Document Type : Original article


1 School of Medicine, Islamic Azad University Tehran Faculty of Medicine, Tehran, Iran

2 School of Medicine, Islamic Azad University Tehran Faculty of Medicine, Tehran, Iran.

3 School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

4 School of Rehabilitation Sciences, Iran University of Medical Sciences, Tehran, Iran.

5 Assistant professor of Orthopedic Department, Islamic Azad University Tehran Faculty of Medicine, Tehran, Iran.


Introduction:One of the most common diabetes complications is diabetic foot ulcer (DFU). Besides conventional treatments, hyperbaric oxygen therapy (HBOT) is known as an adjunctive therapy for DFU. This study aimed to investigate the efficacy of HBOT and possible risk factors.
Methods:This study was conducted in two hyperbaric clinics of Bahar and Khatam, respectively in Isfahan and Tehran, Iran, between September 2016 and September 2017. Eligible participants underwent 100% oxygen at 2 to 2.5 atmosphere absolute for 90 to 120 minutes daily (five days per week). Data were analyzed with SPSS version 24.0.
Results: The recovery rate was 69% in 58 enrolled patients and had a significant direct association with good glycemic control status, before (p <0.01) and during HBOT (P < 0.01), and low-grade ulcers (P= 0.04). The mean number of HBOT sessions of the cured patients (21.5±17.1) was significantly higher than that of the not cured patients (11.3 ± 7.9) (P= 0.02). However, the recovery rate had no significant association with the type of ulcer (P= 0.1).
Conclusion: HBOT had good efficacy and a high recovery rate in DFU treatment. Given the fact that good glycemic control status reduces the incidence of ulcers, this study showed that it increased the DFU recovery rate under HBOT.


Diabetes mellitus (DM) affects around 463 million people worldwide in 2019 and is one of the most common chronic metabolic diseases. It is estimated that the DM prevalence will rise up to 10.9%, by 2045 worldwide. Besides, a study estimated that DM prevalence may affect 5.2 million people in Iran, by 2025 (1-7). DM has multiorgan complications. The increase of the level of blood sugar (BS) raises the susceptibility to infection and ischemia occurrence, thus leads to damage in vessels and nerves. Diabetic foot ulcer (DFU) is one of the most common complications of diabetes. It is

defined as a type of wound in diabetes patients, a good surface for developing infections. DFU occurs in 15% to 25% of diabetes patients during their life. Recent studies estimated the prevalence of DFU to be 6.3% worldwide and declared that it has 2% growth per year (1, 4, 8-13).
DFU has high mortality and morbidity including osteomyelitis, local infections, sepsis, amputation, and psychological disorders, and 84% of lower leg amputations are due to the progression of DFU (14, 15). A study showed that the mortality rate of diabetes patients was three times higher in those with DFU (16).
Surgical and non-surgical treatments, such as maggot therapy, growth factor therapy, and hyperbaric oxygen therapy (HBOT), are used for DFU treatment. Choosing the best therapeutic method with a highly satisfactory and low adverse outcome is still a matter of debate. HBOT, as one of the safest methods, has attracted more attention recently. Some studies showed high acceptability and significant efficacy of HBOT in decreasing the number of amputations among diabetes patients (2, 3, 17-19). HBOT was introduced by Gottlieb in 1977 for the first time for treating DFU, but it is still used as an adjunctive method (4, 16, 19).
Oxygen is an indispensable part of tissue repair, and HBOT uses 100% oxygen with a pressure of two to three atmosphere absolute (ATA). HBOT can increase angiogenesis, enhance the leukocytes and stem cell functions, release the growth factors, decrease the hypoxic area and edema, and finally heal the wounds (1, 3, 18-20). Studies showed that HBOT improved DFU prognosis over long-term use (21-24). In contrast, other studies declared that HBOT could not significantly improve the healing process or decrease the amputation rate (25). A study among 28 patients with DFU reported no significant difference between the case and control groups in terms of using HBOT (26).
Note that the duration for HBOT to be effective varies in different studies, based on the type, size, and condition of the wound, and it mostly reached 40 sessions during 4 to 6 weeks (1).
As very few studies have already investigated the efficacy of HBOT among Iranian patients with DFU, this study aimed to assess the recovery rate of using HBOT for treating DFU and possible associated risk factors. 

Study design
This was a two-center clinical study among diabetes patients with DFU from two private hyperbaric clinics of Bahar in Isfahan and Khatam in Tehran, Iran, between September 2016 and September 2017. The protocol of this study was approved by the ethics committee of Islamic Azad University, Tehran Faculty of Medicine. It was conducted in accordance with the Declaration of Helsinki (7th revision, 2013). The participants were included only after obtaining written informed consent. All information was used anonymously. This study imposed no additional costs to the patients or the healthcare system.

Study population
Diabetes patients over 18 years old who had ulceration of foot tissue associated with neuropathy and/or peripheral artery disease (27) and gave informed consent for using HBOT based on physicians’ decision were enrolled in this study. Patients with a non-diabetic infected ulcer, history of seizure, claustrophobia, or untreated pneumothorax were excluded. We used a convenience sampling method. HBOT was applied using a monoplace hyperbaric oxygen chamber (Sechrist 3600H, Sechrist Industries, Inc., Anaheim, CA). The patients were treated with 100% oxygen at 2 to 2.5 ATA for 90 to 120 minutes per day, 5 days per week (from Saturday to Wednesday).

Data gathering
The patients’ baseline and disease-related information was collected from their medical file, including gender, type of DM (one or two), duration of DM, type of DM treatment (oral medications, insulin therapy, or both), previous history of DFU, and grade of DFU. The grade of the ulcer was also determined for all patients based on the classic Wagner grading system (CWGS) (28).
They underwent a physical examination by a vascular surgeon, infectious disease specialist, endocrinologist, and orthopedist before and after each HBOT session, and the decision for the required HBOT sessions, antibiotic therapy, and debridement was taken by these experts.
The level of blood sugar (BS) and hemoglobin A1C (HbA1c) was measured at the beginning of the treatment and noted as initial laboratory findings. The glycemic control status was assessed before and during HBOT. The desirable and undesirable glycemic control status were defined as HbA1c < 8% and HbA1c ≥ 8%, respectively (29). The levels of BS and HbA1c were measured based on the enzymatic glucose oxidase method. The primary outcomes were defined as the glycemic control status during the treatment and the recovery of DFU (cured and not cured). Cured ulcers were defined as ulcer’s grade reduction to zero, based on CWGS. Significant pain or feeling of popping in ears, pulmonary barotrauma, central nervous system toxicity, and claustrophobia after each session of HBOT were considered as adverse effects and secondary outcomes.
Finally, the frequency of different causes of no improvement (failed cure) including treatment abstinence, and not respecting the guideline, and the reasons of treatment abstinence including physicians’ decision, no trust in the treatment method, high expenses of the procedure, and elongation of the procedure were assessed.

Statistical analysis
Data was analyzed by SPSS version 24 (SPSS Inc., Chicago, IL., USA). Quantitative variables were described using mean ± standard deviation and qualitative variables were described using frequency (percent). Chi-square test, One Way ANOVA test, and independent sample T-test were applied to evaluate the association between different variables. P

From 198 participants (aged: 29.39 ± 7.88 years, range: 18 to 50 years) who had completed the study, 106 (53.5%) individuals were females. The mean spherical equivalent (MSE) was -0.80 ± 1.68 D (range: -4.50 to +3.98 D).
Table 1 presented 6 different parameters measured by LenStar and CASIA2 OCT. Paired t-test analysis showed significantly smaller values of CCT and ACW measured by CASIA2 OCT compared to LenStar. (p Bland-Altman test showed a clinical agreement of ACD measurements between two devices. Fig 3. Bland-Altman plot of anterior chamber width (ACW) compared between LenStar and CASIA2 OCT. Figures 1-3 present the Bland-Altman plots of agreement between two instruments. Figure 1 shows 95% LoA of ACD measurements ranged between – 0.50 and - 0.43.
Bland-Altman test showed a clinical agreement of ACD measurements between two devices. Figures 1-3 present the Bland-Altman plots of agreement between two instruments. Figure 1 shows 95% LoA of ACD measurements ranged between – 0.50 and - 0.43.
95% LoA for CCT measurements between LenStar and OCT has been shown – 20.79, 29.43 in figure 2.
Figure 3 presents 95% LoA of ACW equal to





























cantly higher than that of the neonates who did not recover (2141.7 ± 755.2 g) (p < 0.01). There was also a significant relationship between the TSH level and birth weight (p < 0.01). Moreover, the mean age of mothers in participants was 26.9 ± 3.7 years, with a minimum and maximum of 12 and 35 years, and did not have any significant relation with the level of TSH and with the recovery rate (p > 0.05).
The mean level of TSH in neonates who recovered within three-month was 9.4 ± 3 mIU/L, and in neonates who did not recover was 22 ± 6.5 mIU/L. The relation between the recovery and TSH level




















The present study showed that the prevalence of febrile seizures was associated with gender, living place, temperature, family history of seizure, and the serum level of zinc. In this regard, the frequency of zinc deficiency was higher in patients with febrile seizures compared to febrile patients without seizure, before and after adjusting for gender.
Zinc plays a vital role in the neuronal terminals of the hippocampus and amygdala by producing pyridoxal phosphate and affecting glutamatergic, gamma-aminobutyric acidergic (GABAergic), and glycinergic synapses (13).
Glutamic acid decarboxylase (GAD) acts as a major inhibitory neurotransmitter in the synthesis of gamma-aminobutyric acid (GABA) (14). A study by Ganesh R. and Janakiraman L. on 38 children with febrile convulsion and 38 children as a control group, aged between 3 months and 5 years, indicated that a serum zinc deficiency was significantly more prevalent in their case group than in the control group (15). Another study has reported that there is a correlation between disruption in Zn2+ homeostasis and fever seizure (16).
In studies by Papierkowski A., Mollah M.A., and Gündüz Z. et al., the mean serum zinc level in the febrile convulsion group was significantly lower than in the control group, which indicates the role of zinc in febrile seizure. Comparing the groups in terms of age and gender, no significant difference was found, similar to our study (17-19). Abdel Hameed Z.A. et al. (20), in a study on 100 infants in Egypt, observed that temperature had no significant difference between the case and control groups. But Berg A.T. (21), Ahmed B.W. (22), and our study showed the importance of temperature in febrile seizure. The geographic area can be the cause of this difference. Duangpetsang J. in a study from 2014 to 2017 reported that a high fever with electrolyte disturbance hyponatremia has an important role in FS (23). Sharifi R. et al., in a study in 2007-2014, showed the importance of family history in febrile seizure (24), which is similar to our results.

The findings of this study show that zinc deficiency is significantly associated with the occurrence of febrile seizures. Zinc supplementation in children can therefore be helpful for the prevention and treatment of FS.

Conflict of interest
The authors declare no conflicts of interest.


1.Hyperbaric Oxygen Therapy for the Treatment of Diabetic Foot Ulcers: A Health Technology Assessment. Ontario health technology assessment series. 2017;17(5):1-142.
2.Harrison LE, Giardina C, Hightower LE, et al. Might hyperbaric oxygen therapy (HBOT) reduce renal injury in diabetic people with diabetes mellitus? From preclinical models to human metabolomics. Cell Stress Chaperones. 2018;23(6):1143-52.
3. Irawan H, Semadi IN, Widiana IGR. A Pilot Study of Short-Duration Hyperbaric Oxygen Therapy to Improve HbA1c, Leukocyte, and Serum Creatinine in Patients with Diabetic Foot Ulcer Wagner 3-4. ScientificWorldJournal. 2018;2018:6425857.
4. Kawecki M, Pasek J, Cieslar G, et al. Computerized planimetry evaluation of hyperbaric oxygen therapy in the treatment of diabetic foot. Adv Clin Exp Med. 2018;27(1):39-44.
5. Moradi Y, Baradaran HR, Djalalinia S, et al. Complications of type 2 diabetes in Iranian population: An updated systematic review and meta-analysis. Diabetes & metabolic syndrome. 2019;13(3):2300-12.
6. Babaniamansour S, Aliniagerdroudbari E, Niroomand M. Glycemic control and associated factors among Iranian population with type 2 diabetes mellitus: a cross-sectional study. Journal of Diabetes & Metabolic Disorders. 2020;19(2):933-40.
7. Izadi M, Kheirjou R, Mohammadpour R, et al. Efficacy of comprehensive ozone therapy in diabetic foot ulcer healing. Diabetes & metabolic syndrome. 2019;13(1):822-5.
8. Yazdanpanah L, Shahbazian H, Nazari I, et al. Incidence and Risk Factors of Diabetic Foot Ulcer: A Population-Based Diabetic Foot Cohort (ADFC Study)-Two-Year Follow-Up Study. International journal of endocrinology. 2018;2018:7631659.
9. Grigoropoulou P, Eleftheriadou I, Jude EB, et al. Diabetic Foot Infections: an Update in Diagnosis and Management. Current diabetes reports. 2017;17(1):3.
10. Perren S, Gatt A, Papanas N, et al. Hyperbaric Oxygen Therapy in Ischaemic Foot Ulcers in Type 2 Diabetes: A Clinical Trial. Open Cardiovasc Med J. 2018;12:80-5.
11. Parto Babaniamansour, Maryam Mohammadi, Sepideh Babaniamansour, et al. The Relation between Atherosclerosis Plaque Composition and Plaque Rupture. Journal of Medical Signals and Sensors. 2020;10.
12. Hitchman LH, Totty JP, Raza A, et al. Extracorporeal Shockwave Therapy for Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis. Ann Vasc Surg. 2018.
13. Babaniamansour P, Ebrahimian-Hosseinabadi M, Zargar-Kharazi A. Designing an Optimized Novel Femoral Stem. Journal of medical signals and sensors. 2017;7(3):170-7.
14. Vinkel J, Lohse N, Hyldegaard O. The clinical use of hyperbaric oxygen in the treatment of Danish patients with diabetic foot ulcers. Danish medical journal. 2019;66(2).
15. Kilicoglu OI, Demirel M, Aktas S. New trends in the orthopaedic management of diabetic foot. EFORT Open Rev. 2018;3(5):269-77.
16. Heyboer M, 3rd, Sharma D, Santiago W, et al. Hyperbaric Oxygen Therapy: Side Effects Defined and Quantified. Advances in wound care. 2017;6(6):210-24.
17. Howell RS, Criscitelli T, Woods JS, et al. A Perioperative Approach to Increase Limb Salvage When Treating Foot Ulcers in Patients With Diabetes. AORN J. 2018;107(4):431-40.
18. Babaniamansour S, Aliniagerdroudbari E, Afrakhteh M, et al. Can fasting plasma glucose replace oral glucose-tolerance test for diagnosis of gestational diabetes mellitus? Diabetology International. 2021.
19. Fagher K, Löndahl M. The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers. Diabetologia. 2013;56(5):1140-7.
20. Hayes P, Alzuhir N, Curran G, et al. Topical oxygen therapy promotes the healing of chronic diabetic foot ulcers: a pilot study. Journal of wound care. 2017;26(11):652-60.
21. Oliveira N, Rosa P, Borges L, et al. Treatment of diabetic foot complications with hyperbaric oxygen therapy: a retrospective experience. Foot and Ankle Surgery. 2014;20(2):140-3.
22. Driver VR, Reyzelman A, Kawalec J, et al. A Prospective, Randomized, Blinded, Controlled Trial Comparing Transdermal Continuous Oxygen Delivery to Moist Wound Therapy for the Treatment of Diabetic Foot Ulcers. Ostomy/wound management. 2017;63(4):12-28.
23. Zhao D, Luo S, Xu W, et al. Efficacy and safety of hyperbaric oxygen therapy used in patients with diabetic foot: a meta-analysis of randomized clinical trials. Clinical therapeutics. 2017;39(10):2088-94. e2.
24. Leslie CA, Sapico FL, Ginunas VJ, et al. Randomized controlled trial of topical hyperbaric oxygen for treatment of diabetic foot ulcers. Diabetes Care. 1988;11(2):111-5.
25. van Netten JJ, Bus SA, Apelqvist J, et al. Definitions and criteria for diabetic foot disease. Diabetes/Metabolism Research and Reviews. 2020;36(S1):e3268.
26. Wagner FW, Jr. The dysvascular foot: a system for diagnosis and treatment. Foot & ankle. 1981;2(2):64-122.
27. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2019. Diabetes care. 2019;42(Suppl 1):S61-s70.
28. Huang ET, Mansouri J, Murad MH, et al. A clinical practice guideline for the use of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers. Undersea Hyperb Med. 2015;42(3):205-47.
29. Kaya A, Aydin F, Altay T, et al. Can major amputation rates be decreased in diabetic foot ulcers with hyperbaric oxygen therapy? International orthopaedics. 2009;33(2):441-6.
30. Glik J, Cholewka A, Englisz B, et al. Thermal imaging and planimetry evaluation of the results of chronic wounds treatment with hyperbaric oxygen therapy. Adv Clin Exp Med. 2018.
31. Erdogan A, Duzgun AP, Erdogan K, et al. Efficacy of Hyperbaric Oxygen Therapy in Diabetic Foot Ulcers Based on Wagner Classification. J Foot Ankle Surg. 2018;57(6):1115-9.
32. Niroomand M, Babaniamansour S, Aliniagerdroudbari E, et al. Distress and depression among patients with diabetes mellitus: prevalence and associated factors: a cross‐sectional study. Journal of Diabetes & Metabolic Disorders. 2021.
33. Baroni G, Porro T, Faglia E, et al. Hyperbaric oxygen in diabetic gangrene treatment. Diabetes Care. 1987;10(1):81-6.
34. 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. Diabetic medicine : a journal of the British Diabetic Association. 2019;36(7):813-26.
35. 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.
36. Londahl M, Landin-Olsson M, Katzman P. Hyperbaric oxygen therapy improves health-related quality of life in patients with diabetes and chronic foot ulcer. Diabetic medicine : a journal of the British Diabetic Association. 2011;28(2):186-90.
37. Lobmann R, Zemlin C, Motzkau M, et al. Expression of matrix metalloproteinases and growth factors in diabetic foot wounds treated with a protease absorbent dressing. Journal of diabetes and its complications. 2006;20(5):329-35.
38. Jira M, El Omri N, Sekkach Y, et al. [Hyperbaric oxygen therapy in the treatment of diabetic foot: experience in the management of 80 cases at a department of internal medicine]. Pan Afr Med J. 2018;30:100.
39. Salama SE, Eldeeb AE, Elbarbary AH, et al. Adjuvant Hyperbaric Oxygen Therapy Enhances Healing of Nonischemic Diabetic Foot Ulcers Compared With Standard Wound Care Alone. The international journal of lower extremity wounds. 2019:1534734619829939.
40. Kessler L, Bilbault P, Ortega 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.
41. Fagher K, Katzman P, Londahl M. Hyperbaric oxygen therapy reduces the risk of QTc interval prolongation in patients with diabetes and hard-to-heal foot ulcers. Journal of diabetes and its complications. 2015;29(8):1198-202.
42. Dhatariya KK, Li Ping Wah-Pun Sin E, Cheng JOS, et al. The impact of glycaemic variability on wound healing in the diabetic foot - A retrospective study of new ulcers presenting to a specialist multidisciplinary foot clinic. Diabetes research and clinical practice. 2018;135:23-9.
43. Andrews KL, Houdek MT, Kiemele LJ. Wound management of chronic diabetic foot ulcers: from the basics to regenerative medicine. Prosthetics and orthotics international. 2015;39(1):29-39.