Treating Diabetic Foot Ulcers With Hyperbaric Oxygen

How effective is hyperbaric oxygen (HBO₂) is treating diabetic foot ulcers (DFUs)? These authors take an extensive look at the literature and offer practical pointers for the use of HBO₂.

Diabetes mellitus (DM) is the eighth leading cause of death in the USA. There are approximately 26 million people in the United States who have diabetes mellitus.¹ By 2040, it is predicted that there will be around 640 million people with diabetes worldwide.

As the prevalence of diabetes increases, the cost of treating diabetic foot ulcers (DFU) has vastly increased in the last 20 years. A 2017 study estimated diabetic foot ulcers cost Medicare from $6.2 billion to $18.7 billion.²

At 10 years, the risk of death for a patient with diabetes who had a foot ulcer is twice as high as the risk for a patient who has not had a foot ulcer.³ Diabetic foot ulcers also double the risk of mortality from a heart attack and increase stroke risk by 40%.³ Most amputations in patients with diabetes are preceded by a DFU, accounting for around 70,000 amputations annually.⁴ Every 20 seconds, someone is getting an amputation somewhere in the world. The relative 5-year mortality rate after limb amputation is 68%.⁵ After the initial amputation, the risk of re-amputation of the contralateral extremity is high.^6,7 When a patient with end-stage renal disease and DM type 2 gets a major amputation, they have 50% mortality within one year.⁸

It is also crucial for everyone taking care of patients with diabetes to know that patients with diabetic foot disease fear major lower-extremity amputation more than death.⁹

Pathophysiology and Hyperbaric Effects

Most of the benefits of hyperbaric oxygen therapy (HBO₂) are explained by a simple physical relationship determining gas concentration, volume, and pressure.¹⁰ HBO₂ causes increase oxygen delivery to hypoxic tissues according to Henry's law, which states that the amount of ideal gas dissolved in the solution is directly proportional to its partial pressure. During HBO₂ therapy, when 100% oxygen is given at 3 ATA, dissolved oxygen content is 6 mL/dL. This helps with resting tissue oxygen extraction in hypoxic tissue irrespective of the hemoglobin-bound oxygen pool's adequacy.¹¹

Hyperbaric oxygen therapy causes its effects mainly through controlled and brief increases in reactive oxygen species (ROS) (e.g., reactive nitrogen species [RNS]). The increase in ROS and RNS leads to increased growth factors (GF), growth factor receptors, and increased mobilization of stem/progenitor cells from the bone marrow. The increase in GF, GF receptors, and stem cells causes reduced integrin function. This leads to reduced pathologic neutrophil adhesion, leading to changes in monocyte chemokine synthesis and hemoxygenase-1 heat shock proteins, and hypoxia-inducible factor 1, which reduces pathologic inflammation.¹⁰

In vitro, HBO₂ modulates the local and systemic effects found in acute and chronic injury, ischemia, ischemia-reperfusion injury, and inflammation, helping wound healing.^11,12 HBO₂ helps with fibroblast proliferation, angiogenesis, collagen synthesis, leukocyte function, and angiogenesis, helping with wound healing.^13–17 HBO₂ augments neutrophil bactericidal activity, limits Clostridia exotoxin and spore production, kills anaerobes such as Clostridium perfringens, and inhibits the growth of several other bacterial pathogens.^13–15 It also works synergistically with certain antibiotics to augment bacterial killing.^13–15

Studies Investigating the Efficacy of HBO2 in Diabetic Foot Ulcers

Reviewing the literature on DFU and HBO₂ provides 3 meta-analyses using grade methodology^16–18, 9 randomized controlled trials^19–28, more than 20 observational studies^29–38 and multiple systemic review articles. There is continuous debate about the role of HBO₂ as most studies reviewed have small sample sizes, inconsistent treatment protocols, and no standardization on standard wound management.

HBO₂ in DFU is only recommended as an adjunctive treatment to standard wound management. Standard wound management includes vascular assessment and correction of vascular problems, debridement, moist dressing, offloading, diabetes management, and nutrition management.  

Prospective and retrospective studies. Numerous retrospective studies have shown the efficacy of HBO₂. Davis reviewed a clinical series of 168 patients with compromised refractory diabetic foot wounds treated over a 7-year period and found a 70% success rate.³¹ Thirty percent of the individuals failed to respond and required amputation above or below the knee. Failures were more common in older patients without palpable pedal pulse and with large vessel occlusion at or above the ankle diagnosed by angiography.

In 1988, Cianci treated 19 patients with diabetes in a subset of 39 lower extremity ulcers, with a salvage rate of 89 percent.³² Forty-two percent of these patients had undergone successful revascularization and were referred because of persistent infection or non-healing wound.

In 1992, Oriani reported a 10-year experience that showed 80 percent salvage in a group that received HBO₂, versus 40% in controls (P < .001).³⁹ Initial treatment was with 15 HBO₂ sessions, and reevaluation was recommended. If there was significant improvement, then 10 more treatments were given.

In 1993 study by Stone et al, retrospective data of 501 patients (119 patients in the HBO₂ group and 382 patients in the conservative care group).⁴⁰ Complete follow-up was available in 73% of patients. Both groups received standard wound care. The HBO₂ group had larger, more severe wounds, and 31% of the HBO₂ group patients were recommended for amputation. Despite having the more severe wounds in HBO₂ group, the limb salvage rate was greater in the HBO₂ patients (72% percent vs. 53 percent, P < .002).

Baroni and associates treated 28 patients.³⁰ Eighteen received HBO₂ and 10 received only conservative care. Sixteen out of 18 patients healed in the treatment group and remained healed on follow up at 36 months. Only one patient healed in the conservative group. The amputation rate was 12.5% in the treated group vs. 40 percent in the control group (P < .001). In a follow-up study by the same group in 1990, 62 of 80 patients (78%) received a course of HBO₂, and 96% of the HBO₂ patients went on to heal vs. 66% of the control group. The amputation rate in HBO₂ group was 4.8% vs. 33% in the control group (P < .0001).³⁰

In 2013, a longitudinal observational cohort study in which data of 6,259 individuals was analyzed by the propensity score-adjusted models based on the electronic medical records of one company (November 2005–May 2011) showed that HBO₂ neither improved the likelihood that a wound would heal nor prevented amputation in a cohort of patients that were reviewed.³⁵ Several critics of this study thought that the study was flawed as it is based on electronic medical record data, and there was no control on who was putting the data. HBO₂ was given for Wagner Grade 2 DFU, making it difficult to know whether a data entry error occurred or HBO₂ was given to Wagner grade 2 ulcers. A large group of patients was excluded as there was a 28-day waiting period before the patient could be enrolled. The excluded cohort had higher lower extremity amputation rates in the first 28 days. The excluded cohort was defined as having adequate arterial circulation without mention of what diagnostic test was used to make that determination.

Recent reports from Ennis et al reviewed the retrospective data of 309,350 DFU patients by a third-party research company.⁴¹ They found that the HBO₂ group improved wound healing (CE 0.57 vs. CE 0.45 in the non-HBO₂ group with 95% CI of 0.077,0.161), P = .001). They also found the HBO₂ group had a decreased amputation (CE 0.027 vs. 0.067 in non-HBO₂ group with 95% CI (-0.058, -0.021), P = .001).

Another recent report from Lavery et al showed in their retrospective evaluation of 1,066 HBO patients, 2,893 advanced wound care patients, and 29,964 standard wound management patients found that HBO₂ therapy is utilized on the most medically complex DFU patients and the HBO₂ cohort had approximately 33% fewer major amputations relative to minor compared to the advance wound management cohort.⁴²

Summary of Evidence for HBO₂ in DFUs

•    1979—Hart and Strauss (35 patients, 73% improved, 18% healed)⁴³
•    1979–1992—At least 10 retrospective or non-randomized trials with positive results.²⁹
•    1992—First RCT performed (Doctor²⁵): 15 HBO₂/15 control-hospitalized patients. Above ankle amputation (2/15 HBO2- 7/15 control) P < .05
•    1992–2017—9 RCTs (7 of 9 show fewer major amputations using adjunctive HBO₂) 2 of 9 are negative studies (Fedorko²⁶ and Santema²⁷). Multiple clinical trials and retrospective reviews. Improved wound healing and reduced major amputations.

HBO₂ may be associated with improved healing as a component of diabetic ulcer management. Multiple meta-analyses of randomized trials suggest that hyperbaric oxygen therapy may offer a benefit in the treatment of diabetic foot ulcers.^16–18 However, there was variability in the methodological quality of the included studies.¹⁶ The available trials are limited by small sample size, standard HBO₂ protocol implemented, standard wound management implemented, and heterogeneity of the wounds being treated (e.g., Wagner grade, ulcer size, ulcer depth, microbial involvement, presence of ischemia, and TcPO₂ values.¹⁷ 

A pooled analysis found significantly improved wound healing (OR 9.99, 95% CI 3.97 -25.1) and decreased risk of amputation (OR 0.24%, 95% CI 0.14 -0.43) for HBO₂.¹⁷ A later meta-analysis found almost similar results.⁴⁴ Faglia et al conducted a randomized trial of 70 patients with severely ischemic ulcers; the amputation rate was 9% in the treatment group and 33 percent in the control group.¹⁹ In the Londahl trial that included 94 patients, significantly more wounds healed completely in the HBO₂ group compared with a placebo group (52 versus 29%).²⁴ A recent randomized trial by Santema et al shows that HBO₂ did not significantly improve complete wound healing and limb salvage in a patient with diabetes and lower ischemia.²⁷ However, in the same study they found that patients who finished 30 HBO₂ treatments had improved wound healing and decreased amputation rates.

The GRADE analysis by Cochrane, Huang and O’Reilly all gave varied recommendations but all 3 found HBO₂ to help with diabetic wound healing with standard wound care than standard wound care alone but could not infer that hyperbaric oxygen decreases the amputation rate.^16,17,45

A recent systemic review by Lalieu et al showed HBO₂ might not be recommended for non-ischemic diabetic foot ulcers.⁴⁶ However, another recent systemic review by Brouwer et al found that adjuvant HBO₂ therapy improves the major amputation rate but not wound healing in patients with DFU and peripheral vascular disease.⁴⁷ Better selection of patient based on TcpO₂ was recommended.

Role of TcpO₂ in the Evaluation of Diabetic Wound Patients

The ankle brachial index (ABI) performs poorly in predicting the healing of foot ulcers and only modestly in predicting limb amputations. TcPO₂ is a better test for predicting both outcomes.⁴⁸ Wutschert and Bounamenaux performed a meta-analysis to determine the ability of TcPO₂ to predict amputation level using studies published from 1985–1996 and found that 20 mmHg was the most useful cut off for sea-level oxygen testing for failure to heal with a sensitivity of 82% and specificity of 64%.⁴⁹ The positive predictive value (failed to heal) of the 20 mmHg cutoff was 92%, and the negative predictive value of 42%. The accuracy rate was 79%.

In a retrospective multicenter case series Fife et al reported outcomes with HBO₂ treatment in 1,144 patients, of whom final outcomes could be determined in all but 68 cases.⁵⁰ All patients had hypoxic initial TcPO₂ values prior to the start of adjunctive HBO₂ therapy. Overall, 75.6% of those had a positive response. It was also implied that intra-chamber TcPO₂ might help determine the prognosis of these DFU patients with values about 200 mmHg associated with good prognosis and healing. At the same time, only 18% benefited in patients who had intra-chamber TcPO₂ of 100 mmHg and below.

Recommended Evaluation of the Patient

Every patient with DFU should undergo the following evaluation before starting HBO₂ treatment.

1. Complete history and physical

2. Evaluation of motor, sensor, and autonomic neuropathy.

3. Evaluation of vascular status: (a) Physical exam, (b) Doppler reading if indicated clinically, (c) Transcutaneous oxygen study, (d) Duplex scanning as indicated, (e) Angiography, if indicated, and correction of any vascular problem.

4.  X-ray of an involved body part if clinically indicated

5. Magnetic resonance imaging, bone scans, or indium scan if clinically indicated.

6. Cultures and sensitivity of wounds, wounds(s), bone, abscess, etc. if clinically indicated

7. Document
o    MEASURE the following: Measurement of wound size, Exudate, wound Assessment, pain (Suffering), Undermining, and Reeevaluation and Edge for each wound.  
●    Document Wagner grading for diabetic wounds.  
●    Document confirmatory clinical, lab, radiological or pathological findings that support your Wagner grading.

8. Evaluation and management of diabetes control

9. Nutritional evaluation and management

10. Baseline labs: complete blood cell count with manual diff, erythrocyte sedimentation rate, chemistry profile, zinc, magnesium, and glycosylated hemoglobin levels.

11. Photographs of the affected area taken before starting HBO₂

12. Patient's risk profile assessment to review if the patient has any contraindications to HBO₂.

Technical Treatment Protocol

The treatment pressures should be between 2 ATA and 2.5 ATA for a duration of 90 to 120 minutes. If a patient has responded to HBO₂ therapy and there are measurable signs of healing, HBO2 treatments may be necessary to be continued up to 40–60 treatments. On average most, diabetic foot ulcers require 30–40 treatments for complete healing.

Evaluating Therapy and Finding Endpoints

Endpoint determinations are both clinical and objective. Clinical endpoints include a healed wound. Other endpoints are increased oxygenation on TcPO₂, Complete 100% good granulation tissue on the wound bed.  

Follow-Up Care and Prevention

Patients should be seen in follow-up to ascertain if any adverse effects of hyperbaric therapy have occurred and follow their progress. Wound photographs should be taken to document healing and progress. The healed diabetic wound should be considered as diabetic foot disease in remission.⁴⁹ Patients with healed diabetic foot wounds should be taught about the importance of foot care. Appropriate customized orthotic diabetic shoes should be prescribed. Detailed diabetic foot care instructions should be given to all patients on discharge. Patients should also be educated about proper diabetes control and importance of follow-up with the primary care physician and podiatrist for preventive exams. Temperature monitoring of the foot is also useful in identifying problems in the foot early and is useful in diabetes foot ulcer prevention.

Provider and Facilities

Either the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and Det Norske Veritas (DNV) should approve the treatment facilities. The treatment facilities should also be completely prepared to become equivalently approved if their sites are visited. The UHMS also has a hyperbaric facility accreditation program which is hyperbaric specific accreditation.

All hyperbaric treatment must be directed by a properly trained and credentialed hyperbaric physician and in an appropriate setting. The training in hyperbaric medicine must be formal, completed at recognized training courses meeting requirements of the American College of Hyperbaric Medicine or the Undersea and Hyperbaric Medical Society (UHMS). Fellowship training or Board certification by the American Board of Medical Specialties (ABMS) is preferred. However, certification of added qualification with practice pathway is available by the American College of Hyperbaric Medicine (ACHM). The UHMS PATH program is also available for physicians who cannot do a fellowship or get board certification by ABMS. The hyperbaric physician or the properly trained hyperbaric nurse practitioner or physician assistant should be immediately available while the patient is undergoing HBO₂ under the qualified hyperbaric physician's direction.

Monoplace or multiplace chambers are suitable for treating this disorder and may be present either within a hospital or in a freestanding facility. Emergency resuscitation equipment must be immediately available, and the facility should meet all relevant fire and safety codes. Staff should be properly trained in the delivery of the technical component of HBO₂.

Jayesh B. Shah is Immediate Past president of the American College of Hyperbaric Medicine and serves as medical director for two wound centers based in San Antonio, TX. In addition, he is president of South Texas Wound Associates, San Antonio. He is also the past president of both the American Association of Physicians of Indian Origin and the Bexar County Medical Society and Current of Board of Trustees of Texas Medical Association.

Patricia Rios is Program Director for two wound centers based in San Antonio, Texas.

1. Daniel G, Fincane MM, Lu Y, Singh GM, Cowan MJ, Pacioreck CJ, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country years and 2.7 million participants. Lancet. 2011 Jul 2; 378(9785): 31-40. PubMed PMID: 21705069.

2. Nussbaum SR, Carter MJ, Fife CE, DaVanzo J, Haughty R, Nusgart M, Cartwright D. An economic evaluation of the impact, cost, and medicare policy implications of chronic nonhealing wounds. Value Health. 2018; 21(1):27–32.

3. Brownrigg JRW, Davey J, Holt PJ, et al. The association of ulceration of the foot with cardiovascular and all- cause mortality in patients with diabetes: a meta-analysis. Diabetologia. 2012; Nov; 55(11):2906–12.

4. La Fontaine J, Van Asten S, Lavery L. Diabetic foot ulcer. In The Textbook of Chronic Wound Care (Shah JB, Sheffield PJ, Fife CE, eds). Chapter 10, 2018, pp. 249–294. Best Publishing Company.

5. Armstrong DG, Wrobel J, Robbins JM. Are diabetes related wounds and amputations worse than cancer? Int Wound J. 2007; 4(4):286–7.

6. Calhoun JH, Overgaard KA, Stevens CM, Dowling JP, Mader JT. Diabetic foot ulcers and infections: current concepts. Adv Skin Wound Care. 2002 Jan–Feb; 15(1): 31–42; quiz 4-5. PubMed PMID:11905449.

7. Lavery LA, Peters EJ, Williams JR, Murdoch DP, Hudson A, Lavery DC. Reevaluating the way we classify the diabetic foot: restructuring the diabetic foot risk classification system of the International Working Group on the Diabetic Foot. Diabetes Care. 2008 Jan; 31(1):154-6. PubMed PMID: 17934155.

8. Franz D, Zheng Y, Leeper NJ, et al. Trends in rates of lower extremity amputation among patients with ESRD who receive dialysis. JAMA Intern Med. 2018;178(8):1025–1032.

9. Wukich DK, Raspovic KM, Suder NC. Patients with diabetic foot disease fear major lower-extremity amputation more than death. Foot Ankle Specialist. 2017; 11(1):17–21.  

10. Thom SR. Hyperbaric oxygen: Its mechanisms and efficacy. Plast Reconstr Surg. 2011 Jan; 127 Suppl 1:131S-141S, Review. PMID:21200283; PMCID: PMC3058327.

11. Camporesi EM, Bosco G. Mechanisms of action of hyperbaric oxygen therapy. Undersea Hyperb Med. 2014; 41(3):247

12. Nylander G, Lewis D, Norstrom H, Larsson J. Reduction of post ischemic edema with hyperbaric oxygen. Plast Reconstr Surg. 1985; 76(4):596.

13. Zamboni WA, Wong HP, Stephenson LL. Effects of hyperbaric oxygen on neutrophil concentration and pulmonary sequestration in reperfusion injury. Arch Surg. 1996; 131(70):756.

14. Marx RE, Ehler WJ, Tayapongsak P, Pierce LW. Relationship of oxygen dose to angiogenesis induction in irradiation tissue. Am J Surg. 1990; 160(5):519.

15. Roth RN, Weiss LD. Hyperbaric oxygen and wound healing. Clin Dermatol. 1994; 12(1):141.

16. Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev. 2004; (2):CD004123.

17. 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. UHMS. 2015; 42(3):205–47.

18. Health Quality Ontario. Hyperbaric oxygen therapy for the treatment of diabetic foot ulcers: a health technology assessment. Ont Health Technol Assess Ser. 2017; 17(5):1–142.

19. Faglia E, Favelas F, Aldeghi A, Calia P, Quarantiello A, Oriani G, Michael M, Campgnoli P, Morabito A. Adjunctive systemic hyperbaric oxygen therapy in treatment of severely prevalent ischemic diabetic foot ulcer. A randomized study. Diabetes Care. 1996; 19(12):1338.

20. Duzgun AP, Satir HZ, Ozozan O, Saylam B, Kulah B, Coskun F. Effects of hyperbaric oxygen therapy on healing of diabetic foot ulcers. J Foot Ankle Surg. 2001; 47(6):515.

21. Kessler L, Bilbaut P, Ortega F, Grasso C, Passemard R, Stephan D, Pinget M, Schneider F. Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study. Diabetes Care. 2003; 26(8):2378–82.

22. Abidia A, Laden G, KuhanG, Johnson BF, Wilkinson AR, Renwick PM, Masson EA, McCollum PT. The role of hyperbaric oxygen therapy in ischemic diabetic lower extremity ulcers: a double blind randomized controlled trial. Eur J Vasc Endovasc Surg. 2003:25(6):513–18.

23. Hammarlund C, Sundberg T. Hyperbaric oxygen reduced size of chronic leg ulcers: a randomized double-blind study. Plast Reconstr Surg. 1994; 93(4):829–33.

24. Londahl 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.

25. Doctor N, Pandya S, Supe A. Hyperbaric oxygen therapy in diabetic foot. J Postgrad Med. 1992; 38(3):112–114,111.

26. Fedorko L, Bowen JM, Jones W, Oreopoulos G, Goeree R, Hospkins RB, O’ Reilly DJ. Hyperbaric oxygen therapy does not reduce indications for amputation in patients with diabetes with non-healing ulcers of the lower limb: a prospective, double blind, randomized controlled clinical trial. Diabetes Care. 2016 Mar; 39(3):392–9.

27. Santema KTB, Stoekenbroek RM, Koelemay MJW, et al. Hyperbaric oxygen therapy in the treatment of ischemic lower extremity ulcers in patients with diabetes: results of the DAMO₂CLES multicenter randomized trial. Diabetes Care. 2018; 41(1):112–19.

28. Ma L, Pingsong L, Shi Z. A prospective, randomized controlled study of hyperbaric oxygen therapy: effects on healing and oxidative stress of ulcer tissue in patients with diabetic foot ulcer. Ostomy Wound Manage. 2013; 59(3):18–24.

29. Kindwal EP, Whelan HT. Hyperbaric Oxygen Therapy Textbook, 4th Edition. Best Publishing, 2017.

30. Baroni G, Porro T, Faglia E, et al. Hyperbaric oxygen in diabetic gangrene treatment. Diabetes Care. 1987; 10(1):81–86.

31. Davis JC, Buckley CJ, Barr P. Compromised soft tissue wounds: Correction of wound hypoxia. In Davis JC and Hunt TK (eds) Problem Wounds: The Role of Oxygen, New York: Elsevier Science Publishing Co., 1988, pp. 143–152.

32. Cianci P, Petrone G, Drager S, et al. Salvage of the difficult wound/Potential amputation in the diabetic patient, in Hyperbaric Medicine: Proceedings of the Joint Meeting, Second Siss Symposium on Hyperbaric Medicine and Second European Conference on Hyperbaric Medicine. Base: Foundation for Hyperbaric Medicine, 1990, PP 177-87.

33. Stone JA, Scott RG, Brill LR, Levine BD. The role of hyperbaric oxygen therapy in the treatment of the diabetic foot. Diabetes. 1995; 44(Suppl 1):71A.

34. Zamboni WA, Wong HP, Stephenson LL, Pfeifer MA. Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study. Undersea Hyperb Med. 1997; 24(3):175–9.

35. Margolis DJ, Gupta J, Hoffstad O, Papadopoulos M, Glick HA, Thom SR, Mitra N. Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study. Diabetes Care. 2013; 36(7):1961–6.

36. Lin T, Chen S, Niu K. The vascular effects of hyperbaric oxygen therapy in treatment of early diabetic foot. Undersea Hyperb Med. 2001; 28(Suppl):67.

37. Kaur S, Pawar M, Banerjee N, Garg R. Evaluation of the efficacy of hyperbaric oxygen therapy in the management of chronic non-healing ulcer and role of peri-wound transcutaneous oximetry as a predictor of wound healing response: A randomized prospective controlled trial. J Anaesthesiol Clin Pharmacol. 2012; 28(1):70–75.

38. Bishop AJ, Mudge E. A retrospective study of diabetic foot ulcers treated with hyperbaric oxygen therapy. Int Wound J. 2012; 9(6):665–676.

39. Oriani G, et al. Hyperbaric oxygen therapy in diabetic gangrene. J Hyperbar Med. 1990; 5(3):171–175.

40. Oriani G, et al. Diabetic foot and hyperbaric oxygen therapy: a ten-year experience. J Hyperbar Med. 1992; (94):213–221.

41. Ennis WJ, Huang ET, Gordan H. Impact of hyperbaric oxygen on more advanced wagner grades 3 and 4 diabetic foot ulcers; matching therapy to specific wound conditions. Adv Wound Care (New Rochelle). 2018 Dec 1; 7(12): 397–407.Published online 2018 Dec 20. doi: 10.1089/wound.2018.0855

42. Rice B, Desai U, Lavery LA. Abstract presented at SAWC fall 2018 meeting

43. Hart G, Strauss M. Response of ischemic ulcerative conditions to OHP. In Sixth International Congress on Hyperbaric Medicine. Aberdeen University Press: Aberdeen, 1979.

44. Liu R, Li L, Yang M, et al. Systematic review of the effectiveness of hyperbaric oxygenation therapy in the management of chronic diabetic foot ulcers. Mayo Clin Proc.  2013; 88(2):166–175.

45. O’ Reilly D, Pasricha A, Campbell K, et al. Hyperbaric oxygen therapy for diabetic ulcers: Systemic review and meta-analysis. Int J Technol Assess Health Care. 2013; 29(3):269–281.

46. Lalieu RC, Brouwer RJ, Ubbink DT, et al. Hyperbaric oxygen therapy non-ischemic diabetic foot ulcer: A systemic review. Wound Rep Reg. 2020; 28(2):266–75.

47. Brouwer, RJ, Lalieu RC, Hoencamp R, et al. A systemic review and meta-analysis of hyperbaric oxygen therapy for diabetic foot ulcers with arterial insufficiency. J Vasc Surg. 2020; 71(2):682–92.

48. Wang Z, Hasan R, Firwana B, et al. A systematic review and meta-analysis of tests to predict wound healing in diabetic foot. J Vasc Surg. 2016; 63(2 Suppl):29S–36S.

49. Wutschert R, Bounameaux H. Determination of amputation levels in ischemic limbs. Reappraisal of the measurements of TcPO₂. Diabetes Care. 1997; 20(8):1315–1318.

50. Fife CE, Buyukcakir C, Otto GH, et al. The predictive value of transcutaneous oxygen tension measurement in diabetic lower extremity ulcers treated with hyperbaric oxygen therapy: a retrospective analysis of 1,144 patients. Wound Repair Regen. 2002; 10(4):198–207.

51. Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. New Engl J Med. 2017; 376(24):2367–2375. https://doi.org/10.1056/NEJMra1615439

Additional References

52. Kalani M, Jorneskog G, Naderi N, et al. Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow-up. J Diabetes Complications. 2002; 16(2):153–158.

53. Liu R, LI L, Yang M, Boden G, Yang G. Systemic review of the effectiveness of hyperbaric oxygenation therapy in the management of chronic diabetic foot ulcers. Mayo Clinic Proc. 2013 Feb; 88(2):166–75.

54. Goldman RJ. Hyperbaric oxygen therapy for wound healing and limb salvage: a systemic review. PMR. 2009; 1(5):471.

55. Wattel F, et al. Hyperbaric oxygen in the treatment of diabetic foot lesions: search for predictive healing factors. J Hyperbar Med. 1991; 6(4):263–268.

56. Bishop AJ, Mudge E. Diabetic foot ulcers treated with hyperbaric oxygen therapy: a review of the literature. Int Wound J. 2014; 11(1):28–34.

57. 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):119–141.

58. Goldman RJ. Hyperbaric oxygen therapy for wound healing and limb salvage: a systemic review. PMR. 2009; 1(5):471–489.

59. Stoekenbroek RM, Santema TB, Legemate DA, et al. Hyperbaric oxygen for the treatment of diabetic foot ulcers; a systematic review. Eur J Vasc Endovasc Surg. 2014; 47(6):647–655.

60. Wang C, et al. Hyperbaric oxygen for treating wounds a systemic review of the literature. Arch Surg. 2003; 138(3):272–279:; discussion 280.

61. Roeckl-Wiedmann I, Bennett M, Kranke P. Systematic review of hyperbaric oxygen in the management of chronic wounds. Br J Surg. 2005; 92(1):24–32.