Advertisement

A systematic review and meta-analysis of adjunctive therapies in diabetic foot ulcers

      Background

      Multiple adjunctive therapies have been proposed to accelerate wound healing in patients with diabetes and foot ulcers. The aim of this systematic review is to summarize the best available evidence supporting the use of hyperbaric oxygen therapy (HBOT), arterial pump devices, and pharmacologic agents (pentoxifylline, cilostazol, and iloprost) in this setting.

      Methods

      We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2011. Pairs of independent reviewers selected studies and extracted data. Predefined outcomes of interest were complete wound healing and amputation.

      Results

      We identified 18 interventional studies; of which 9 were randomized, enrolling 1526 patients. The risk of bias in the included studies was moderate. In multiple randomized trials, the addition of HBOT to conventional therapy (wound care and offloading) was associated with increased healing rate (Peto odds ratio, 14.25; 95% confidence interval, 7.08-28.68) and reduced major amputation rate (odds ratio, 0.30; 95% confidence interval, 0.10-0.89), compared with conventional therapy alone. In one small trial, arterial pump devices had a favorable effect on complete healing compared with HBOT and in another small trial compared with placebo devices. Neither iloprost nor pentoxifylline had a significant effect on amputation rate compared with conventional therapy. No comparative studies were identified for cilostazol in diabetic foot ulcers.

      Conclusions

      There is low- to moderate-quality evidence supporting the use of HBOT as an adjunctive therapy to enhance diabetic foot ulcer healing and potentially prevent amputation. However, there are only sparse data regarding the efficacy of arterial pump devices and pharmacologic interventions.
      Foot ulcers are a major complication of diabetes and are associated with a substantial burden for the patients and the entire health care system.
      • Ragnarson Tennvall G.
      • Apelqvist J.
      Health-economic consequences of diabetic foot lesions.
      Multiple factors are involved in the etiology of diabetic foot ulcers, the main ones being peripheral neuropathy, external trauma, and peripheral vascular disease.
      • Boulton A.J.
      The diabetic foot: from art to science. The 18th Camillo Golgi lecture.
      Several therapies have been proposed as adjuncts to traditional wound care (dressing changes, offloading, and débridement) to improve tissue oxygenation and enhance the healing process. To aid clinicians and patients in the process of decision making and choosing the best approach for managing diabetic foot ulcers, the Society for Vascular Surgery selected a priori several adjunct therapies that require a systematic review to summarize the best available evidence.
      These therapies are hyperbaric oxygen therapy (HBOT), with the possible physiologic effects of reducing regional and local ischemia, stimulation of oxygen-dependent components of wound repair, release of bone marrow stem cells, enhancing host antimicrobial responses, and stimulation of angiogenic healing responses to the point of local host competency; pharmacologic agents that improve oxygenation by causing vasodilatation; and pneumatic compression devices that aim at augmenting distal regional blood flow.
      • Doctor N.
      • Pandya S.
      • Supe A.
      Hyperbaric oxygen therapy in diabetic foot.
      • Ramani A.
      • Kundaje G.N.
      • Nayak M.N.
      Hemorheologic approach in the treatment of diabetic foot ulcers.
      • Armstrong D.G.
      • Nguyen H.C.
      Improvement in healing with aggressive edema reduction after debridement of foot infection in persons with diabetes.
      • Gallagher K.A.
      • Goldstein L.J.
      • Thom S.R.
      • Velazquez O.C.
      Hyperbaric oxygen and bone marrow-derived endothelial progenitor cells in diabetic wound healing.
      In this systematic review, we sought to identify and summarize the best available evidence that supports the use of these therapies and estimate the magnitude of benefit in patient-important outcomes.

      Methods

      The systematic review was based on a prespecified protocol approved by a committee from the Society for Vascular Surgery and is being reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

       Eligibility criteria

      Eligible studies were randomized trials and controlled observational studies in patients with diabetic foot ulcers in which a discrete list of adjunctive therapies was compared with other adjunctive therapies or with a control group and reported the outcomes of interest. The control group is a group of patients in the same study that received comprehensive wound care (dressing changes, offloading, and débridement) but did not receive the intervention being tested. The control group could be contemporary or historical, matched or unmatched, realizing that historical and unmatched control groups offer weaker inference. The interventions we evaluated were HBOT, arterial pump device, and pharmacologic agents (pentoxifylline, cilostazol and iloprost). We were interested in studies that assessed the effect of the intervention on patient-important outcomes
      • Gandhi G.Y.
      • Murad M.H.
      • Fujiyoshi A.
      • Mullan R.J.
      • Flynn D.N.
      • Elamin M.B.
      • et al.
      Patient-important outcomes in registered diabetes trials.
      such as rate of complete wound healing and major amputation. Studies were included regardless of language, size, or duration of patient follow-up. We excluded nonoriginal studies, such as review articles, commentaries, and letters, and uncontrolled studies (single-arm cohorts).

       Study identification

      The search strategy was designed and conducted by an experienced reference librarian (L.P.) with input from the study's principle investigator (M.H.M.). We used controlled vocabulary (eg, Medical Subject Headings terms) with keywords to define the concepts of adjunctive therapy and diabetic foot. We conducted a comprehensive search of several databases from each database's earliest inclusive dates to October 2011. Databases included were Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, and Scopus. We identified additional candidate studies by review of the bibliographies f included articles and contact with experts. The detailed search strategy is available in the Appendix (online only).

       Study selection and data collection

      All relevant abstracts were downloaded into an endnote library and uploaded into an online reference management system (DistillerSR; Evidence Partners, Ottawa, ON, Canada). Reviewers working independently and in duplicate screened the abstracts for eligibility. Included abstracts were screened in full text. When reviewers disagreed on including an abstract, the full-text article was automatically reviewed. Full-text screening was also done in duplicate (Fig 1). Disagreements at this level were resolved by discussion and consensus. We calculated the inter-reviewer agreement beyond chance (κ) during the full-text screening level. Descriptive, methodologic, and outcome data were abstracted from eligible studies using a standardized piloted Web-based form.
      Figure thumbnail gr1
      Fig 1Flow diagram shows how studies were screened and selected. RCT, Randomized controlled trial.
      For each study, at least one reviewer abstracted the following descriptive data: detailed description of baseline characteristics (main demographic characteristics, type and duration of diabetes, size and duration of the ulcer, etc) and interventions received (active or control) for all participants enrolled. We also collected quality assessment and outcome data. Another reviewer checked the entered data for accuracy and resolved inconsistencies by referring to the full-text article.

       Risk of bias assessment

      Two reviewers independently assessed the quality of studies included. Nonrandomized studies were evaluated using the Newcastle-Ottawa scale,

      Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed September 8, 2015.

      and we assessed outcome ascertainment, adjustment for confounders, proportion of patients lost to follow-up, and sample selection in each study. Randomized trials were evaluated using the Cochrane risk of bias assessment tool.
      • Higgins J.P.
      • Altman D.G.
      Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions.
      Domains assessed included randomization, blinding, allocation concealment, baseline imbalances, loss to follow-up, and bias due to funding. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods.
      • Murad M.H.
      • Montori V.M.
      • Sidawy A.N.
      • Ascher E.
      • Meissner M.H.
      • Chaikof E.L.
      • et al.
      Guideline methodology of the Society for Vascular Surgery including the experience with the GRADE framework.
      • Murad M.H.
      • Swiglo B.A.
      • Sidawy A.N.
      • Ascher E.
      • Montori V.M.
      Methodology for clinical practice guidelines for the management of arteriovenous access.
      Following this approach, randomized trials are considered to warrant high quality of evidence (ie, high certainty) and observational studies warrant low quality of evidence. The evidence grading can be increased (if a large effect is observed) or decreased if other factors are noted such as studies being at increased risk of bias or imprecise (small with wide confidence intervals [CIs]).

       Statistical analysis

      We estimated from each study Peto odds ratios (ORs) with the 95% CI due to the small number of events. Between-studies heterogeneity was calculated by the I2 statistic, which estimates the proportion of variation in results across studies that is not due to chance.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      Meta-analysis was completed using Comprehensive Meta-Analysis 2.2 software (Biostat Inc, Englewood, NJ).
      Data were insufficient to perform subgroup analysis. Evaluation of publication bias was not feasible due to the small number of included studies per comparison.
      • Sterne J.A.
      • Sutton A.J.
      • Ioannidis J.P.
      • Terrin N.
      • Jones D.R.
      • Lau J.
      • et al.
      Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.

      Results

       Search results and included studies

      The literature search yielded 624 potentially relevant abstracts. After abstract screening, we excluded 538 studies and retrieved 86 articles in full text. Fifteen articles fulfilled our inclusion criteria and were eligible for data extraction. We identified three additional articles by manually searching the bibliographies of the included articles to a total of 18 articles, of which 12 reported sufficient data for meta-analyses (Fig 1). The identified studies included nine randomized controlled trials (RCTs) and nine controlled cohorts, including data from 1526 patients with diabetic foot ulcers who received some sort of an adjunctive therapy. The characteristics of included studies are described in Table I. The interventions are described in detail in Table II. The adjusted agreement between reviewers (κ) averaged 0.82 as calculated by the online system. Experts from the Society for Vascular Surgery continued to monitor the literature after the search date for new studies that may affect the diabetic foot ulcer guidelines. They identified one additional systematic review and meta-analysis,
      • 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.
      with a search date of April 20, 2012, and one additional large observational study,
      • Margolis D.J.
      • Gupta J.
      • Hoffstad O.
      • Papdopoulos M.
      • Glick H.A.
      • Thom S.R.
      • et al.
      Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study.
      both of which addressed the efficacy of HBOT.
      Table ICharacteristics of the included studies
      StudyNo.GroupsAge, yearsMale, %T2D/T1DDuration of diabetes, yearHbA1c, %Ulcer descriptionFollow-up, months
      Abidia,
      • Abidia A.
      • Laden G.
      • Kuhan G.
      • Johnson B.F.
      • Wilkinson A.R.
      • Renwick P.M.
      • et al.
      The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial.
      2003
      18HBOT7250NR13<8.5 (all patients)Size: 1.06 cm2

      Duration: 6 months

      All patients grade 1
      12
      Control7011Size 0.78 cm2

      Duration: 9 months

      All patients grade 2
      Armstrong,
      • Armstrong D.G.
      • Nguyen H.C.
      Improvement in healing with aggressive edema reduction after debridement of foot infection in persons with diabetes.
      2000
      115Arterial pump device4974NR12.59.7 ± 1.9Size: 6.7 cm21.5
      Placebo5112.79.2 ± 2.5Size: 7.5
      Ay,
      • Ay H.
      • Yildiz S.
      The evaluation of TcPO2 and TcPCO2 measurement as a follow up criteria in diabetic foot treated with HBO therapy [Turkish].
      2004
      50HBOT5766NR16.1 ± 3.29.1NR1
      Standard care6015.4 ± 2.77.8
      Baroni,
      • Baroni G.
      • Porro T.
      • Faglia E.
      • Pizzi G.
      • Mastropasqua A.
      • Oriani G.
      • et al.
      Hyperbaric oxygen in diabetic gangrene treatment.
      1987
      28HBOT5860.713/1516.4 ± 6.88.8 ± 1.2Size: 33.4 ± 28.913.5
      Standard care5913.9 ± 6Size: 28.1 ± 21.9
      Doctor,
      • Doctor N.
      • Pandya S.
      • Supe A.
      Hyperbaric oxygen therapy in diabetic foot.
      1992
      30HBOT567083/1710NRNR1.5
      Standard care6011
      Duzgun,
      • Duzgun A.P.
      • Satir H.Z.
      • Ozozan O.
      • Saylam B.
      • Kulah B.
      • Coskun F.
      Effect of hyperbaric oxygen therapy on healing of diabetic foot ulcers.
      2008
      100HBOT586414/86178.0 ± 1.9According to Wagner's Classification:

      Grade 2: 6 patients

      Grade 3: 19 patients

      Grade 4: 25 patients
      23 ± 3
      Standard care63168.7 ± 2.9Grade 2: 12 patients

      Grade 3: 18 patients

      Grade 4: 20 patients
      Faglia,
      • Faglia E.
      • Favales F.
      • Aldeghi A.
      • Calia P.
      • Quarantiello A.
      • Oriani G.
      • et al.
      Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study.
      1996
      70HBOT6271NR169.3 ± 2.5According to Wagner's classification:

      Grade 2: 4 patients

      Grade 3: 9 patients

      Grade 4: 22 patients
      2
      Standard care66198.5 ± 2.3Grade 2: 5 patients

      Grade 3: 8 patients

      Grade 4: 20 patients
      Faglia,
      • Faglia E.
      • Favales F.
      • Aldeghi A.
      • Calia P.
      • Quarantiello A.
      • Barbano P.
      • et al.
      Change in major amputation rate in a center dedicated to diabetic foot care during the 1980s: prognostic determinants for major amputation.
      1998
      115HBOT5173NR178.8 ± 2.3According to Wagner's classification:

      Grade 2: 13 patients

      Grade 3: 32 patients

      Grade 4: 70 patients
      NR
      Standard care65
      Kalani,
      • Kalani M.
      • Jorneskog G.
      • Naderi N.
      • Lind F.
      • Brismar K.
      Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow-up.
      2002
      38HBOT607944/54277.1Size: 10.77 cm236
      Standard care7.3Size: 4.49 cm2
      Kessler,
      • Kessler L.
      • Bilbault P.
      • Ortega F.
      • Grasso C.
      • Passemard R.
      • Stephan D.
      • et al.
      Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study.
      2003
      28HBOT606885/1518.2 ± 6.69.4 ± 2.4Size: 2.31 cm21
      Standard care8.1 ± 1.4Size: 2.82 cm2
      Londahl,
      • Londahl M.
      • Katzman P.
      • Nilsson A.
      • Hammarlund C.
      Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes.
      2010
      94HBOT618167/33207.8Size: 3.5 cm212
      Placebo69238.1Size: 2.8 cm2
      Margolis,
      • Margolis D.J.
      • Gupta J.
      • Hoffstad O.
      • Papdopoulos M.
      • Glick H.A.
      • Thom S.R.
      • et al.
      Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study.
      2013
      6259HBOT793

      5466
      62

      63
      64

      56
      Not availableNot available≥3: 46%

      ≥3: 18%
      767,060 person-days of wound care
      Standard careNot availableNot available
      Oriani,
      • Oriani G.
      • Meazza D.
      • Favales F.
      • Pizzi G.L.
      • Aldeghi A.
      • Faglia E.
      Hyperbaric oxygen therapy in diabetic gangrene.
      1990
      80HBOT5360NR14.5 ± 9.69.5NRNR
      Standard care5816.1 ± 6.48.2
      Ramani,
      • Ramani A.
      • Kundaje G.N.
      • Nayak M.N.
      Hemorheologic approach in the treatment of diabetic foot ulcers.
      1993
      40Pentoxifylline59NRNR11.5NRAccording to Wagner's Classification:

      Grade 2: 2 patients

      Grade: 6 patients

      Grade: 10 patients

      Grade: 2 patients
      3
      Standard care6212.5Grade: 2 patients

      Grade: 6 patients

      Grade: 12 patients
      Sert,
      • Sert M.
      • Soydas B.
      • Aikimbaev K.
      • Tetiker T.
      Effects of iloprost (a prostacyclin analogue) on the endothelial dysfunction and foot ulcers in diabetic patients with peripheral arterial disease.
      2008
      60Iloprost6260100/01510.4 ± 2.1Duration: 2.3 months1
      Standard care1410.8 ± 2.3
      Sousa,
      • Sousa J.A.E.
      [Long-term evaluation of chronic diabetic foot ulcers, non-healed after hyperbaric oxygen therapy].
      2005
      95HBOT6470.882/1820NRAccording to Wagner's classification:

      Grade 2: 8 patients

      Grade 3: 11 patients

      Grade 4: 36 patients
      50
      Standard care6122Grade 2: 4 patients

      Grade 3: 9 patients

      Grade 4: 28 patients
      Stone,
      • Stone J.A.
      • Scott R.G.
      • Brill L.R.
      • Levine B.D.
      The role of hyperbaric-oxygen in the treatment of diabetic foot wounds.
      1995
      469HBOTNANANANANASize: 25.33 ± 0.98NA
      Standard careSize: 11.99 ± 0.61
      Wang,
      • Wang C.J.
      • Wu R.W.
      • Yang Y.J.
      Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy.
      2011
      86HBOT62NR

      NR
      NR

      NR
      20 ± 108.1 ± 1.8Size: 7 cm2

      Size: 4 cm2
      11

      14
      ESWT6116.1 ± 6.48.7 ± 2.2
      Zamboni,
      • Zamboni W.A.
      • Wong H.P.
      • Stephenson L.L.
      • Pfeifer M.A.
      Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study.
      1997
      10HBOT63750/100>10NRSize: 6.0 cm24-6
      Standard care54Size: 4.4 cm2
      ESWT, Extracorporeal shockwave therapy; HbA1c, glycated hemoglobin; HBOT, hyperbaric oxygen therapy; NA, not available; NR, not reported; T2D/T1D, type 2 diabetes/type 1 diabetes.
      Table IIObjectives, inclusion criteria, and interventions of each study
      Study IDObjectiveInclusion and exclusion criteriaTreatment in group 1Treatment in group 2
      Abidia,
      • Abidia A.
      • Laden G.
      • Kuhan G.
      • Johnson B.F.
      • Wilkinson A.R.
      • Renwick P.M.
      • et al.
      The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial.
      2003
      To evaluate the role of HBOT in the management of these ulcers.Patients were included if they had an ulcer >1 cm and <10 cm in maximum diameter which had not shown any signs of healing, despite optimum medical management for >6 weeks since presenting. Patients for whom vascular surgery, angioplasty, or thrombolysis was planned were excluded. Occlusive arterial disease was confirmed by an ankle-brachial pressure index <0.8. Acceptable metabolic control of their diabetes was judged by glycated hemoglobin level of <8.5%.HBOT: hyperbaric 100% oxygen. The treatment was given in a multiplace chamber via hood at a pressure of 2.4 atm abs for 90 minutes daily, 5 days/week, totalling 30 sessions. Medical management was optimized and equivalent for all patients in both groups.Control group: hyperbaric air with the same specification as the treatment group in addition to the standard medical management.
      Armstrong,
      • Armstrong D.G.
      • Nguyen H.C.
      Improvement in healing with aggressive edema reduction after debridement of foot infection in persons with diabetes.
      2000
      To evaluate the proportion of healing of foot infections in subjects with diabetes undergoing aggressive edema reduction with the use of intermittent pneumatic foot compression after foot-level débridement.The study included patients with diabetes who had foot infections requiring incision and débridement. They excluded patients with diagnosed active congestive heart failure, end-stage renal disease, or a serum creatinine level >177 μmol/L (>2.0 mg/dL) on the day of hospital admission. They also excluded any subjects who received a lower extremity bypass graft within the period of study.Functioning pulsatile pneumatic foot compression system. This system includes a wrap that goes around the foot and a pneumatic pump that intermittently fires bursts of air through tubing to the wrap. The wrap contains a bladder that is rapidly inflated to ∼160 mm Hg for 2 seconds to empty the veins of the foot. This cycle is repeated every 20 seconds.Placebo pulsatile pneumatic foot compression system with the same specifications. In the placebo device, all lights, audible alerts, and programming indicators were functional and identical to and indistinguishable from those of the active device. The placebo foot wrap that was applied to the foot, however, was fenestrated so as not to inflate and impart compression. Because all patients who participated in this project had moderate to severe peripheral sensory neuropathy, they were not generally able to feel whether they were receiving substantial compression therapy.
      Ay,
      • Ay H.
      • Yildiz S.
      The evaluation of TcPO2 and TcPCO2 measurement as a follow up criteria in diabetic foot treated with HBO therapy [Turkish].
      2004
      To study the therapeutic efficiency of HBOT by measuring TcPo2 and TcPco2 in patients who had wounds caused by diabetes mellitus.Diabetic patients with diabetic wound. Patients with untreated pneumothorax were excluded from the study.HBOT + standard diabetes and wound management + pentoxifylline, Ginkgo glycosides, and ascorbic acid.Standard diabetes and wound management + pentoxifylline, Ginkgo glycosides, and ascorbic acid.
      Baroni,
      • Baroni G.
      • Porro T.
      • Faglia E.
      • Pizzi G.
      • Mastropasqua A.
      • Oriani G.
      • et al.
      Hyperbaric oxygen in diabetic gangrene treatment.
      1987
      To study the effect of HBOT in diabetic foot ulcers.Diabetic patients with ulcers or necrotic foot lesions.Combined therapeutic regimen consisting of HBO, strict metabolic control, and daily débridement.Standard care. The same except for HBOT.
      Doctor,
      • Doctor N.
      • Pandya S.
      • Supe A.
      Hyperbaric oxygen therapy in diabetic foot.
      1992
      To study the effect of HBOT in chronic diabetic foot lesions.Diabetic patients with chronic foot lesions.HBOT was administered in a monoplace HBO chamber at atmosphere pressure for 45 minutes for 4 separate sessions over a period of 2 weeks. In addition patients received conventional wound therapy.Standard care.
      Duzgun,
      • Duzgun A.P.
      • Satir H.Z.
      • Ozozan O.
      • Saylam B.
      • Kulah B.
      • Coskun F.
      Effect of hyperbaric oxygen therapy on healing of diabetic foot ulcers.
      2008
      To study the use of HBOT vs standard therapy for the treatment of foot ulcers in diabetic patients.Diabetic patients were considered eligible if they were ≥18 years and if they had a foot wound that had been present for at ≥4 weeks despite appropriate local and systemic wound care.Standard therapy plus HBOT group standard therapy was supplemented by HBOT administered at a maximum working pressure of 2 ATA, using a unichamber pressure room using a volume of 10 m3 at 2 to 3 ATA for 90 minutes. Treatment was administered as 2 sessions per day, followed by 1 session on the following day, alternating throughout the course of therapy, which typically extended for 20 to 30 days.Standard treatment, which is daily wound care, including dressing changes and local débridement at bedside or in the operating room, as well as amputation when indicated.
      Faglia,
      • Faglia E.
      • Favales F.
      • Aldeghi A.
      • Calia P.
      • Quarantiello A.
      • Oriani G.
      • et al.
      Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study.
      1996
      To evaluate the effectiveness of the systemic HBOT in addition to a comprehensive protocol in decreasing major amputation rate in diabetic patients hospitalized for severe foot ulcer.Diabetic patients consecutively hospitalized for foot ulcer.HBOT group received pure oxygen in multiplace hyperbaric chamber, pressurized with air. Pressure was 2.5 ATA and then dropped to 2.4 to 2.2 ATA. They received daily sessions of 90 minutes each.Patients only received the standard wound care and diabetic management.
      Faglia,
      • Faglia E.
      • Favales F.
      • Aldeghi A.
      • Calia P.
      • Quarantiello A.
      • Barbano P.
      • et al.
      Change in major amputation rate in a center dedicated to diabetic foot care during the 1980s: prognostic determinants for major amputation.
      1998
      To report the evolution that took place in our hospital between the end of the 1970s and the beginning of the 1990s in the prevalence of major amputations in hospitalized diabetic patients with severe foot ulcer and to assess in our cases the prognostic determinants involved in major amputations.Diabetic patients who were consecutively hospitalized for foot ulcers. No criteria described.HBOT, breathed pure oxygen in a hyperbaric chamber pressurized with air, and used a soft helmet. The pressure was 2.5 ATA in the first phase. In the second phase, we applied 2.4 to 2.2 ATA.Standard care.
      Kalani,
      • Kalani M.
      • Jorneskog G.
      • Naderi N.
      • Lind F.
      • Brismar K.
      Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow-up.
      2002
      To investigate the long-term effect of HBOT in treatment of diabetic foot ulcers.The patients had been referred due to chronic nonhealing foot ulcers. They were included in the study if the foot ulcers did not heal despite the treatment program.Patients underwent 40 to 60 sessions of HBOT. The daily treatment sessions were given at a pressure of 250 kPa, equivalent to 15 m H2O, in an acrylic monoplace chamber pressurized with 100% oxygen, allowing the patient to breathe without a mask or hood. Patients also received the standard therapy as the control group.Control group: All patients were treated with nonweight-bearing protective shoes, orthosis, and improvement of metabolic control, blood pressure, and nutrition. Regular control of off-loading was performed.
      Kessler,
      • Kessler L.
      • Bilbault P.
      • Ortega F.
      • Grasso C.
      • Passemard R.
      • Stephan D.
      • et al.
      Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study.
      2003
      To study the effect of systemic HBOT on the healing course of nonischemic chronic diabetic foot ulcers.Included were patients with type 1 and type 2 diabetes admitted for chronic foot ulcers. Their ulcers (depth <2 mm) were characterized by the absence of favorable evolution for at ≥3 months despite the stabilization of glycemia, the absence of clinical local infection, and satisfactory off-loading measures. Exclusion criteria: patients with gangrenous ulcer with severe sepsis, severe arteriopathy (TcPo2 ± 30 mm Hg), with emphysema, proliferating retinopathy, and claustrophobia.Patients randomized for HBO underwent two 90-minute daily sessions of 100% O2 breathing in a multiplace hyperbaric chamber pressurized at 2.5 ATA. This regimen lasted 5 days/wk for 2 consecutive weeks. They also received conventional therapy.The conventional additional treatment was applied to both groups of patients during hospitalization and the ambulatory period. Each patient was provided with an orthopedic device to remove mechanical stress and pressure at the site of the ulcer during walking. The optimization of metabolic control required subcutaneous insulin administration (2 or 3 injections or bedtime treatment) for the majority of patients.
      Londahl,
      • Londahl M.
      • Katzman P.
      • Nilsson A.
      • Hammarlund C.
      Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes.
      2010
      To evaluate whether HBOT improves the health-related quality of life in these patients.All patients had diabetes and at ≥1 full-thickness wound below the ankle for >3 months. They were previously treated at a diabetes foot clinic for a period of not <2 months. All patients were assessed by a vascular surgeon at the time of inclusion, and only patients with adequate distal perfusion or nonreconstructible peripheral vascular disease were included in the study. Patients with an acute foot infection were included when the acute phase was resolved. Oral or local antibiotic treatment did not exclude patients from study participation. Exclusion criteria for study participation were contraindications for HBOT (severe obstructive pulmonary disease, malignancy, and untreated thyrotoxicosis), current drug or alcohol misuse, vascular surgery in the lower limbs within the last 2 months, participation in another study, or suspected poor compliance. All participants provided written informed consent.HBOT treatment sessions were given in a multi-place hyperbaric chamber 5 days/wk for 8 weeks (40 treatment sessions). Study treatment was given as an adjunct to regular treatment at the multidisciplinary diabetes foot clinic, which included treatment of infection, revascularization, débridement, off-loading, and metabolic control according to high international standardsPatients received hyperbaric air through separate double-blinded pipes at the same frequency as HBOT. Study treatment was given as an adjunct to regular treatment at the multidisciplinary diabetes foot clinic, which included treatment of infection, revascularization, débridement, off-loading, and metabolic control according to high international standards
      Margolis,
      • Margolis D.J.
      • Gupta J.
      • Hoffstad O.
      • Papdopoulos M.
      • Glick H.A.
      • Thom S.R.
      • et al.
      Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study.
      2013
      To compare the effectiveness of HBOT with other conventional therapies administered in a wound care network for the treatment of a diabetic foot ulcer and prevention of lower extremity amputation.Treated between November 2005 and May 2011 by a provider with contractual agreement with HBOT facility, agreed to provide data for research, have diabetes, have adequate lower extremity arterial flow (as determined by the clinician), have a wound on plantar foot (hindfoot, heel, midfoot, or forefoot, toes), experienced failure to heal during the first 4 weeks of wound center care and experienced failure of decrease in wound size by at least 40%.HBOTStandard care.
      Oriani,
      • Oriani G.
      • Meazza D.
      • Favales F.
      • Pizzi G.L.
      • Aldeghi A.
      • Faglia E.
      Hyperbaric oxygen therapy in diabetic gangrene.
      1990
      To report the effect of HBOT on diabetic foot ulcers.Diabetic patients who were consecutively hospitalized for foot ulcers. No criteria described.HBOT in a hyperbaric chamber at 2.8 ATA and then at 2.5 ATA 6 days/wk until the beginning of granulation and them 5 days/wk until recovery.Standard care.
      Ramani,
      • Ramani A.
      • Kundaje G.N.
      • Nayak M.N.
      Hemorheologic approach in the treatment of diabetic foot ulcers.
      1993
      To study the effect of pentoxifylline in ischemic diabetic wounds.Patients with diabetic ischemic ulcer grade ≥2. All patients had evidence of peripheral vascular disease. Neurotrophic ulcers were excluded.Oral pentoxifylline, 400 mg, 3 times daily, + conventional therapy.Conventional therapy.
      Stone,
      • Stone J.A.
      • Scott R.G.
      • Brill L.R.
      • Levine B.D.
      The role of hyperbaric-oxygen in the treatment of diabetic foot wounds.
      1995
      To test the hypothesis that a defined course of intermittent increased tissue oxygenation will result in a reduction of amputation rate.Consecutive patients with diabetic wounds treated at a referral wound center. No further criteria available.HBOT, 100% oxygen at a greater than normal sea level atmospheric pressure.Standard care.
      Sert,
      • Sert M.
      • Soydas B.
      • Aikimbaev K.
      • Tetiker T.
      Effects of iloprost (a prostacyclin analogue) on the endothelial dysfunction and foot ulcers in diabetic patients with peripheral arterial disease.
      2008
      To assess the efficiency of iloprost (an analog of prostacyclin) infusion on endothelial functions and amputation rate in diabetic foot ulcers with complicated macroangiopathy.Patients with type 2 diabetes mellitus and severe peripheral ischemic foot ulcer unsuitable for revascularization hospitalized for treatment. The study excluded patients who had septic shock, renal and liver failure, decompensated heart failure, acute or subacute coronary syndromes, active peptic ulcer, acute cerebral hemorrhage, using anticoagulant drug and a known contraindication to iloprost.Patients were administered iloprost with a dose of 0.5 to 2 ng/kg/min over 6-h infusions for 10 consecutive days.Patients only received the standard wound care and diabetic management.
      Sousa,
      • Sousa J.A.E.
      [Long-term evaluation of chronic diabetic foot ulcers, non-healed after hyperbaric oxygen therapy].
      2005
      To evaluate the long-term clinical evolution of chronic ulcers on lower limbs of patients with diabetes that could not heal with HBOT.Diabetic patients with infected postsurgical wounds or neuroischemic ulcers in lower limbs (grade 2 or 4 according to Wagner classification) with at least 1 month of evolution and who had received usual care previously with drugs and/or surgery, including arterial revascularization if requiredHBOTStandard care.
      Wang,
      • Wang C.J.
      • Wu R.W.
      • Yang Y.J.
      Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy.
      2011
      To compare the effectiveness of ESWT and HBOT in chronic diabetic foot ulcers.Inclusion criteria: patients with chronic nonhealing diabetic foot ulcers for >3 months' duration. Exclusion criteria: patients with cardiac arrhythmia or a pacemaker, pregnancy, skeletal immaturity, patients with malignancy, and patients lacking complete follow-up data.HBOT was performed with patients in a sealed multiplace chamber at a pressure of 2.5 ATA. Air pressure was gradually increased from 1 ATA to 2.5 ATA over a 15-minuute interval. HBO was performed daily, 5 times/wk, for a total of 20 treatments. After HBOT, patients resumed their initial wound care protocol including off-loading on the affected foot, wound cleansing with sterile normal saline solution, and application of silver sulfadiazine cream.ESWT: The treatment dosage was ulcer-size dependent with the numbers of impulses equal to the treatment area in cm2 ×8, with a minimum of 500 impulses at energy setting E2 (equivalent to 0.23 mJ/mm2 energy flux density) at a rate of 4 shocks/s. The treatments were conducted 2 times/wk for 3 weeks for a total of 6 treatments. After ESWT, patients resumed their initial wound care protocol including off-loading on the affected foot, wound cleansing with sterile normal saline solution, and application of silver sulfadiazine cream.
      Zamboni,
      • Zamboni W.A.
      • Wong H.P.
      • Stephenson L.L.
      • Pfeifer M.A.
      Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study.
      1997
      To evaluate the effect of HBOT on the healing of diabetic lower extremity wounds.Type 1 diabetic patients with chronic nonhealing lower extremity wounds.HBOT consisting of 100% oxygen for 120 minutes per at a depth of 2.0 ATA. Patients were treated 5 days/wk for a total of 30 treatments. All patients seen weekly in the clinic for wound assessment. In addition patients received the standard wound care and diabetic management.Patients only received the standard wound care and diabetic management.
      ATA, Atmospheres absolute; ESWT, extracorporeal shock wave therapy; HBO, hyperbaric oxygen; HBOT, hyperbaric oxygen treatment; TcPco2, transcutaneous partial pressure of carbon dioxide; TcPo2, transcutaneous partial pressure of oxygen.

       Methodologic quality and risk of bias

      The quality of the included studies ranged from low to moderate. Randomization and allocation concealment were adequately described in only six and two of nine RCTs, respectively. In three RCTs, the patients the physicians were both blinded. In one RCT, only the physicians were blinded. Details of blinding were not reported in the remaining RCTs. No baseline imbalances were mentioned in any of the studies. The percentage lost to follow-up ranged from 0% to 15.6%, with three studies reporting no losses.
      The overall risk of bias in the observational studies was high. Although the samples were representative in most of the studies and follow-up was adequate, no baseline imbalances were mentioned in six of the 10 studies and all but one adjusted for confounders. Many concerns were raised regarding one large observational study by Margolis et al,
      • Margolis D.J.
      • Gupta J.
      • Hoffstad O.
      • Papdopoulos M.
      • Glick H.A.
      • Thom S.R.
      • et al.
      Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study.
      such as insufficient exposure (small number of HBOT sessions), high loss to follow-up (57%), not using transcutaneous oxygen measurements or other vascular assessment to select patients for HBOT, and selection bias (higher Wagner scores in patients receiving HBOT). Therefore, this study was included in the sensitivity analysis. Tables III and IV describe the quality of included studies.
      Table IIIRisk of bias assessment in randomized trials
      Study IDRandomization methodsConcealed allocationBlindingBaseline imbalanceEfficient follow-upAdherence to treatmentLost of follow-up. %Funding source
      Abidia,
      • Abidia A.
      • Laden G.
      • Kuhan G.
      • Johnson B.F.
      • Wilkinson A.R.
      • Renwick P.M.
      • et al.
      The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial.
      2003
      NRSealed envelopesYes, double-blindedNoRegular clinic visitsNR11.1NR
      Armstrong,
      • Armstrong D.G.
      • Nguyen H.C.
      Improvement in healing with aggressive edema reduction after debridement of foot infection in persons with diabetes.
      2000
      Computerized tableNRYes, double blindedNoRegular clinic visitsYes15.6For-profit
      Doctor,
      • Doctor N.
      • Pandya S.
      • Supe A.
      Hyperbaric oxygen therapy in diabetic foot.
      1992
      NRNRNRNoHospitalizedNR0Not for-profit
      Duzgun,
      • Duzgun A.P.
      • Satir H.Z.
      • Ozozan O.
      • Saylam B.
      • Kulah B.
      • Coskun F.
      Effect of hyperbaric oxygen therapy on healing of diabetic foot ulcers.
      2008
      Random number tableNoNRNoRegular clinic visitsNR0NR/unclear
      Faglia,
      • Faglia E.
      • Favales F.
      • Aldeghi A.
      • Calia P.
      • Quarantiello A.
      • Oriani G.
      • et al.
      Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study.
      1996
      Randomization tableNRNRNoHospitalizedYes2.8NR
      Kessler,
      • Kessler L.
      • Bilbault P.
      • Ortega F.
      • Grasso C.
      • Passemard R.
      • Stephan D.
      • et al.
      Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study.
      2003
      Randomization tableNRYes, physiciansNoHospitalization for 2 weeks then regular clinic visits for 2 weeksNR3.5Not for-profit
      Londahl,
      • Londahl M.
      • Katzman P.
      • Nilsson A.
      • Hammarlund C.
      Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes.
      2010
      In blocks of 10Sealed envelopesYes, double blindedNoRegular clinic visitsNR11.7Not for-profit
      Sert,
      • Sert M.
      • Soydas B.
      • Aikimbaev K.
      • Tetiker T.
      Effects of iloprost (a prostacyclin analogue) on the endothelial dysfunction and foot ulcers in diabetic patients with peripheral arterial disease.
      2008
      NRNRNRNoHospitalizedYes0NR
      Wang,
      • Wang C.J.
      • Wu R.W.
      • Yang Y.J.
      Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy.
      2011
      Computer-generated block labelsNRNoNoRegular clinic visitsNR10.5Not for-profit
      NR, Not reported.
      Table IVRisk of bias assessment in nonrandomized studies
      Study IDSelectionControlled for confounders?Outcome
      Representativeness of exposed cohortAscertainment of exposureSimilarity between groups at the baselineAssessment of outcomeEnough follow-up lengthFollow-up adequacy of cohorts
      Ay,
      • Ay H.
      • Yildiz S.
      The evaluation of TcPO2 and TcPCO2 measurement as a follow up criteria in diabetic foot treated with HBO therapy [Turkish].
      2004
      Truly representativeYesYesNoNo descriptionYesComplete
      Baroni,
      • Baroni G.
      • Porro T.
      • Faglia E.
      • Pizzi G.
      • Mastropasqua A.
      • Oriani G.
      • et al.
      Hyperbaric oxygen in diabetic gangrene treatment.
      1987
      Truly representativeYesYesNoNo descriptionYesComplete
      Faglia,
      • Faglia E.
      • Favales F.
      • Aldeghi A.
      • Calia P.
      • Quarantiello A.
      • Barbano P.
      • et al.
      Change in major amputation rate in a center dedicated to diabetic foot care during the 1980s: prognostic determinants for major amputation.
      1998
      Truly representativeYesNo, age was significantly different between 2 groups (P = .05)NoNo descriptionYesComplete
      Kalani,
      • Kalani M.
      • Jorneskog G.
      • Naderi N.
      • Lind F.
      • Brismar K.
      Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow-up.
      2002
      Truly representativeYesNo, larger ulcer area in HBO group, older people in conventional groupNoNo descriptionYes5 patients died
      Margolis,
      • Margolis D.J.
      • Gupta J.
      • Hoffstad O.
      • Papdopoulos M.
      • Glick H.A.
      • Thom S.R.
      • et al.
      Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study.
      2013
      Possibly not, study did not use TcPo2 measurements or other vascular assessment to select patient for HBOTYes, but insufficient exposure (small number of HBOT sessions)No, higher Wagner scores in patients receiving HBOTPropensity matching and instrumental variable analysisNo descriptionYesHigh loss to follow-up (57%)
      Oriani,
      • Oriani G.
      • Meazza D.
      • Favales F.
      • Pizzi G.L.
      • Aldeghi A.
      • Faglia E.
      Hyperbaric oxygen therapy in diabetic gangrene.
      1990
      Truly representativeYesYesNoNo descriptionNRComplete
      Ramani,
      • Ramani A.
      • Kundaje G.N.
      • Nayak M.N.
      Hemorheologic approach in the treatment of diabetic foot ulcers.
      1993
      Truly representativeYesYesNoNo descriptionYes3 patients died
      Sousa,
      • Sousa J.A.E.
      [Long-term evaluation of chronic diabetic foot ulcers, non-healed after hyperbaric oxygen therapy].
      2005
      Truly representativeYesYesNoNo descriptionYesComplete
      Stone,
      • Stone J.A.
      • Scott R.G.
      • Brill L.R.
      • Levine B.D.
      The role of hyperbaric-oxygen in the treatment of diabetic foot wounds.
      1995
      Truly representativeYesNo, HBOT group had more serious woundsNoNo descriptionNRComplete
      Zamboni,
      • Zamboni W.A.
      • Wong H.P.
      • Stephenson L.L.
      • Pfeifer M.A.
      Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study.
      1997
      Truly representativeYesYesNoBlindedYesComplete
      HBOT, Hyperbaric oxygen therapy; NR, not reported; TcPo2, transcutaneous partial pressure of oxygen.

       Meta-analysis

      Based on six RCTs, HBOT was associated with increased healing rate (OR, 14.25; 95% CI, 7.08-28.68, I2 = 0%) and reduced major amputation rate (OR, 0.30; 95% CI, 0.10-0.89, I2 = 59%) compared with conventional therapy. The quality of this evidence is considered low to moderate, potentially downgraded due to methodologic limitations of the included studies. HBOT was given in most studies at 2.0 to 3.0 atmospheric pressure in daily 90-minute sessions in a monoplace or multiplace chamber. On average, patients received 30 sessions, although a few patients in one study received 60 sessions.
      Meta-analysis of the six available observational studies was highly sensitive to study selection. When the older five studies were pooled in the meta-analysis, HBOT was associated with a statistically significant increase in healing rates and with a significant reduction in the amputation rate (Figs 2 and 3). When we added the study by Margolis et al
      • Margolis D.J.
      • Gupta J.
      • Hoffstad O.
      • Papdopoulos M.
      • Glick H.A.
      • Thom S.R.
      • et al.
      Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study.
      in the sensitivity analysis, the effect on amputation becomes imprecise (OR, 0.58; 95% CI, 0.24-1.40) and on the healing rate becomes reversed (OR, 2.88; 95% CI, 1.14-7.25). Therefore, the true effect should be derived from RCTs because they provide higher-quality evidence (here, moderate). Lastly, we performed a sensitivity analysis for the outcome of amputation, excluding the study by Oriani et al
      • Oriani G.
      • Meazza D.
      • Favales F.
      • Pizzi G.L.
      • Aldeghi A.
      • Faglia E.
      Hyperbaric oxygen therapy in diabetic gangrene.
      in which it was not possible to distinguish minor from major amputations, and the results were unchanged (OR, 0.35; 95% CI, 0.25-0.50).
      Figure thumbnail gr2
      Fig 2Meta-analysis of major amputation rate. The solid squares indicate the odds ratios and are proportional to the weights used in the meta-analysis. The diamond indicates the pooled odds ratio, and the lateral tips of the diamond indicate the associated 95% confidence interval (CI). The horizontal lines represent the 95% CIs. HBOT, Hyperbaric oxygen therapy; RCT, randomized controlled trial.
      Figure thumbnail gr3
      Fig 3Meta-analysis of healing rate. The solid squares indicate the odds ratios and are proportional to the weights used in the meta-analysis. The diamond indicates the pooled odds ratio, and the lateral tips of the diamond indicate the associated 95% confidence interval (CI). The horizontal lines represent the 95% CIs. HBOT, Hyperbaric oxygen therapy; RCT, randomized controlled trial.

       Results of individual studies (meta-analysis not feasible)

      One RCT
      • Wang C.J.
      • Wu R.W.
      • Yang Y.J.
      Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy.
      compared extracorporeal shockwave therapy (ESWT) to HBOT and found statistically significant increase in the wound-healing rate in favor of ESWT (relative risk [RR], 2.34; 95% CI, 1.30-4.21; P = .003). ESWT is done as an outpatient procedure, with no anesthesia, through a sterile cellulose barrier, ultrasound gel, and a shockwave applicator. The treatments are given twice weekly for 3 weeks for a total of six treatments. ESWT is hypothesized to induce neovascularization and upregulation of angiogenic growth factors. The quality of evidence is low, downgraded due to methodologic limitations of the study and imprecision (small number of events).
      Armstrong et al
      • Armstrong D.G.
      • Nguyen H.C.
      Improvement in healing with aggressive edema reduction after debridement of foot infection in persons with diabetes.
      conducted an RCT and compared arterial pump device to a placebo device and reported a significantly higher proportion of healing in the active group than in the placebo group (RR, 1.47; 95% CI, 1.06-2.03). Quality of evidence is low, downgraded due to methodologic limitations of the study and imprecision (small number of events).
      Another RCT
      • Sert M.
      • Soydas B.
      • Aikimbaev K.
      • Tetiker T.
      Effects of iloprost (a prostacyclin analogue) on the endothelial dysfunction and foot ulcers in diabetic patients with peripheral arterial disease.
      comparing iloprost to placebo was identified. It reported no statistically significant difference between the two groups in amputation rates (RR, 0.086; 95% CI, 0.72- 1.02; P = .097). The quality of evidence is low, downgraded due to methodologic limitations of the study and imprecision (small number of events).
      An observational study by Ramani et al
      • Ramani A.
      • Kundaje G.N.
      • Nayak M.N.
      Hemorheologic approach in the treatment of diabetic foot ulcers.
      found pentoxifylline was as effective as conventional therapy, with no statistically significant difference in amputation rates between the 2 groups (RR, 0.83; 95% CI, 0.47-1.46). Quality of evidence is low, downgraded due to methodologic limitations of the included study and imprecision (wide CI and small number of events).
      No study comparing cilostazol to standard care or any other adjunctive therapy—in the setting of diabetic foot ulcer—was found.

      Discussion

      We conducted a systematic review and meta-analyses to evaluate the comparative effectiveness of different adjunctive therapies for diabetic foot ulcers. We identified a significant beneficial effect of HBOT compared with standard care in improving the healing rate and reducing the risk of major amputations. This effect was consistent across RCTs and controlled cohorts when analyzed pooled or separately. Nevertheless, the overall quality of the evidence is low to moderate due to several limitations that are associated with the methodologic quality of the studies.
      Data from one small RCT suggest that ESWT is better than HBOT in enhancing wound healing.
      • Wang C.J.
      • Wu R.W.
      • Yang Y.J.
      Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy.
      However, the quality of this comparative evidence was low, and this finding needs to be verified in additional future comparative effectiveness trials. Moreover, there is also only sparse data regarding the effectiveness of arterial pump devices, iloprost, and pentoxifylline; hence, one should verify their effect on patient-important outcomes for diabetic foot ulcers in rigorously designed studies.
      In regard to HBOT, our results are consistent with other systematic reviews.
      • 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.
      • Game F.L.
      • Hinchliffe R.J.
      • Apelqvist J.
      • Armstrong D.G.
      • Bakker K.
      • Hartemann A.
      • et al.
      A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes.
      • Kranke P.
      • Bennett M.H.
      • Martyn-St James M.
      • Schnabel A.
      • Debus S.E.
      Hyperbaric oxygen therapy for chronic wounds.
      It is important to note, however, that the effect of HBOT on amputation was imprecise in some these reviews when estimated using a RR measure, whereas using Peto OR showed more precise estimates. The sensitivity of conclusions to the choice of the measure of effect used is a sign of imprecision that can lower confidence warranted by this evidence. Although conventional therapy (the comparison arm in most of the included studies in this review) included comprehensive wound care (débridements, wound dressing, and offloading), the way this care was provided was clearly heterogenous across studies.
      Our conclusions regarding the benefit of HBOT in diabetic foot setting are consistent with reviews that evaluated its potential role in a variety of other types of chronic wounds.
      • Wang C.
      • Schwaitzberg S.
      • Berliner E.
      • Zarin D.A.
      • Lau J.
      Hyperbaric oxygen for treating wounds: a systematic review of the literature.
      • Goldman R.J.
      Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review.
      Our review updated the evidence base and expanded on previous findings exploring the role of other adjunctive therapies in patients with diabetic foot ulcers.

       Clinical and practice implications

      There is low- to moderate-quality evidence that suggests a beneficial effect of HBOT when used as an adjunct to standard treatment for diabetic foot ulcers. HBOT should always be used as an adjunctive procedure (along with comprehensive wound care, regular wound monitoring and débridement, and offloading). HBOT is unlikely to be helpful in patients with severe uncorrectable ischemia because oxygen will not reach the ischemic area in a sufficient tension to provoke angiogenesis. The decision to start HBOT should be made after ischemia status is evaluated. In the included studies, it is challenging to tell whether such principles have always been followed or to conduct stratified analysis based on the vascular status. Therefore, the estimates we provide (in increased healing and reduction of major amputations) should be viewed as an average expected effect in a heterogeneous group of patients with diabetic foot ulcers.
      Other adjunctive therapy methods need to be further studied using well-designed RCTs to provide enough evidence to support their use in the clinical practice. Evidence of treatments that were shown beneficial in other types of chronic wounds may be extrapolated to the setting of diabetic foot ulcers; for example, patients with critical limb ischemia and nonhealing wounds had improved wound healing and limb preservation by using an intermittent pneumatic compression device.
      • Montori V.M.
      • Kavros S.J.
      • Walsh E.E.
      • Rooke T.W.
      Intermittent compression pump for nonhealing wounds in patients with limb ischemia. The Mayo Clinic experience (1998-2000).
      A meta-analysis suggested that negative-pressure therapy is likely effective in the treatment of chronic wounds.
      • Suissa D.
      • Danino A.
      • Nikolis A.
      Negative-pressure therapy versus standard wound care: a meta-analysis of randomized trials.
      A systematic review of negative-pressure therapy specifically in diabetic foot ulcer suggested possible benefit but highlighted the smaller body of evidence in this setting.
      • Noble-Bell G.
      • Forbes A.
      A systematic review of the effectiveness of negative pressure wound therapy in the management of diabetes foot ulcers.
      The accompanying guidelines by the Society for the Vascular Surgery will supply more details on the various options of adjunctive therapies and their use in different clinical situations, so that the patient and the clinician can both make an informed decision and select the right option according to the given clinical scenario. This systematic review addresses certain a priori chosen adjunctive therapies for diabetic foot ulcers. Other treatments, such as noncontact low-frequency ultrasound therapy, negative-pressure wound therapy, platelet-derived growth factor, various cellular matrix materials and dressings, bioengineered skin substitutes, and split-thickness skin grafting, are not addressed in this report and will be discussed in the guidelines when appropriate.

      Conclusions

      There is low- to moderate-quality evidence supporting the use of HBOT as an adjunctive therapy to enhance diabetic foot ulcer healing and prevent amputation. More studies are needed to provide adequate data regarding the effectiveness of arterial pumps and pharmacologic interventions.

      Author contributions

      Conception and design: TE, AT, GP, JD, RH, BF, MN, LP, AH, PC, LS, MM
      Analysis and interpretation: TE, MM
      Data collection: TE, AT, GP, JD, RH, BF, MN, LP, AH, PC, LS, MM
      Writing the article: TE, AT, GP, JD, RH, BF, MN, LP, AH, PC, LS, MM
      Critical revision of the article: TE, AT, GP, JD, RH, BF, MN, LP, AH, PC, LS, MM
      Final approval of the article: TE, AT, GP, JD, RH, BF, MN, LP, AH, PC, LS, MM
      Statistical analysis: MM
      Obtained funding: MM
      Overall responsibility: MM

      Appendix (online only).

       Data sources and search strategies

      A comprehensive search of several databases from each database's earliest inclusive dates to October 2011 (any language, any population) was conducted. The databases included Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, and Scopus. The search strategy was designed and conducted by an experienced librarian with input from the study's principle investigator. Controlled vocabulary supplemented with keywords was used to search for the topic: adjunctive therapy for diabetic foot, limited to randomized and nonrandomized studies.

       Actual search strategy

       OVID

      Database(s): Embase 1988 to 2011 Week 40, Ovid MEDLINE In-Process & Other Non-Indexed Citations and Ovid MEDLINE 1948 to Present, EBM Reviews-Cochrane Central Register of Controlled Trials 4th Quarter 2011, EBM Reviews-Cochrane Database of Systematic Reviews 2005 to October 2011
      Tabled 1
      No.SearchesResults
      1((diabetic or diabetes) adj3 (foot or feet)).mp.14925
      2exp Diabetic Foot/11809
      31 or 214925
      4exp Hyperbaric Oxygenation/17396
      5hyperbaric oxygen*.mp.19469
      6exp pentoxifylline/12889
      7cilostazol.mp.3684
      8ilioprost.mp.5
      9iloprost.mp. or exp iloprost/7387
      10“art-assist”.mp.7
      11((compression or arterial) adj3 (device or pump)).mp.3594
      12exp cilostazol/2463
      13(adjuvant or adjunctive).mp.268148
      14exp Negative-Pressure Wound Therapy/ or “negative pressure”.mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, ps, rs, nm, ui, tx, ct]11821
      15“vacuum assisted”.mp.4586
      16exp Hydrogel/ or hydrogel.mp.22949
      17(moist adj2 therap*).mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, ps, rs, nm, ui, tx, ct]96
      18exp platelet derived growth factor/24972
      19(platelet adj2 “growth factor*”).mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, ps, rs, nm, ui, tx, ct]44119
      20exp artificial skin/2678
      21“artificial skin”.mp.1681
      22or/4-21395511
      233 and 221434
      24exp controlled study/3639965
      25exp evidence based medicine/518786
      26evidence-based.mp.176190
      27((control$ or randomized) adj2 (study or studies or trial or trials)).mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, ps, rs, nm, ui, tx, ct]4670105
      28meta analysis/87832
      29meta-analys$.mp.139695
      30exp “systematic review”/44105
      31systematic review$.mp.98805
      32exp Guideline/ or exp Practice Guideline/271973
      33guideline$.ti.87253
      34or/24-335190301
      35exp case study/1573936
      36exp Cohort Studies/1332357
      37exp longitudinal study/881229
      38exp retrospective study/629108
      39exp prospective study/532545
      40exp observational study/23108
      41exp comparative study/2199767
      42exp clinical trial/1478242
      43exp evaluation/1089572
      44exp twins/39295
      45exp validation study/28010
      46exp experimental study/ or exp field study/ or exp in vivo study/ or exp panel study/ or exp pilot study/ or exp prevention study/ or exp quasi experimental study/ or exp replication study/ or exp theoretical study/ or exp trend study/6880306
      47((clinical or evaluation or twin or validation or experimental or field or “in vivo” or panel or pilot or prevention or replication or theoretical or trend or comparative or cohort or longitudinal or retrospective or prospective or population or concurrent or incidence or follow-up or observational) adj (study or studies or survey or surveys or analysis or analyses or trial or trials)).mp.6829746
      48(“case study” or “case series” or “clinical series” or “case studies”).mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, ps, rs, nm, ui, tx, ct]155006
      49or/35-4812895186
      5023 and (34 or 49)964
      51from 23 keep 814-1331518
      52limit 51 to (clinical trial or clinical trial, phase I or clinical trial, phase II or clinical trial, phase III or clinical trial, phase IV or comparative study or controlled clinical trial or guideline or meta analysis or multicenter study or practice guideline or randomized controlled trial or twin study) [Limit not valid in Embase, CDSR; records were retained]126
      5350 or 52964
      54limit 53 to (book or book series or editorial or erratum or letter or note or addresses or autobiography or bibliography or biography or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts) [Limit not valid in Embase, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process, CCTR, CDSR; records were retained]68
      5553 not 54896
      56from 23 keep 1332-1434103
      5755 or 56938
      58remove duplicates from 57619

       Scopus

      • 1
        TITLE-ABS-KEY((diabetes w/3 foot) or (diabetic w/3 foot) or (diabetes w/3 feet) or (diabetic w/3 feet))
      • 2
        TITLE-ABS-KEY(“hyperbaric oxygen*” or pentoxifylline or cilostazol or ilioprost or iloprost or “art-assist” or (compression w/3 device) or (compression w/3 pump) or (arterial w/3 device) or (arterial w/3 pump) or adjuvant or adjunctive or “negative pressure” or “vacuum assisted” or hydrogel or (moist w/2 therap*) or (platelet w/2 “growth factor*”) or “artificial skin”)
      • 3
        1 and 2
      • 4
        TITLE-ABS-KEY( (evidence W/1 based) or (meta W/1 analys*) or (systematic* W/2 review*) or guideline or (control* W/2 stud*) or (control* W/2 trial*) or (randomized W/2 stud*) or (randomized W/2 trial*))
      • 5
        TITLE-ABS-KEY(“comparative study” or “comparative survey” or “comparative analysis” or “cohort study” or “cohort survey” or “cohort analysis” or “longitudinal study” or “longitudinal survey” or “longitudinal analysis” or “retrospective study” or “retrospective survey” or “retrospective analysis” or “prospective study” or “prospective survey” or “prospective analysis” or “population study” or “population survey” or “population analysis” or “concurrent study” or “concurrent survey” or “concurrent analysis” or “incidence study” or “incidence survey” or “incidence analysis” or “follow-up study” or “follow-up survey” or “follow-up analysis” or “observational study” or “observational survey” or “observational analysis” or “case study” or “case series” or “clinical series” or “case studies” or “clinical study” or “clinical trial” or “evaluation study” or “evaluation survey” or “evaluation analysis” or “twin study” or “twin survey” or “twin analysis” or “validation study” or “validation survey” or “validation analysis” or “experimental study” or “experimental analysis” or “field study” or “field survey” or “field analysis” or “in vivo study” or “in vivo analysis” or “panel study” or “panel survey” or “panel analysis” or “pilot study” or “pilot survey” or “pilot analysis” or “prevention study” or “prevention survey” or “prevention analysis” or “replication study” or “replication analysis” or “theoretical study” or “theoretical analysis” or “trend study” or “trend survey” or “trend analysis”)
      • 6
        3 and (4 or 5)
      • 7
        PMID(0*) or PMID(1*) or PMID(2*) or PMID(3*) or PMID(4*) or PMID(5*) or PMID(6*) or PMID(7*) or PMID(8*) or PMID(9*)
      • 8
        6 and not 7
      • 9
        DOCTYPE(le) or DOCTYPE(ed) or DOCTYPE(bk) or DOCTYPE(er) or DOCTYPE(no) or DOCTYPE(sh)
      • 10
        8 and not 9

      References

        • Ragnarson Tennvall G.
        • Apelqvist J.
        Health-economic consequences of diabetic foot lesions.
        Clin Infect Dis. 2004; 39: S132-S139
        • Boulton A.J.
        The diabetic foot: from art to science. The 18th Camillo Golgi lecture.
        Diabetologia. 2004; 47: 1343-1353
        • Doctor N.
        • Pandya S.
        • Supe A.
        Hyperbaric oxygen therapy in diabetic foot.
        J Postgrad Med. 1992; 38 (111): 112-114
        • Ramani A.
        • Kundaje G.N.
        • Nayak M.N.
        Hemorheologic approach in the treatment of diabetic foot ulcers.
        Angiology. 1993; 44: 623-626
        • Armstrong D.G.
        • Nguyen H.C.
        Improvement in healing with aggressive edema reduction after debridement of foot infection in persons with diabetes.
        Arch Surg. 2000; 135: 1405-1409
        • Gallagher K.A.
        • Goldstein L.J.
        • Thom S.R.
        • Velazquez O.C.
        Hyperbaric oxygen and bone marrow-derived endothelial progenitor cells in diabetic wound healing.
        Vascular. 2006; 14: 328-337
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6: e1000097
        • Gandhi G.Y.
        • Murad M.H.
        • Fujiyoshi A.
        • Mullan R.J.
        • Flynn D.N.
        • Elamin M.B.
        • et al.
        Patient-important outcomes in registered diabetes trials.
        JAMA. 2008; 299: 2543-2549
      1. Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed September 8, 2015.

        • Higgins J.P.
        • Altman D.G.
        Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions.
        John Wiley & Sons, Ltd, Chichester, UK2008: 187-241
        • Murad M.H.
        • Montori V.M.
        • Sidawy A.N.
        • Ascher E.
        • Meissner M.H.
        • Chaikof E.L.
        • et al.
        Guideline methodology of the Society for Vascular Surgery including the experience with the GRADE framework.
        J Vasc Surg. 2011; 53: 1375-1380
        • Murad M.H.
        • Swiglo B.A.
        • Sidawy A.N.
        • Ascher E.
        • Montori V.M.
        Methodology for clinical practice guidelines for the management of arteriovenous access.
        J Vasc Surg. 2008; 48: 26S-30S
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Sterne J.A.
        • Sutton A.J.
        • Ioannidis J.P.
        • Terrin N.
        • Jones D.R.
        • Lau J.
        • et al.
        Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
        BMJ. 2011; 343: d4002
        • 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: 166-175
        • Margolis D.J.
        • Gupta J.
        • Hoffstad O.
        • Papdopoulos M.
        • Glick H.A.
        • Thom S.R.
        • 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: 1961-1966
        • Oriani G.
        • Meazza D.
        • Favales F.
        • Pizzi G.L.
        • Aldeghi A.
        • Faglia E.
        Hyperbaric oxygen therapy in diabetic gangrene.
        J Hyperb Med. 1990; 5: 171-175
        • Wang C.J.
        • Wu R.W.
        • Yang Y.J.
        Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy.
        Diabetes Res Clin Pract. 2011; 92: 187-193
        • Sert M.
        • Soydas B.
        • Aikimbaev K.
        • Tetiker T.
        Effects of iloprost (a prostacyclin analogue) on the endothelial dysfunction and foot ulcers in diabetic patients with peripheral arterial disease.
        Int J Diabetes Metab. 2008; 16: 7-11
        • Game F.L.
        • Hinchliffe R.J.
        • Apelqvist J.
        • Armstrong D.G.
        • Bakker K.
        • Hartemann A.
        • 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: 119-141
        • Kranke P.
        • Bennett M.H.
        • Martyn-St James M.
        • Schnabel A.
        • Debus S.E.
        Hyperbaric oxygen therapy for chronic wounds.
        Cochrane Database Syst Rev. 2012; 4: CD004123
        • Wang C.
        • Schwaitzberg S.
        • Berliner E.
        • Zarin D.A.
        • Lau J.
        Hyperbaric oxygen for treating wounds: a systematic review of the literature.
        Arch Surg. 2003; 138 (discussion: 280): 272-279
        • Goldman R.J.
        Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review.
        PM R. 2009; 1: 471-489
        • Montori V.M.
        • Kavros S.J.
        • Walsh E.E.
        • Rooke T.W.
        Intermittent compression pump for nonhealing wounds in patients with limb ischemia. The Mayo Clinic experience (1998-2000).
        Int Angiol. 2002; 21: 360-366
        • Suissa D.
        • Danino A.
        • Nikolis A.
        Negative-pressure therapy versus standard wound care: a meta-analysis of randomized trials.
        Plast Reconstr Surg. 2011; 128: 498e-503e
        • Noble-Bell G.
        • Forbes A.
        A systematic review of the effectiveness of negative pressure wound therapy in the management of diabetes foot ulcers.
        Int Wound J. 2008; 5: 233-242
        • Abidia A.
        • Laden G.
        • Kuhan G.
        • Johnson B.F.
        • Wilkinson A.R.
        • Renwick P.M.
        • et al.
        The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial.
        Eur J Vasc Endovasc Surg. 2003; 25: 513-518
        • Ay H.
        • Yildiz S.
        The evaluation of TcPO2 and TcPCO2 measurement as a follow up criteria in diabetic foot treated with HBO therapy [Turkish].
        Gulhane Med J. 2004; 46: 20-24
        • Baroni G.
        • Porro T.
        • Faglia E.
        • Pizzi G.
        • Mastropasqua A.
        • Oriani G.
        • et al.
        Hyperbaric oxygen in diabetic gangrene treatment.
        Diabetes Care. 1987; 10: 81-86
        • Duzgun A.P.
        • Satir H.Z.
        • Ozozan O.
        • Saylam B.
        • Kulah B.
        • Coskun F.
        Effect of hyperbaric oxygen therapy on healing of diabetic foot ulcers.
        J Foot Ankle Surg. 2008; 47: 515-519
        • Faglia E.
        • Favales F.
        • Aldeghi A.
        • Calia P.
        • Quarantiello A.
        • Oriani G.
        • et al.
        Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study.
        Diabetes Care. 1996; 19: 1338-1343
        • Faglia E.
        • Favales F.
        • Aldeghi A.
        • Calia P.
        • Quarantiello A.
        • Barbano P.
        • et al.
        Change in major amputation rate in a center dedicated to diabetic foot care during the 1980s: prognostic determinants for major amputation.
        J Diabetes Complications. 1998; 12: 96-102
        • 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 Complications. 2002; 16: 153-158
        • Kessler L.
        • Bilbault P.
        • Ortega F.
        • Grasso C.
        • Passemard R.
        • Stephan D.
        • et al.
        Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study.
        Diabetes Care. 2003; 26: 2378-2382
        • 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: 998-1003
        • Sousa J.A.E.
        [Long-term evaluation of chronic diabetic foot ulcers, non-healed after hyperbaric oxygen therapy].
        Rev Port Cir Cardiotorac Vasc. 2005; 12: 227-237
        • Stone J.A.
        • Scott R.G.
        • Brill L.R.
        • Levine B.D.
        The role of hyperbaric-oxygen in the treatment of diabetic foot wounds.
        Diabetes. 1995; 44 (A71)
        • Zamboni W.A.
        • Wong H.P.
        • Stephenson L.L.
        • Pfeifer M.A.
        Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study.
        Undersea Hyperb Med. 1997; 24: 175-179