANE. Keywords used to identify relevant studies were “hyperbaric oxygen therapy”, “diabetic foot”, “foot ulcer”, and their synonyms. Search time for articles in the database is from 2014 until March 2024.

Selection Criteria:

The PICO is as follows: (1) patients with diabetic foot ulcers (without severity restrictions); (2) hyperbaric oxygen therapy as an intervention in the treatment group; (3) the control group received standard treatment or conventional treatment; (4) outcomes included ulcer healing time, ulcer healing rate, minor/major amputation rate, incidence of adverse events or quality of life; and (6) full-text articles in English without publication date restrictions. Studies with irrelevant topics, no controls, duplicated data, or insufficient data were also excluded.

Data Extraction:

Data from retrieval studies were extracted and entered independently by two researchers. If there are differences of opinion between authors, the authors discussed to get concensus. Characteristics of articles included in the systematic review in the form of first author, country, Wagner assessment, number of control groups and intervention groups, number of HBOT sessions, and follow-up time (Table 1).

Quality Assessment:

The authors assessed the quality of studies according to inclusion criteria using Cochrane and ROBINS-I for randomized and non-randomized studies, respectively. Risk of bias assessment was conducted based on selection, allocatio, and performance bias. The risk score on the ROBINS-I scale was graded as ‘low,’ ‘moderate,’ ‘high,’ or ‘critical,’ or if insufficient information was available, it was graded as ‘NI’ (no information).

RESULT:

Study Selection:

The systematic search conducted yielded 953 studies. PUBMED, COHCRANE and SCOPUS resulted 222, 51 and 680 studies, respectively. Among them, 117 were duplicates, therefore these articles were removed before the title and abstract screening. From 719 records retrieved, 18 articles were selected for detailed review. One article was excluded because it was not an experimental research article, and one study was not available as a full-text article. The 16 studies meet inclusion criterias. The design and location of this study are shown in Table 1. The characteristics and findings of each study that met inclusion are summarized in Table 2.

Basic characteristics of the selected studies:

Characteristics of studies which suitable for inclusion consisted of 13 randomized controlled trials (RCTs),^27-39 1 controlled clinical trial,⁴⁰ 1 world retrospective data,⁴¹ and 1 retrospective cohort study⁴². Most studies used the 90minute HBOT protocol with pressure between 2.3-2.8 ATA for 5- 6 days a week, for 20 to 40 sessions. In Fadol's study, the number of HBOT sessions adjusted for the severity of the injury which was classified into <20 and >20 sessions. Thirteen studies measured clinical outcomes in the form of ulcer healing^{28,29,31-36,38-42}, four studies measured wound improvement^29,30,35,37, and seven studies monitored side effects^{27,28,30,32,34,36,42}. Amputation was measured in nine studies ^{27,28,31,32,35,36,39-41} most of which classified minor and major amputations. Mortality was obtained from two studies^32,36 as well as two other studies^32,39reporting TcpO2 values measured on the dorsum of foot. HBOT follow-up is carried out for 2 weeks to 3 years.

Gambar 1. Prisma diagram of HBOT studies

Characteristics of patients in the study:

Baseline characteristics of patients in the included studies are shown in Table 2. Six studies^{33-34,36-37,40-41}did not provide baseline statistics for subgroups. One study found significant differences in the initial characteristics²¹. One study included patients with ulcers classified as Wagner II-V⁴², seven studies included patients with ulcers in Wagner grades classified as II-IV^{27,31,32,34,36,39,41}, four studies included patients in Wagner grades I-III^29,30,35,37, two studies included Wagner class III-IV^33,41, one study included Wagner class II-III³⁸ and another included patient of Wagner class I-II²⁸.

Article quality assessment:

Due to the differences in protocol and the session of HBOT interventions, as well as the grade and size of wounds at inclusion, clinical heterogeneity in the studies was substantial. In general, the Cochrane risk of bias assessment yielded mostly positive results, although the authors failed to provide sufficient details about the blinding of investigators or assessors. or the randomization method used. One study⁴⁰ showed a serious risk of bias and other studies^41,42showed a moderate risk of bias based on the ROBINS-I.

Wound healing:

A comprehensive meta-analysis was not possible for HBOT in the treatment of diabetic ulcers due to variations in clinical factors. Heterogeneity was caused by different Wagner levels and HBOT sessions. Both the randomized controlled trials^{28-32,35,37,38} and the non-randomized^40,41 studies reported significant differences in wound healing. Duzgu et al.³¹ found that 66% of patients in the HBOT group achieved complete wound healing, while Abidia et al. and Santema et al. reported complete ulcer healing after 1 year. Abidia et al.²⁸ reported that there was a significant difference in the reduction of ulcer area in the HBOT group compared to the control group (P=0.027)) at week 6. Ma et al.³⁰ observed a significant reduction in ulcer size on days 7 and 14. Perren et al found a significantly different reduction in wounds at week 4. Kessler et al found a statistically significant decrease in the percentage of ulcer surface area within 2 weeks of treatment and no statistically significant decrease after 4 weeks. Santema et al³⁶discovered no significant difference in wound repair rates between the HBOT (50%) and control groups (47%) after a year (RD, 3%; 95% CI, 15-22). Khandelwal et al³³ and Ferdoko et al³⁴ also found no significant difference between complete ulcer healing in the HBOT group versus the control group.

Table 1. Study Characteristics

Writer	Year	Country	Method	Wagner level	HBOT Subjects	Control Subjects	HBOT Protocol	Number of sessions	Follow-up	Outcomes
Faglia²⁷	1996	Italy	RCT	II-IV	35	33	2.5 ATA 90' (5x/week)	NA	NA	Amputation
Abidia²⁸	2003	UK	RCT	I-II	8	8	2.4 ATA 90' (5x/week)	30	6 months, 1 year	Wound healing, amputations, side effects
Kessler²⁹	2003	French	RCT	I-III	15	13	2.5 ATA 90' (5x/week)	20	4 weeks	Wound improvement, TcPO2, side effects
Ma³⁰	2013	China	RCT	I-III	18	18	2.5 ATA 90' (2x/day)	20	NA	Wound improvement, TcPO2, side effects
Duzgun³¹	2008	Türkiye	RCT	II-IV	50	50	2-3 ATA, 90' (2x/day, 1x/day)	20-30	92 + 12 weeks	Wound improvement, amputation
Londahl³²	2010	Sweden	RCT	II-IV	38	37	2.5 ATA, 90' (5x/week)	40	3 months, 1 year	Wound healing, amputation, side effects, death
Khandelwal³³	2013	India	RCT	III-IV	15	14	2.5 ATA 60'	30	NA	Wound healing
Fedorko³⁴	2016	Canada	RCT	II-IV	39	48	2.4 ATA 90' (5x/week)	30	6 weeks	Wound improvement, side effects
Chen³⁵	2017	Taiwan	RCT	I-III	30	18	2.5 ATA 120' (5x/week)	20	2 weeks	Wound healing, amputation
Santema³⁶	2018	Dutch	RCT	II-IV	39	56	2.4-2.5 ATA 90' (5x/week)	40	3, 6, 12 months	Wound healing, amputation, side effects, death
Perren³⁷	2019	Malta	RCT	NA	13	13	5x/week	40	NA	Wound improvement
Salama³⁸	2019	Egypt	RCT	II-III	15	15	2.5 ATA 60' (5x/week)	20-40	12 months	Wound healing
Kumar³⁹	2020	India	RCT	II-IV	28	26	2.4 ATA 90' (6x/week)	36	Every 3 months/ 1 year	Wound improvement, amputation
Baroni⁴⁰	1987	Italy	CCT	NA	18	10	2.8 ATA 90'	34+21.8	3 years	Wound healing
Ennis⁴¹	2019	Illinois	RW	III-IV	6616	18946	>2 ATA 90-120'	>40	NA	Wound improvement, amputation
Fadol⁴²	2021	Sudan	DR	II-IV	120	0	2.5 ATA 90' (6x/week)	According to severity	1 year	Wound improvement, side effects

Table 2. Patient Demographic Baseline

Writer	HBOT (n)	Control (n)	Wound Improves n (%)		Wound Heals n (%)		Amputation n (%)				Death n (%)
			Wound Improves n (%)		Wound Heals n (%)		Minor		Major		Death n (%)
			HBOT	Control	HBOT	Control	HBOT	Control	HBOT	Control	HBOT	Control
Faglia²⁷	35	33	-	-	-	-	5(14)*	4 (12)	3 (9)*	11 (33)	-	-
Abidia²⁸	8	8	-	-	5* (63)	1 (13)	1	0	1	1	-	-
Kessler²⁹	15	13	41*^	21	2 (13)	0 (0)	-	-	-	-	-	-
Ma³⁰	18	18	42^	18	-	-	-	-	-	-	-	-
Duzgun³¹	50	50	-	-	33 (66)*	0 (0)	0 (0)*	17 (34)	4 (8)*	24 (48)	-	-
Londahl³²	38	37	-	-	25 (52)*	12 (29)	4 (11)	4 (11)	3 (8)	1 (3)	1 (3)	3 (8)
Khandelwal³³	15	14	-	-	9 (60)	6 (40)	-	-	-	-	-	-
Fedorko³⁴	39	48	-	-	10 (20)	12 (22)	-	-	-	-	-	-
Chen³⁵	30	18	3 (10)	1 (6)	5 (17)*	1 (6)	-	-	2 (6)	2 (11)	-	-
Santema³⁶	39	56	-	-	33 (55)	29 (48)	-	-	7 (12)	13 (22)	5 (8)	9 (15)
Perren³⁷	13	13	6.5 cm2*	2.8 cm2	-	-	-	-	-	-	-	-
Salama³⁸	15	15	-	-	5 (33)*	0 (0)	-	-	-	-	-	-
Kumar³⁹	28	26	-	-	22 (78)*	0 (0)	2 (7)*	12 (46)	0 (0)*	3 (11)	-	-
Baroni⁴⁰	18	10	-	-	16 (89)	1 (10)	-	-	2 (11)*	4 (40)	-	-
Ennis⁴¹	6616	18946	-	-	3970(60)	10230 (54)	-	-	4.16	4.06	-	-
Fadol⁴²	120	-	-	-	72 (60)	-	-	-	-	-	-	-

Note: *=statistically significant different; ^=percentage of injury reduction

Amputation rate:

Nine studies^{27,28,31,32,35,39-41} reported amputation rates in patients with DFU. Five studies^{27,28,31,32,39} differentiated between major and minor amputations, as well as distal and proximal amputations, while four studies^35,36,40,41 only reported on amputations. The incidence of major and minor amputations shows a statistically significant difference based on data from Faglia et al²⁷, Duzgun et al³¹, and Kumar et al.³⁹, while Baroni⁴⁰ notes that there is a significant difference in the incidence of major amputations. This contrast withthe results obtained by Abidia et al¹⁸, Londahl et al³², Chen et al³⁵, Santema et al³⁶, and Ennis et al⁴¹.

Death:

Two studies^32,36 did not report significant differences in mortality. The mortality rates in HBOT group varied from 3% to 8%, while in the control group, they ranged from 8% to 15%.

HBOT Session:

The total number of HBOT sessions received by patients varied between studies. The majority of studies utilized a set amount of 20, 30, or 40 sessions. Out of the five studies, completion rates for HBOT were reported in five. Abidia et al.²⁸ reported 100% treatment completion, Ferdoko et al,³⁴ reported that 76% of patients completed 30 sessions of HBOT, Santema et al.³⁶ found that 65% of patients completed HBOT therapy, Chen³⁵ reported that 38 patients completed 20 sessions and Londahl³² reported that 57% of patients attended 40 sessions; 75% of patients attended more than 35 sessions; and 9 patients were followed for fewer than 10 sessions

Quality of Life:

Two studies^28,35 measured patient’s quality of life. Abidia et al.²⁸ reported that the use of HBOT did not lead to an improvement in the participants' quality of life. Two questionnaires, the SF-36 and the Hospital Anxiety and Depression Scale (HADS), were used to measure the quality of life, and there was no notable difference observed between the group that received HBOT and the control group.Chen's³⁵ study shows that HBOT can improve quality of life by using the SF-36 and Health-Related Quality of Life (HRQOL) to compare the two arms, and with results indicating that the HBOT group relieves the patient's stress.

Adverse events:

Seven studies looked at adverse events that emerged during studies of hyperbaric oxygen therapy in diabetic ulcer patients. The side effect found in all reporting articles was barotrauma (Table 3). Ferdoko et al.³⁴ reported that one patient experienced (Chronic Heart Failure) CHF. Other patients experienced ear barotrauma in the HBOT and sham groups, respectively 5 and 3. Other complaints in both groups, namely visual impairment, were 4 and 3 respectively. Santema et al.³⁶ documented five incidence of side effects. Myringotomy was necessary for three patients, while one patient suffereded from oxygen-induced seizures, and another patient experienced barotrauma. Faglia et al.²⁷ detailed two occurrences of barotraumatic otitis. According to Kessler et al., one out of 14 patients (7.1%) was discharged following an episode of barotraumatic otitis, which resolved without any further issues. Abidia et al.²⁸ and Ma et al.³⁰ reported that no side effects occurred.

DISCUSSION:

Diabetic ulcer is the leading cause of amputation and disability in diabetic patients. Since the 1990s, hyperbaric oxygen therapy has been reported to be effective for treating diabetic ulcers, but experimental studies supporting the effectiveness of HBOT therapy are lacking., this systematic review observed the effectiveness of HBOT for diabetic ulcers. This review assesses the clinical outcomes of HBOT in treating diabetic foot ulcers and the impact on the patients’ quality of life.

Our study confirms that HBOT may has benefits in healing diabetic ulcers and accelerates wound healing. This review analysis shows that HBOT reduces major amputations and provides no benefit in minor amputations. Despite of some benefits of the hyperbaric oxygen therapy, there were also some group that experienced HBOT-related side effects, such as middle ear barotrauma, ear pain, oxygen-induced seizures, myringotomy, and advanced cataracts.

The differences in HBOT protocol included in this study are different hyperbaric conditions, duration, and number of treatment sessions for each patient. Some patients are unable to complete 30 HBOT sessions due to various reasons. Protocols with shorter HBOT periods may improve patient compliance. Research conducted by Kessler et al. and Ma et al. applied twice daily HBOT, so the resulting protocol was shorter than other studies^29,30. Santema et al reported that 35% of patients did not complete 30 HBOT sessions³⁶. This can be interpreted as the patient finds it difficult to complete treatment due to comorbidities and travel. A total of 57% of patients completed 40 HBOT sessions and 75% completed at least 35 sessions in the study by Löndahl et al. Chen et al reported that 91% of patients completed treatments; Abidia et al. reported 100%^32,35,36. Eligible patients must receive information about the HBOT protocol for a minimum of 4 weeks.

The results of our review are in line with most systematic reviews and meta-analyses, but there is some controversy regarding the effectiveness of HBOT in reducing amputation rates (Table 2) and improving quality of life. According to Sharma et al., HBOT effectively reduced the need for large amputations but did not have a significant impact on the rate of small amputations⁴³. Brouwer et al conducted a systematic review and meta-analysis on diabetic foot ulcers with arterial insufficiency, reporting that adjuvant HBOT was effective in reducing the rate of major amputation, but did not heal the wound⁴⁴. HBOT enhances transcutaneous oxygen pressure measurement (TcpO2) and local tissue oxygenation. Further studies showed that HBOT may enhance bacteriostatic activity on anaerobic bacterial, activate stem cells and growth factors, reduce inflammatory responses, and enhance neovascularization⁴⁵. In contrast, Stoekenbroek et al. conducted a similar meta-analysis and proved that although HBOT did not show enough evidence to reduce diabetic ulcer amputations but wound size was reduced in the HBOT group⁴⁶. This difference may be due to articles in languages other than English being included in the inclusion criteria. The study conducted by Di Zhao et al showed that HBOT had no significant differences compared to the control group in ulcer healing, risk of amputation, and side effects. In lowering the amputation rate among DFU patients, HBOT is not the only one crucial point⁴⁷. Rather, the total duration and number of sessions may be more effective⁴³. O'Reilly et al. conducted research that was included in the observationalstudies ⁴⁸. The study findings indicated that HBOT led to a substantial decrease in the likelihood of major amputation (RR = 0.39, 95% CI: 0.21-0.73) and were in line with our analysis.

In a Cochrane review of chronic diabetic wounds and HBOT conducted by Kranke et al., the conclusion was that wound healing was achieved more frequently with HBOT at 6 weeks (although there was no difference after 6 and 12 months)⁴⁹. A meta-analysis conducted by Zhang confirmed that hyperbaric oxygen therapy increased the healing rate of diabetic ulcers (RR 1.901; 95%CI=1.484-2.435, p<0.0001)⁵⁰. Golledge et al reported that HBOT can improve the healing of diabetic foot ulcers and reduce major and minor amputations⁵¹. HBOT lowers inflammation, the second step in wound healing, by controlling the quantity and activity pf several inflammatory cell types. At the molecular level, oxygen has the ability to promote anti-inflammatory factors (IL-1Ra, IL-4 and IL-10) and inhibit pro-inflammatory ones (IL-1b, IL-2, IL-6, TNF-a, PGE2 and COX2)⁵². Oxygen triggers macrophages to generate angiogenic substances, such as HIF-1a, IL-1a, FGF-2, SDF-1 and VEGF (vascular endothelial growth factor), which draw and activate endothelial cells. Consequently, the process of neovascularization is weakened by hypoxia. By creating an oxygen-rich environment that promotes collagen formation and deposition, HBOT increases fibroblast activity^53,54.

Brouwer et al. found no discernible difference in the quality of life between the group that received Hyperbaric Oxygen Therapy (HBOT) and the control group, which aligns with our study's results. The disparity in findings can be attributed to the distinct attributes of the two studies. A systematic review and meta-analysis carried out by Liu et al. demonstrated that hyperbaric oxygen therapy has the potential to enhance the quality of life for patients undergoing HBOT.

The limitations of this review are the small sample size and the fact that only a few studies met the inclusion criteria. High heterogeneity means that a meta-analysis cannot be carried out, so care needs to be taken when using the results of this review. The second limitation is that the number of articles examining side effects is still not optimal.

Future research is expected to focus on the effectiveness of HBOT, especially on total ulcer healing, cost analysis, side effects, and patient quality of life. Patient selection is necessary to identify criteria for patients who will benefit most from adjuvant HBOT therapy. A larger-scale study determining effective HBOT sessions needs to be conducted.

CONCLUSION:

Hyperbaric oxygen therapy may has benefits in healing diabetic ulcer wounds and reducing amputations. The mild side effect during HBOT such as otitis barotrauma. Future research should be enlarging the patient sample number to evaluate the effectiveness and safety of HBOT in DFU.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank LPDP (Educational Fund Management Institution) and BPPT (Higher Education Financing Centre) Indonesian Ministry of Education and Culture for funding this research.

REFERENCES:

1. Mendes J. Neves J. Diabetic Foot Infections: Current Diagnosis and Treatment. The Journal of Diabetic Foot Complications. 2012; 4(2): 26-45.

2. Prasad J. Netam AK. Sahu MK. Satapathy T. Current Concepts in Clinical Based Management of Diabetic Foot Infections: A Review. Research Journal of Pharmacology and Pharmacodynamics. 2017; 9(3): 157–166. doi: 10.5958/2321-5836.2017.00027.1

3. Frykberg RG. Number eight in the service of diabetic foot ulcer healing. Diabetes Care. 2020; 43: 515–517. doi: 10.2337/dc20-0729.

4. Gong XB, Feng RH, Dong HM, Liu WH, Gu YN, Jiang XY, et al. Efficacy and Prognosis of Hyperbaric Oxygen as Adjuvant Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Meta-Analysis Study. Front Pediatr. 2022; 10: 707136. doi:10.3389/fped.2022.707136

5. Boulton AJM, Armstrong DG, Kirsner RS, Attinger CE, Lavery LA, Lipsky BA, et al. Diagnosis and management of diabetic foot complications. Diabetes. 2018; (2): 1–20. doi: 10.2337/db20182-1

6. Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017; 376(24): 2367–75. doi: 10.1056/NEJMra1615439.

7. Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJG, Armstrong DG, et al. Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections. Clinical Infectious Diseases. 2012: 54(12): e132–73. https://doi.org/10.1093/cid/cis346

8. Lipsky BA, Senneville É, Abbas ZG, Aragón‐Sánchez J, Diggle M, Embil JM, et al. Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update). Diabetes Metabolism Res. 2020 Mar [cited 2024 Jun 10]; 36(S1): e3280. Available from: https://onlinelibrary.wiley.com/doi/10.1002/dmrr.3280

9. Skrepnek GH, Mills JL, Armstrong DG. A Diabetic Emergency One Million Feet Long: Disparities and Burdens of Illness among Diabetic Foot Ulcer Cases within Emergency Departments in the United States, 2006-2010. PLoS One. 2015; 10(8): e0134914. doi: 10.1371/journal.pone.0134914

10. Abbas HA, El-Sayed AES, Al-Kadi L, Gad IG. Diabetic foot infections in Zagazig University Hospital: bacterial etiology, antimicrobial resistance and biofilm formation. Research J Pharm and Tech. 2014; 7(7): 783–8.

11. Abbas HA. Diabetic Foot Infection. Research Journal of Pharmacy and Technology. 2015; 8(5): 575–9.

12. Dewangan V, Pandey H. Pathophysiology and Management of Diabetes: A Review. Research Journal of Pharmacology and Pharmacodynamics. 2017; 9(4): 219–22.

13. Sangeetha V, Nandhini PS, Saraswathy M, Sasmitha D, Senthilkumar T, Deepa R. Diabetic Foot Care: A study. Asian Journal of Nursing Education and Research. 2019; 9(3): 422–8. Available from: https://ajner.com/AbstractView.aspx?PID=2019-9-3-30

14. Shilpa S. Risk Status of Lower Extremity Arterial Disease (LEAD) among persons with Diabetes Mellitus. Int J of Advances in Nur Management. 2019; 7(1): 13–9. Available from: https://www.indianjournals.com/ijor.aspx?target=ijor:ijanm&volume=7&issue=1&article=004

15. Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, et al. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. European Journal of Vascular and Endovascular Surgery. 2019; 58(1): S1-S109.e33. doi: 10.1016/j.jvs.2019.02.016.

16. Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, Bus SA. Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res. 2020; 13(1): 16. doi: 10.1186/s13047-020-00383-2.

17. Nussbaum SR, Carter MJ, Fife CE, DaVanzo J, Haught R, Nusgart M, et al. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value Health. 2018; Jan; 21(1): 27–32. doi: 10.1016/j.jval.2017.07.007.

18. Barshes NR, Sigireddi M, Wrobel JS, Mahankali A, Robbins JM, Kougias P, et al. The system of care for the diabetic foot: objectives, outcomes, and opportunities. Diabet Foot Ankle. 2013; 4(10): 4. doi: 10.3402/dfa.v4i0.21847.

19. Maheshwari P, Pavithra D, Neethu TT, Shanmugarajan TS, Shanmugasundaram P. Study on Health Outcomes in Diabetic Patients - Association Between Diabetic Foot Ulcer and Psychological Distress. Research Journal of Pharmacy and Technology. 2017; 10(1): 44–8. doi: 10.5958/0974-360X.2017.00011.7

20. Geetha V, Shrimant K, Sahu C, Susila. Assess Quality of Life (QOL) and Glycemic Level among Type 2 Diabetic Patients in Global Hospital and Research Centre and its Units, Sirohi, Rajasthan. Asian J Nur Edu and Research. 2017; 7(4): 577–82. doi: 10.5958/2349-2996.2017.00112.4

21. Sajel S, Saranya P. Quality of Life in patients experiencing Diabetic Foot Ulcer: A cross sectional study in a Clinical Pharmacist’s Perspective. Research J Pharm and Tech. 2017; 10(1): 219–22. doi: 10.5958/0974-360X.2017.00046.4

22. Capo X. Hyperbaric Oxygen Therapy Reduces Oxidative Stress and Inflammation, and Increases Growth Factors Favouring the Healing Process of Diabetic Wounds - PMC. Int J Mol Sci. 2023; 24(8): 7040. doi: 10.3390/ijms24087040.

23. Sunkari VG, Lind F, Botusan IR, Kashif A, Liu ZJ, Ylä-Herttuala S, et al. Hyperbaric oxygen therapy activates hypoxia-inducible factor 1 (HIF-1), which contributes to improved wound healing in diabetic mice. Wound Repair Regen. 2015; 23(1):98–103. doi: 10.1111/wrr.12253.

24. Memar MY, Yekani M, Alizadeh N, Baghi HB. Hyperbaric oxygen therapy: Antimicrobial mechanisms and clinical application for infections. Biomed Pharmacother. 2019; 109: 440–7. doi:10.1016/j.biopha.2018.10.142.

25. Yildirim AO, Eryilmaz M, Kaldirim U, Eyi YE, Tuncer SK, Eroǧlu M, et al. Effectiveness of hyperbaric oxygen and ozone applications in tissue healing in generated soft tissue trauma model in rats: An experimental study. Ulusal Travma ve Acil Cerrahi Dergisi. 2014; 20(3): 167–75. doi: 10.5505/tjes.2014.09465

26. Sonia M. Hyperbaric Oxygen Therapy (HBOT): An Overview. International Journal of Advances in Nursing Management. 2021; 9(1): 99–101.

27. Faglia E, Favales F, Aldeghi A, Calia P, Quarantiello A, Oriani G, et al. Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study. Diabetes Care. 1996; 19(12): 1338–43. doi: 10.2337/diacare.19.12.1338.

28. Abidia A, Laden G, Kuhan G, Johnson BF, Wilkinson AR, Renwick PM, et al. The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: A double-blind randomized-controlled trial. European Journal of Vascular and Endovascular Surgery. 2003; 25(6): 513–8. doi: 10.1053/ejvs.2002.1911.

29. Kessler L, Bilbault P, Ortéga F, Grasso C, Passemard R, Stephan D, 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. doi: 10.2337/diacare.26.8.2378.

30. Ortega MA, Fraile-Martinez O, Garcia-Montero, et al. A General Overview on the Hyperbaric Oxygen Therapy: Applications, Mechanisms and Translational Opportunities. Medicina (Kaunas). 2021; 57(9):864. doi: 10.3390/medicina57090864.

31. Duzgun AP, Satir HZ, Ozozan O, Saylam B, Kulah B, Coskun F. Effect of Hyperbaric Oxygen Therapy on Healing of Diabetic Foot Ulcers. Journal of Foot and Ankle Surgery. 2008; 47(6): 515–9. doi:10.1053/j.fas.2008.08.002.

32. Löndahl M. Hyperbaric oxygen therapy as adjunctive treatment of diabetic foot ulcers. Medical Clinics of North America. 2013; 97(5): 957–80. doi: 10.1177/1534734613486154.

33. Khandelwal S, Chaudhary P, Poddar DD, Saxena N, Singh RAK, Biswal UC. Comparative Study of Different Treatment Options of Grade III and IV Diabetic Foot Ulcers to Reduce the Incidence of Amputations. Clinics and practice. 2013; 3(1): e9–e9. doi: 10.4081/cp.2013.e9.

34. Fedorko L, Bowen JM, Jones W, Oreopoulos G, Goeree R, Hopkins RB, et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care. 2016; 39(3): 392–9. doi: 10.2337/dc15-2001.

35. Chen CY, Wu RW, Hsu MC, Hsieh CJ, Chou MC. Adjunctive Hyperbaric Oxygen Therapy for Healing of Chronic Diabetic Foot Ulcers: A Randomized Controlled Trial. J Wound Ostomy Continence Nurs. 2017; 44(6): 536–45. doi: 10.1097/WON.0000000000000374.

36. Santema KTB, Stoekenbroek RM, Koelemay MJW, Reekers JA, Van Dortmont LMC, Oomen A, et al. Hyperbaric oxygen therapy in the treatment of ischemic lower-extremity ulcers in patients with diabetes: Results of the DAMO2CLES multicenter randomized clinical trial. Diabetes Care. 2018; 41(1): 112–9. doi: 10.2337/dc17-0654.

37. Perren S. Hyperbaric Oxygen Therapy in Ischaemic Foot Ulcers in Type 2 Diabetes: A Clinical Trial. Open Cardiovasc Med J. 2018; 12: 80–5. doi:10.2174/1874192401812010080.

38. Salama SE, Eldeeb AE, Elbarbary AH, Abdelghany SE. Adjuvant Hyperbaric Oxygen Therapy Enhances Healing of Nonischemic Diabetic Foot Ulcers Compared With Standard Wound Care Alone. International Journal of Lower Extremity Wounds. 2019; 18(1): 75–80. doi: 10.1177/1534734619829939.

39. Kumar A, Shukla U, Prabhakar T, Srivastava D. Hyperbaric oxygen therapy as an adjuvant to standard therapy in the treatment of diabetic foot ulcers. Journal of Anaesthesiology Clinical Pharmacology. 2020; 36(2): 213–8. doi: 10.4103/joacp.JOACP_94_19.

40. Baroni G, Porro T, Faglia E, Pizzi G, Mastropasqua A, Oriani G, et al. Hyperbaric oxygen in diabetic gangrene treatment. Diabetes Care. 1987; 10(1): 81–6. doi: 10.2337/diacare.10.1.81.

41. Ennis WJ, Huang ET, Gordon H. Impact of Hyperbaric Oxygen on More Advanced Wagner Grades 3 and 4 Diabetic Foot Ulcers: Matching Therapy to Specific Wound Conditions. Advances in Wound Care. 2018; 7(12): 397–407. doi: 10.1089/wound.2018.0855.

42. Fadol EM, Suliman HM, Osman B, Abdalla SA, Osman WJA, Mohamed EM, et al. Therapeutic outcomes evaluation of adjuvant hyperbaric oxygen therapy for non-healing diabetic foot ulcers among sudanese patients. Diabetes Metab Syndr. 2021; 15(4): 102173. doi: 10.1016/j.dsx.2021.06.010.

43. Sharma R, Sharma SK, Mudgal SK. Efficacy of hyperbaric oxygen therapy for diabetic foot ulcer, a systematic review and meta-analysis of controlled clinical trials. Sci rep. 2019; 11(1): 2189. doi: 10.1038/s41598-021-81886-1.

44. Brouwer RJ, Lalieu RC, Hoencamp R, van Hulst RA, Ubbink DT. A systematic review and meta-analysis of hyperbaric oxygen therapy for diabetic foot ulcers with arterial insufficiency. Journal of Vascular Surgery. 2020; 71(2): 682-692.e1. doi: 10.1016/j.jvs.2019.07.082.

45. Camporesi EM. Side effects of hyperbaric oxygen therapy. Undersea Hyperb Med. 2014; 41(3): 253–7.

46. Stoekenbroek RM, Santema TB, Legemate DA, Ubbink DT, Van Den Brink A, Koelemay MJW. Hyperbaric oxygen for the treatment of diabetic foot ulcers: A systematic review. European Journal of Vascular and Endovascular Surgery. 2014; 47(6): 647–55. doi: 10.1016/j.ejvs.2014.03.005.

47. Zhao D, Luo S, Xu W, Hu J, Lin S, Wang N. Efficacy and Safety of Hyperbaric Oxygen Therapy Used in Patients With Diabetic Foot: A Meta-analysis of Randomized Clinical Trials. Clin Ther. 2017t; 39(10) :2088-2094.e2. doi: 10.1016/j.clinthera.2017.08.014.

48. O’Reilly D, Linden R, Fedorko L, Tarride JE, Jones WG, Bowen JM, et al. A prospective, double-blind, randomized, controlled clinical trial comparing standard wound care with adjunctive hyperbaric oxygen therapy (HBOT) to standard wound care only for the treatment of chronic, non-healing ulcers of the lower limb in patients with diabetes mellitus: a study protocol. Trials. 2011; 7(12): 69. doi: 10.1186/1745-6215-12-69.

49. Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE, Weibel S. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev. 2015; 2015(6): CD004123. doi: 10.1002/14651858.CD004123.pub4.

50. Zhang Z, Zhang W, Xu Y, Liu D. Efficacy of hyperbaric oxygen therapy for diabetic foot ulcers: An updated systematic review and meta-analysis. Asian Journal of Surgery. 2022; 45(1): 68–78. doi: 10.1016/j.asjsur.2021.07.047.

51. Golledge J, Singh TP. Systematic review and meta-analysis of clinical trials examining the effect of hyperbaric oxygen therapy in people with diabetes-related lower limb ulcers. Diabet Med. 2019; 36(7): 813–26. doi: 10.1111/dme.13975.

52. Fu Q, Duan R, Sun Y, Li Q. Hyperbaric oxygen therapy for healthy aging: From mechanisms to therapeutics. Redox Biology. 2022; 53: 102352. doi: 10.1016/j.redox.2022.102352.

53. Bhutani S, Vishwanath G. Hyperbaric oxygen and wound healing. Indian J Plast Surg. 2012; 45(2):316–24. doi: 10.4103/0970-0358.101309.

54. Capo X. Hyperbaric Oxygen Therapy Reduces Oxidative Stress and Inflammation, and Increases Growth Factors Favouring the Healing Process of Diabetic Wounds - PMC. Int J Mol Sci. 2023; 24(8):7040. doi: 10.3390/ijms24087040.

Received on 11.06.2024 Revised on 16.10.2024

Accepted on 17.12.2024 Published on 02.05.2025

Available online from May 07, 2025

Research J. Pharmacy and Technology. 2025;18(5):2399-2406.

DOI: 10.52711/0974-360X.2025.00343

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

	Faglia²⁷	Abidia²⁸	Ma³⁰	Londahl³²		Fedorko³⁴		Santema³⁶	Fadol³²
	Faglia²⁷	Abidia²⁸	Ma³⁰	HBOT	Sham	HBOT	Sham	Santema³⁶	Fadol³²
No side effects	-	(+)	(+)	-	-	-	-	-	-
Otitis barotrauma	2	-	-	1	-	5	3	1	24
Myringotomy	-	-	-	2	2			1
Visual disturbances	-	-	-	1	-	4	3	-	-
Balance disorder	-	-	-	1	1	9	0	-	-
Dizziness	-	-	-	1	1	-	-	-	-
Seizures	-	-	-	-	-	-	-	1	-