Great Debates and Updates: HBOT vs. Topical Oxygen in DFUs

The prevalence rate of diabetic foot ulcers (DFUs) is high and DFUs are life- and limb-threatening, emphasizes Caroline E. Fife, MD. In the USA, about 30 million people (8%) are affected by diabetes.¹ Research notes 60% of non-traumatic amputations the USA occur in patients with diabetes, while a DFU precedes 85% of amputations. The 5-year mortality rate of patients with diabetes after a single leg amputation is 60%, which Dr. Fife notes is worse than most cancers.
 
“Healing rates are not as good as we pretend,” said Dr. Fife. She notes studies showing a healing rate of about 43% in 12 weeks in patients with DFUs graded Wagner 1–2, and a 12-week healing rate of about 27% in Wagner 3 DFUs.^2,3 DFUs also range in cost from $631 million to $4.4 billion.³
 
Dr. Fife pointed out several differences between hyperbaric oxygen therapy (HBOT) and topical oxygen. HBOT is delivered at a pressure between 2 and 3 ATA, while topical oxygen is delivered at less than 1.1 ATA. Patients receive HBOT 1.5 hours a day, 3 to 5 days a week, while patients receive topical oxygen between 1.5 hours and 24 hours a day. HBOT is delivered by perfusion while topical oxygen is delivered by diffusion.
 
“Oxygen is a drug even though we don’t think of it like that," notes Dr. Fife.

The Affirmative Position on Topical Oxygen for DFUs

Harriet W. Hopf, MD, argued in favor of topical oxygen for DFUs, saying topical oxygen delivers molecular oxygen to the surface of the open wound where it can accelerate granulation and epithelialization. The therapy’s effectiveness is supported by multiple case series, retrospective reviews, RCTs, systematic reviews, and meta-analyses. Dr. Hopf noted topical oxygen is relatively simple and inexpensive to use and patients can use it at home. She notes it is underutilized compared to HBOT.
 
Dr. Hopf cited a sham-controlled, double-blinded RCT of adjunctive, cyclical, pressurized topical oxygen for healing DFUs, consisting of 220 patients.⁴ Patients had DFUs between 1– 20 cm², graded 1 or 2 in the University of Texas Classification and had failed 4 weeks of standard care. Patients had a reasonable vascular supply and ankle brachial indices (ABI) were > 0.7 and/or PtcO₂, skin perfusion pressure, and/or toe pressure >30 mmHg and/or biphasic duplex ultrasound. At 12 weeks, Dr. Hopf noted a topical oxygen closure rate of 41.7% versus 13.5% in control patients. At 12 months, the topical oxygen closure rate was 56% versus 27% in control patients. 
 
“It is strongly suggested that we continue because there is some really good evidence that (topical oxygen) works,” said Dr. Hopf.
 
As Sandra Wainwright, MD, argued, topical oxygen speeds healing among DFUs that are well perfused and superficial and that were likely to heal anyway. In contrast, she noted the majority of DFUs seen in wound centers are Wagner 3 or worse, and that the majority of DFUs we see in clinical practice are not candidates for topical oxygen, which isn’t a solution for the wounds that are limb-threatening.
 
“This is real-world medicine,” said Dr. Wainwright. “You guys are taking care of the (Wagner) 3s and 4s.”

The Constructive Case for HBOT

As Dr. Wainwright emphasized, HBOT delivers near 100% oxygen in a hard-sided chamber at pressures greater than 1.3 ATA. Each hemoglobin molecule, she explains, combines with 4 oxygen molecules (and no more). When patients breathe room air, each gram of HbO2 carries 1.34 cc of oxygen, meaning that 15 g of Hb can transport 20 cc of oxygen per 100 cc of blood (ie, 20 vol%), so Hgb cannot carry more oxygen even if the patient is breathing oxygen, according to Dr. Wainwright.

HBOT prevents ischemia/reperfusion injury, noted Dr. Wainwright. As she explains, HBOT inhibits polymorphonuclear (PMN) leukocyte endothelial adherence selectively by blocking B2 integrin function. This prevents “activation” and oxygen radical production. In addition, HBOT delivers oxygen through the alveolus to the capillary bed. Cellular and vascular mechanisms include: Stem cell mobilization, increased gene expression of vascular endothelial growth factor (VEGF), neovascularization, enhanced phagocytic killing of microbes, antibiotic potentiation, enhanced collagen synthesis and cross-linking, and vasoconstriction with preservation of oxygenation.
 
“All these mechanisms make HBOT a powerful tool for wound healing,” said Dr. Wainwright.
 
Dr. Wainwright noted some risks of HBOT, including middle ear barotrauma, oxygen seizure, pulmonary edema, and pneumothorax.
 
Faglia and colleagues completed a RCT of HBOT for 68 patients with Wagner 3 DFUs, 35 of whom received HBOT.⁵ Among HBOT patients, 3 underwent major amputation, compared to 11 major amputations in control patients. The authors also found TcPO₂ increased in HBOT patients by 14 mmHg vs. 5.4 mmHg in control patients.
 
Londahl and colleagues conducted a randomized, double-blinded, placebo-controlled clinical trial of HBOT vs. hyperbaric air for patients with DFUs.⁶ Patients had DFUs of Wagner grades 2, 3 or 4 that had been present for 3 months. The HBOT protocol was 2.5 ATA for 85 minutes for maximum of 40 sessions compared to the hyperbaric air protocol of 2.5 ATA. At one year, complete healing of the index ulcer had occurred in 25 of 48 in the HBOT group, compared to 12 of 42, noted Dr. Wainwright.
 
Dr. Hopf emphasized that not all studies of HBOT have been favorable, citing a longitudinal, observational, propensity-matched cohort study by Margolis and colleagues of patients with diabetes, adequate lower limb arterial perfusion, and a foot ulcer extending through the dermis, and treated within a one national system of wound centers between 2005–2011.⁷ Researchers concludes that HBOT “neither improved the likelihood that a wound would heal nor prevented amputation in a cohort of patients defined by Centers for Medicare and Medicaid Services eligibility criteria.” The authors argued for the reevaluation of the usefulness of HBOT for DFUs.
 
Dr. Hopf also cited a study by Fedorko and colleagues of Wagner grade 2–4 DFUs randomly assigned to HBOT or sham treatment.⁸ A six-week follow-up indicated neither major amputation criteria nor wound healing rates significantly differed between groups. The authors concluded that HBOT “does not offer any additional advantage over comprehensive wound care,” said Dr. Hopf.
 
Dr. Wainwright responded that Margolis and colleagues studied effectiveness and not efficacy, saying the authors used a retrospective analysis to evaluate how effectively HBOT has been applied towards producing expected outcomes in real world practice. She cited major problems in the study with propensity scoring; no information regarding vascular screening, offloading or other aspects of care such as infection management; and the fact that many patients had Wagner 2 DFUs, an indication not covered by Medicare. even though Medicare does not cover HBOT for this indication. Dr. Wainwright says the study results are not generalizable given the overall lack of information about standard of care.⁹
 
Dr. Wainwright said in the study by Fedorko, and colleagues, nearly 50% of patients had Wagner 2 lesions.8 In addition, the outcome was determined by one vascular surgeon who only looked at photographs and did not actually examine the patients or evaluate the actual outcome. Of 17 patients adjudicated to amputation, she noted only three underwent amputation, representing an error rate of 82%. “The primary goal was to assess efficacy of HBOT in reducing the indications for amputation,” rather than reducing amputation events themselves, noted Dr. Wainwright, and the study noted “that we did not use actual amputation rates in this placebo-controlled trial may be considered a limitation.”

In Summary

Dr. Wainwright noted HBOT has systemic effects that topical oxygen does not. She said the use of HBOT is supported in the treatment of Wagner 3 DFUs with significant clinical data, while HBOT is not used for DFUs that are as superficial and well perfused as those in the topical oxygen trial.
 
In addition, Dr. Wainwright did acknowledge that topical oxygen had benefit over standard of care in superficial DFUs that would never be considered for HBOT because they aren’t severe enough. While HBOT is used for limb threatening lesions, she noted the DFUs treated with topical oxygen are not limb threatening, and most topical oxygen lesions are not at risk of amputation. While HBOT Is more expensive it compares favorably to amputation.
 
Dr. Hopf concluded that the mechanism of effectiveness of topical oxygen is understood, and the data support its effectiveness in improving outcomes from Wagner Grade 1–2 DFUs. While topical oxygen is limited to Grade 1–2 DFUs, adjuncts that accelerate and improve success rates in healing those wounds reduce the number of patients who progress to wounds that require HBOT, which is not approved for Grade 1-2 wounds.

References
 
1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet, 2011. https://stacks.cdc.gov/view/cdc/13329
2. Fife CE, Eckert KA, Carter MJ. Publicly reported healing rates: the fantasy and the reality. Adv Wound Care (New Rochelle). 2018;7(3):77-94.
3. Nussbaum SR, Carter MJ, Fife CE, et al. An economic evaluation of the impact, cost and Medicare policy implications of chronic nonhealing wounds. Value Health. 2018;21(1):27-32.
4. Frykberg, Franks PJ, Edmonds M, et al. A multinational, multicenter randomized, double-blinded, placebo-controlled trial to evaluate the efficacy of cyclical topical wound oxygen (TWO) therapy in the treatment of chronic diabetic foot ulcers: the TWO₂ study. Diabetes Care. 2020;43(3):616-624.
5. Faglia E, Favales F, Aldeghi A, et al. Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study. Diabetes Care. 1996;19(12):1338-1343.
6. Londahl M. Hyperbaric oxygen therapy as treatment of diabetic foot ulcers. Diabetes Care. 2013;33(5):998-1003.
7. Margolis DJ, Gupta J, Hoffstad O, et al. 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.
8. Fedorko L, Bowen JM, Jones W, 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.
9. Carter MJ, Fife CE, Bennett M, et al. Comment on Margolis et al. 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;36:1961-6. Diabetes Care. 2013;36(8):e131.