Hyperbaric oxygen therapy for chronic diabetic foot ulcers: An overview of systematic reviews



      Hyperbaric oxygen therapy in the treatment of diabetic foot ulcer has been widely used in medical practice, but its clinical effect is not clear. The purpose of this overview of systematic reviews is to evaluate the clinical evidence of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers.


      PubMed, Cochrane Library, Web of Knowledge, Embase, MEDLINE, Chinese National Knowledge Infrastructure Database, the Chongqing VIP Database, Chinese Biomedical Database, and Wanfang Database were searched in 1st December 2020. Systematic reviews (SRs) evaluating the effects of Hyperbaric oxygen therapy in people with diabetic foot ulcer were included. Methodological quality of the included SRs was assessed using the AMSTAR-2 tool. The quality of evidence of the primary studies was assessed using GRADE. The integrity of the included SRs was assessed using PRISMA. The bias risk of each SR was assessed using ROBIS evaluation tool.


      Eleven SRs/MAs met all inclusion criteria. According to the results of the AMSTAR-2, only 1 included review were rated critically as being of high quality, 6 included review were rated critically as being of medium quality. With PRISMA, the reporting checklist was relatively complete, but some reporting weaknesses remained in the topics of the protocol and registration, search strategy, and additional analyses. Based on the ROBIS tool, only five SRs/MAs had a low risk of bias. With the GRADE system, no high-quality evidence was found, and only 13 outcomes provided moderate-quality evidence.


      There is limited clinical evidence to support hyperbaric oxygen therapy in the treatment of diabetic foot ulcers, it is not recommended to routinely apply hyperbaric oxygen therapy to all patients with diabetic foot ulcers, especially those with non-ischemic diabetic foot ulcers. Hyperbaric oxygen therapy has certain potential to promote ulcer healing and reduce amputation rate in patients with ischemic diabetic foot ulcers, but due to the low quality and small quantity of the SRs/MAs supporting these results, high-quality studies with rigorous study designs and larger samples are needed before widespread recommendations can be made.


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        • Guariguata L.
        • Whiting D.R.
        • Hambleton I.
        • Beagley J.
        • Linnenkamp U.
        • Shaw J.E.
        Global estimates of diabetes prevalence for 2013 and projections for 2035.
        Diabetes Res ClinPract. 2014; 103: 137-149
        • Lipsky B.A.
        • Berendt A.R.
        • Cornia P.B.
        • Pile J.C.
        • Peters E.J.
        • Armstrong D.G.
        • et al.
        2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections.
        Clin Infect Dis. 2012; 54: 132-173
        • Gregg E.W.
        • Hora I.
        • Benoit S.R.
        Resurgence in Diabetes-Related Complications.
        JAMA. 2019 May 21; 321 (PMID: 30985875): 1867-1868https://doi.org/10.1001/jama.2019.3471
      1. US Centers for Disease Control and Prevention. US diabetes surveillance system and diabetes atlas,2019.https://www.cdc.gov/diabetes/data.Accessed March 7, 2019.

        • Geiss L.S.
        • Li Y.
        • Hora I.
        • et al.
        Resurgence of diabetes-related nontraumatic lower-extremity amputation in the young and middle-aged adult US population.
        Diabetes Care. 2019; 42: 50-54
        • Warriner R.A.H.H.
        Enhancement of healing in selected problem wounds.
        in: Feldmeier J. The Hyperbaric Oxygen Committee Report. Undersea and Hyperbaric Medical Society Inc, Kensington, Maryland2003: 41-55
        • Hailey D.
        • Jacobs P.
        • Perry D.C.
        • Chuck A.
        • Morrison A.
        • Boudreau R.
        Adjunctive hyperbaric oxygen therapy for diabetic foot ulcer: an economic analysis.
        Canadian Agency for Drugs and Technologies in Health, Ottawa2007
        • McMillan G.
        • Glover M.
        The clinical and economic potential of hyperbaric oxygen therapy in the treatment of diabetic ulceration and other conditions.
        Int J Low Extrem Wounds. 2007; 6: 130-138
        • Löndahl M.
        • Fagher K.
        • Katzman P.
        Hyperbaric oxygen therapy for chronic diabetic foot ulceration.
        Diabet Foot J. 2011; 14: 39-44
      2. Diabetes Branch of Chinese Medical Association, Infectious Diseases Branch of Chinese Medical Association, tissue repair and Regeneration Branch of Chinese Medical Association. Guidelines for Prevention and treatment of Diabetic foot in China (2019 Edition) (Ⅰ). Chinese Journal of Diabetes, 2019. 11 (2): 92-108.

        • Lee Williams R.
        Hyperbaric oxygen therapy and the diabetic foot.
        J Am Podiatr Med Assoc. 1997; 87: 279-292
        • Löndahl M.
        • Boulton A.J.M.
        Hyperbaric oxygen therapy in diabetic foot ulceration: Useless or useful? A battle.
        Diabetes Metab Res Rev. 2020 Mar; 36 (Epub 2020 Jan 11. PMID: 31927787)e3233https://doi.org/10.1002/dmrr.3233
        • Fedorko L.
        • Bowen J.M.
        • 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: 392-399
      3. 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 Jun 24;2015(6):CD004123. doi: 10.1002/14651858.CD004123.pub4. PMID: 26106870; PMCID: PMC7055586.

        • 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. 2017 Oct; 39 (Epub 2017 Sep 19 PMID: 28935291): 2088-2094.e2https://doi.org/10.1016/j.clinthera.2017.08.014
      4. Pollock M, Fernandes R, Becker L, Pieper D, Hartling L. Chapter V: Overviews of Reviews. Draft version (8 October 2018). In: Higgins JPT, ThomasJ, Chandler J, Cumpston MS, Li T, Page MJ, Welch V (editors). Cochrane Handbook for Systematic Reviews of Interventions. London: Cochrane.

        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6 (PMID: 19621072)e1000097https://doi.org/10.1371/journal.pmed.1000097
      5. Shea, B. J., Reeves, B. C., Wells, G., Thuku, M., Hamel, C., Tugwell, P., et al. (2017). AMSTAR 2: a critical appraisal tool for systematic reviews that include randomized or non-randomized studies of healthcare interventions, or both.BMJ 358:4008. doi: 10.1136/bmj.j4008

      6. Wang, X., Chen, Y., Liu, Y., Y ao L., Estill, J., Bian, Z., et al. (2019a).Reporting items for systematic reviews and meta-analyses of acupuncture: the PRISMA for acupuncture checklist. BMC Complement. Altern. Med. 19:208.doi: 10.1186/s12906-019-2624-3

      7. Whiting, P., Savoví c, J., Higgins, J. P., Caldwell, D. M., Reeves, B. C., Shea, B.et al. (2016). ROBIS: a new tool to asses srisk of bias in systematic reviews was developed. J. Clin. Epidemiol. 69, 225–234. doi: 10.1016/j.jclinepi.2015.06.005

        • Atkins D.
        • Best D.
        • Briss P.A.
        • Eccles M.
        • Falck-Ytter Y.
        • Flottorp S.
        • et al.
        Grading quality of evidence and strength of recommendations.
        BMJ. 2004; 328: 1490https://doi.org/10.1136/bmj.328.74 54.1490
        • Brouwer R.J.
        • Lalieu R.C.
        • Hoencamp R.
        • van Hulst R.A.
        • Ubbink D.T.
        A systematic review and meta-analysis of hyperbaric oxygen therapy for diabetic foot ulcers with arterial insufficiency.
        J Vasc Surg. 2020; 71 (PMID: 32040434): 682-692.e1https://doi.org/10.1016/j.jvs.2019.07.082
      8. 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 Mar;28(2):266-275. doi: 10.1111/wrr.12776. Epub 2019 Nov 26. PMID: 31667898; PMCID: PMC7079107.

        • Golledge J.
        • Singh T.P.
        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 (Epub 2019 May 26 PMID: 31002414): 813-826https://doi.org/10.1111/dme.13975
      9. Elraiyah T, Tsapas A, Prutsky G, Domecq JP, Hasan R, Firwana B, Nabhan M, Prokop L, Hingorani A, Claus PL, Steinkraus LW, Murad MH. A systematic review and meta-analysis of adjunctive therapies in diabetic foot ulcers. J Vasc Surg. 2016 Feb;63(2 Suppl):46S-58S.e1-2. doi: 10.1016/j.jvs.2015.10.007. PMID: 26804368.

      10. He Jidong, Wu Xiaohua, Liu Li, Lan Zhiliang. A systematic review of hyperbaric oxygen in the treatment of diabetic foot ulcers [J]. Chinese Journal of evidence-based Medicine, 2014 Journal 14 (12): 1476-1481.

        • Stoekenbroek R.M.
        • Santema T.B.
        • Legemate D.A.
        • Ubbink D.T.
        • van den Brink A.
        • Koelemay M.J.
        Hyperbaric oxygen for the treatment of diabetic foot ulcers: a systematic review.
        Eur J Vasc Endovasc Surg. 2014; 47 (Epub 2014 Apr 14 PMID: 24726143): 647-655https://doi.org/10.1016/j.ejvs.2014.03.005
      11. Li Yafan, Gong Yizhen, Pang Jinjun, Lu Miao, Wei Zhixiao. Meta analysis of clinical efficacy and safety of hyperbaric oxygen in the treatment of diabetic foot ulcer [J]. Chinese General Medicine, 2013 Regent 16 (26): 2369-2373.

        • Liu R.
        • Li L.
        • Yang M.
        • Boden G.
        • Yang G.
        Systematic review of the effectiveness of hyperbaric oxygenation therapy in the management of chronic diabetic foot ulcers.
        Mayo Clin Proc. 2013; 88 (PMID: 23374620): 166-175https://doi.org/10.1016/j.mayocp.2012.10.021
        • O'Reilly D.
        • Pasricha A.
        • Campbell K.
        • Burke N.
        • Assasi N.
        • Bowen J.M.
        • et al.
        Hyperbaric oxygen therapy for diabetic ulcers: systematic review and meta-analysis.
        Int J Technol Assess Health Care. 2013; 29 (PMID: 23863187): 269-281https://doi.org/10.1017/S0266462313000263
        • Guo S.
        • DiPietro L.
        Factors affecting wound healing.
        J Dental Res. 2010; 89: 219-229
        • Adler A.I.
        • Boyko E.J.
        • Ahroni J.H.
        • Smith D.G.
        Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers.
        Diabetes Care. 1999; 22: 1029-1035
        • Sun J.H.
        • Tsai J.S.
        • Huang C.H.
        • Lin C.H.
        • Yang H.M.
        • Chan Y.S.
        • et al.
        Risk factors for lower extremity amputation in diabetic foot disease categorized by Wagner classification.
        Diabetes Res Clin Pract. 2012; 95: 358-363
        • Londahl M.
        • Katzman P.
        • Hammarlund C.
        • Nilsson A.
        • Landin-Olsson M.
        Relationship between ulcer healing after hyperbaric oxygen therapy and transcutaneous oximetry, toe blood pressure and ankle–brachial index in patients with diabetes and chronic foot ulcers.
        Diabetologia. 2011; 54: 5-68
        • Wetterslev J.
        • Thorlund K.
        • Brok J.
        • et al.
        Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis.
        J Clin Epidemiol. 2008; 61: 64-75
      12. CTU. TSA—trial sequential analysisCopenhagen trial unit. Available: http://www. ctu. dk/ tsa/ [Accessed 10 Apr 2019].

        • Brok J.
        • Thorlund K.
        • Gluud C.
        • et al.
        Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta- analyses.
        J Clin Epidemiol. 2008; 61: 763-769
        • Brok J.
        • Thorlund K.
        • Wetterslev J.
        • et al.
        Apparently conclusive meta-analyses may be inconclusive–Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta- analyses.
        Int J Epidemiol. 2009; 38: 287-298
        • Kalani M.
        • Jorneskog G.
        • Naderi N.
        • Lind F.
        • Brismar K.
        Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers - long-term follow-up.
        J Diabetes Complic. 2002; 16: 153-158
        • Hajhosseini B.
        • Chiou G.J.
        • Virk S.S.
        • Chandra V.
        • Moshrefi S.
        • Meyer S.
        • et al.
        Hyperbaric Oxygen Therapy in Management of Diabetic Foot Ulcers: Indocyanine Green Angiography May Be Used as a Biomarker to Analyze Perfusion and Predict Response to Treatment.
        Plast Reconstr Surg. 2021; 147 (PMID: 33370067): 209-214https://doi.org/10.1097/PRS.0000000000007482