Does Hyperbaric Oxygen Improve Lower Extremity Ulcer Outcomes?

Reference: Begić A, Dilić M. Evaluation of the occlusive arterial disease and diabetic angiopathy treatment effects by hyperbaric oxygenation. Med Arch. 2019;73(4):244–248. doi:10.5455/medarh.2019.73.244-248

Rationale: Diabetic foot ulcers are often complicated by ischemia related to arterial occlusive disease (AOD) and commonly associated with diabetic angiopathy (DA). Hyperbaric oxygen has been used to treat various forms of ischemia.

Objective: Conduct a prospective clinical trial comparing the healing outcomes of patients receiving standard care with or without HBO for ischemic lower extremity wounds associated with either AOD or DA but not AOD and DA combined.

Methods: With appropriate ethics committee approval and patient consent, 80 patients with lower extremity wounds who did not require surgery were enrolled in a study at the Clinical Center of the University of Sarajevo, Bosnia and Herzegovina. Inclusion criteria mandated a confirmed diagnosis of either AOD without diabetes (n = 40) or DM and DA (n = 40). All enrolled patients received standard treatment as appropriate, using vasodilators, antibiotics, anti-clotting agents, and statins. Placed into subgroups, 20 patients with AOD and 20 patients with DA were assigned to receive once daily 80-minute HBO with 2.4 ATA in a monospace chamber for an average of 21 days. Wound area, depth, granulation, drainage, and inflammation were monitored during the 12-month study to produce a composite healing outcome expressed as deteriorated, unchanged, improved, or significantly improved. Details regarding the blinded status of outcome evaluators and basis for calculating the composite study endpoint ratings were not clear from the publication. A student’s t-test assessed the difference in healing outcomes, with a statistical significance set at P < .05. 

Results: There were no significant differences in age, sex, smoking status, fibrinogen value, total cholesterol value, LDL cholesterol level, and previously diagnosed hypertension. At the end of treatment, fibrinogen values were slightly higher in those not receiving HBO (P < .02). Patients with DA who received HBO were younger, with lower fibrinogen levels, and with less hypertension compared with those not receiving HBO. There were more smokers in the subgroup who received HBO. Patients receiving HBO in both groups experienced more wound improvement during the study than those not receiving HBO. The article did not mention baseline comparability of wound characteristics. More patients receiving standard treatment with HBO experienced wound improvement during the study among participants with AOD or DA (P < .01). No patient receiving HBO experienced lower extremity wound deterioration, compared with 11 reports of wound deterioration experienced by those not receiving HBO (4 with AOD; 7 with DA) during the 12-month study. 

Authors’ Conclusion: Adding HBO to a standard aggressive protocol of care can improve healing outcomes in patients with DA or those with AOD without DM.

Reference: Lalieu RC, Brouwer RJ, Ubbink DT, Hoencamp R, Bol Raap R, van Hulst RA. Hyperbaric oxygen therapy for nonischemic diabetic ulcers: a systematic review. Wound Repair Regen. 2020;28(2):266–275. doi:10.1111/wrr.12776

Rationale: Diabetic foot ulcers affect up to 25% of individuals with DM, with most DFUs being of neuropathic rather than vascular origin. Prior research on the effectiveness of HBO therapy for diabetic and/or ischemic ulcers has been conducted despite heterogenic pathways to DFU development.

Objective: Conduct a systematic literature review to evaluate the beneficial and harmful effects of HBO added to local or systemic treatments for DFU healing and/or amputation rates in patients with DFUs and without peripheral arterial occlusive disease.

Methods: A clinical librarian assisted in the development of a strategy for the authors to search for primary and derivative controlled clinical studies in the MEDLINE, EMBASE, and Cochrane CENTRAL databases from inception through September 2018. The search contained MeSH or free-text terms corresponding to DFUs and HBO (ie, ulcer, diabetes mellitus, hyperbaric oxygen therapy, and synonyms). Results were described per the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.⁶ Study characteristics and outcomes were tabulated by 2 authors who independently assessed study quality and risk of bias per the Cochrane checklist for randomized studies and the ROBINS-I checklist for non-randomized interventional studies. Analyses were conducted for the effects on healing and primary outcomes of major and minor amputations using Review Manager (Version 5.3; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration) and statistical significance was set at P < .05.

Results: Among the 818 studies returned by the literature search, 7 qualified for analysis of healing or amputation outcomes. This included 2 RCTs (2 and 4 weeks long) on a combined total of 64 patients receiving 90-minute HBO sessions at 2.5 ATA twice daily for a total of 20 sessions, 2 non-randomized prospective studies, and 3 retrospective studies. A total of 6438 patients without peripheral AOD were treated with HBO protocols ranging from 2 to 2.5 ATA on 3 to 6 days per week for 60 to 120 minutes per session. Total study HBO sessions varied from 15 to 110, and study durations varied from 2 weeks to 12 months. Significant differences in baseline patient characteristics (sex, age, ulcer size, and Wagner grade) were reported in only one study, which did not adjust analyses for these risk factors. Of note, 4 studies reported transcutaneous partial pressure of oxygen (TcPO₂) to validate the absence of DFU ischemia. Though some studies reported outcomes favorable to HBO, meta-analyses could not be performed due to heterogeneity of primary healing or amputation outcomes. Barotraumatic otitis resulted in the discharge of a patient in one of the studies. Some non-randomized studies reported larger or higher Wagner grade ulcers assigned to HBO treatment, possibly as a result of HBO being considered a “last resort” intervention.

Authors’ Conclusions: Hyperbaric oxygen did not accelerate healing or prevent major or minor amputations in patients with nonischemic DFUs. Sound evidence regarding the subgroup of patients is scarce, and there is a need to better identify those who may benefit from HBO.

These studies indicate the need to improve research on the effects of HBO in DFUs, standardization of diagnosis, baseline risk factors for nonhealing DFUs, treatment and outcomes measurement, and techniques regarding reporting and analysis. Lalieu et al⁴ noted that one cannot reach firm conclusions standing on the quicksand of heterogeneous data. More homogeneous data require more rigorously designed RCTs, with sham or placebo controls, applied using the same schedules, posture, and environment as the HBO. Patient smoking status, sex, age, neuropathy, and peripheral arterial disease (TcPO₂  or ankle- or toe-brachial systolic pressure index) and wound area, depth, and infection status are among the minimum baseline metrics to control or adjust in regard to outcome measures. Consistent use of validated DFU healing and amputation outcome measures would also reduce unidentified sources of variability permitting bona fide meta-analyses.⁷ 

With regard to Lalieu et al,⁴ it would have been more accurate to conclude that there was insufficient data to reach a sound conclusion about HBO efficacy on non-ischemic DFUs. More compelling evidence to firmly conclude that HBO did not affect healing or amputation rates would have been beneficial/crucial to their study.⁴ Begić et al⁵ reported significant HBO lower extremity ulcer healing benefits for 20 patients with AOD compared with similar controls. Patients with DFUs and arteriopathy (n = 20), sex, age, and non-smoking differences at baseline may have accounted for significantly improved lower extremity ulcer healing in those receiving HBO. The notable limitations were as follows: lack of randomization, absence of a sham control, baseline risk factor differences for nonhealing risk factors in those with DA, and use of a non-standard healing measures based on combined wound area, depth, granulation, drainage, and inflammation.⁵ Despite the limitations, the authors suggested important clinical research opportunities to resolve the controversy, including the merit of quality RCTs on HBO that focus on replicating the healing or amputation benefits of improving tissue oxygenation³ or circulation using structured exercise or electrical calf muscle stimulation.⁸ However, the RCTs should maintain a rigorous standard of care, including consistent lower limb ulcer offloading, smoking cessation, and blood glucose management. 

These findingshighlight the importance of diagnosing and addressing peripheral arterial disease in patients with lower limb nonhealing wounds.^4,5 This may be especially important for those with hypercoagulative status likely related to COVID-19.⁹ Valid and reliable hemodynamic measures of affected tissue oxygenation, toe systolic blood pressure less than 30 mm Hg,¹⁰ digital pulse oximetry, and/or toe-brachial pressure index less than 0.9¹¹ can alert caregivers to evaluate compromised peripheral circulation, tissue oxygenation, and healing capacity. These studies^4,5 are a reminder to look beyond the wound to address the variables delaying wound healing. Only sound science measuring valid outcomes will lead clinicians from this swamp of uncertainty to a firmer understanding of which patients with lower extremity ulcers may benefit from the addition of HBO to consistently applied multidisciplinary patient care and wound standards of care.