Advertisement

A systematic review and meta-analysis of débridement methods for chronic diabetic foot ulcers

      Background

      Several methods of débridement of diabetic foot ulcers are currently used. The relative efficacy of these methods is not well established.

      Methods

      This systematic review and meta-analysis was conducted to find the best available evidence for the effect of débridement on diabetic foot wound outcomes. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2011 for randomized controlled studies (RCTs) and observational comparative studies.

      Results

      We identified 11 RCTs and three nonrandomized studies reporting on 800 patients. The risk of bias was moderate overall. Meta-analysis of three RCTs showed that autolytic débridement significantly increased the healing rate (relative risk [RR], 1.89; 95% confidence interval [CI] 1.35-2.64). Meta-analysis of four studies (one RCT) showed that larval débridement reduced amputation (RR, 0.43; 95% CI, 0.21-0.88) but did not increase complete healing (RR, 1.27; 95% CI, 0.84-1.91). Surgical débridement was associated with shorter healing time compared with conventional wound care (one RCT). Insufficient evidence was found for comparisons between autolytic and larval débridement (one RCT), between ultrasound-guided and surgical débridement, and between hydrosurgical and surgical débridement.

      Conclusions

      The available literature supports the efficacy of several débridement methods, including surgical, autolytic, and larval débridement. Comparative effectiveness evidence between these methods and supportive evidence for other methods is of low quality due to methodologic limitations and imprecision. Hence, the choice of débridement method at the present time should be based on the available expertise, patient preferences, the clinical context and cost.
      Chronic foot ulcers are frequent complications in patients with diabetes that lead to high hospitalization and amputation rates.
      • Margolis D.J.
      • Kantor J.
      • Berlin J.A.
      Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis.
      Approximately 15% of patients with diabetes will suffer foot ulcer at some point in their lives. Among them, 14% to 24% will require an amputation, making the foot ulcer the main predictor of future amputation.
      Consensus development conference on diabetic foot wound care: 7-8 April 1999, Boston, Massachusetts. American Diabetes Association.
      Débridement is generally defined as “the process in which all materials incompatible with healing are removed from a wound.”
      • Cornell R.S.
      • Meyr A.J.
      • Steinberg J.S.
      • Attinger C.E.
      Debridement of the noninfected wound.
      Several methods are currently used for débridement, including surgery, conventional dressing, larvae, enzyme preparation, polysaccharide beads, and hydrogels.
      • Edwards J.
      • Stapley S.
      Debridement of diabetic foot ulcers.
      The best method among these is yet to be determined. Therefore, the Society for Vascular Surgery commissioned this evidence synthesis report to evaluate the quality of the evidence supporting the existing methods of débridement and estimate the magnitude of benefit and relative efficacy.

      Methods

      This systematic review is protocol-driven and 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 (RCTs) and controlled observational studies that enrolled patients with diabetic foot ulcers treated by any method of débridement and compared with any different method and reported the outcomes of interest. We were interested in studies that assess 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 complete wound healing, time to complete wound healing, amputation, infection, and relapse rates. Studies were included regardless of language, size, or duration of patient follow-up. We excluded articles that were not original studies, such as review articles, commentaries, and letters, and also excluded uncontrolled studies.

       Study identification

      An expert reference librarian (L.P.) designed and conducted the electronic search strategy with input from a study investigator with expertise in conducting systematic reviews (M.H.M.). We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2011. We identified additional candidate studies by review of the bibliographies of included articles and contact with experts. Controlled vocabulary supplemented with keywords was used to search for the topic of diabetic foot débridement, limited to randomized and nonrandomized studies. The detailed search strategy is available in the Appendix (online only).

       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. Disagreements were automatically upgraded to the next level of screening. Full text of eligible abstracts were retrieved and screened in duplicate. 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.
      Data were extracted in duplicate using a standardized, piloted, Web-based form. For each study we abstracted a 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 the quality assessment and outcome data. A third reviewer compared the reviewers' data and resolved inconsistencies by referring to the full-text article.

       Methodologic quality 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.

      We assessed outcome ascertainment, adjustment for confounders, proportion of patients lost to follow-up, and sample selection in each study. RCTs 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.
      We assessed randomization, blinding, allocation concealment, baseline imbalances (ie, differences between the study arms within individual studies in distribution of prognostic factors), follow-up data, 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 then 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).

       Statistical analysis

      We pooled the relative risk (RR) and 95% confidence interval (CI) across included studies using random-effect meta-analysis described by DerSimonian and Laird.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      Between-studies heterogeneity was calculated by the I
      Consensus development conference on diabetic foot wound care: 7-8 April 1999, Boston, Massachusetts. American Diabetes Association.
      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 (CMA) 2.2 software (Biostat Inc, Englewood, NJ).

       Subgroup analysis and publication bias

      We did not perform subgroup analyses because of the limited number of studies that compared each intervention. Evaluation of publication bias was not feasible due to the small number of included studies.
      • 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 692 potentially relevant abstracts. Thirteen studies fulfilled our inclusion criteria and were eligible for data extraction, of which six reported sufficient data for a meta-analysis (Fig 1). We identified 14 interventional studies (11 RCTs and three controlled cohorts), including data from 800 patients with foot ulcers undergoing débridement with surgical, autolytic, larval, or ultrasound-assisted approaches. The characteristics of the included studies are described in Table I, and details of the intervention methods are described in Table II. The adjusted agreement between reviewers (κ) averaged 0.94, as calculated by the online system.
      Figure thumbnail gr1
      Fig 1The process of study selection. RCT, Randomized controlled trial.
      Table ICharacteristics of the included studies
      Study nameCountryCare settingDM type and duration, HbA1c, ulcer duration, comorbiditiesPatients, No.Follow-up, monthsAge, Mean yearsMale, %Ulceration area, cm2
      Apelqvist,
      • Apelqvist J.
      • Larsson J.
      • Stenstrom A.
      Topical treatment of necrotic foot ulcers in diabetic patients: a comparative trial of DuoDerm and MeZinc.
      1990
      SwedenOutpatients with combined foot care teamMean DM duration, 20 years; HbA1c, 8.2; ulcer duration, 1-105 weeks441.2563592.2
      Armstrong,
      • Armstrong D.G.
      • Salas P.
      • Short B.
      • Martin B.R.
      • Kimbriel H.R.
      • Nixon B.P.
      • et al.
      Maggot therapy in “lower-extremity hospice” wound care: fewer amputations and more antibiotic-free days.
      2005
      USALarge referral-based diabetic foot clinicDM duration, 15.5 years60≥67286.7All: 12.1 ± 5.7; MDT: 11.8 ± 4.5; control: 12.4 ± 6.7
      Bowling,
      • Bowling F.L.
      • Crews R.T.
      • Salgami E.
      • Armstrong D.G.
      • Boulton A.J.
      The use of superoxidized aqueous solution versus saline as a replacement solution in the versajet lavage system in chronic diabetic foot ulcers: a pilot study.
      2011
      USAHospital and community patientsType 1 or type 2 DM, chronic ulcers >4 weeks2015460All: 2.4; super oxidized group: 3.0 ± 3.7, saline group: 1.8 ± 1.7
      Caputo,
      • Caputo W.J.
      • Beggs D.J.
      • DeFede J.L.
      • Simm L.
      • Dharma H.
      A prospective randomised controlled clinical trial comparing hydrosurgery debridement with conventional surgical debridement in lower extremity ulcers.
      2008
      USACommunity hospital (Clara Maass Medical Center)NR4136863.4(Median) All: 4.3; Versajet: 5.9; conventional: 3.9
      D'Hemecourt,
      • d'Hemecourt P.A.
      • Smiell J.M.
      • Karim M.R.
      Sodium carboxymethylcellulose aqueous-based gel vs. becaplermin gel in patients with nonhealing lower extremity diabetic ulcers.
      1998
      USAMulticenter (10 sites)Type 1 or type 2 DM172Up to 519 years or older74NaCMC gel: 3.2; good wound care: 3.5
      Jensen,
      • Jensen J.L.
      • Seeley J.
      • Gillin B.
      Diabetic foot ulcerations. A controlled, randomized comparison of two moist wound healing protocols: Carrasyn Hydrogel Wound dressing and wet-to-moist saline gauze.
      1998
      USAOutpatient settingNR31Up to 4-5NRNRNR
      Markevich,
      • Markevich M.R.
      • Mousley M.
      • Melloy E.
      Maggot therapy for diabetic neuropathic foot wounds.
      2000
      EuropeMulticenter studyDM duration, 16 years, with neuropathic wounds that required débridement1403054NRMDT: 14.9; hydrogel: 15.1
      Paul,
      • Paul A.G.
      • Ahmad N.W.
      • Lee H.L.
      • Ariff A.M.
      • Saranum M.
      • Naicker A.S.
      • et al.
      Maggot debridement therapy with Lucilia cuprina: a comparison with conventional debridement in diabetic foot ulcers.
      2009
      MalaysiaGeneral hospital orthopedics serviceNR59NR5664.4NR
      Piaggesi,
      • Piaggesi A.
      • Schipani E.
      • Campi F.
      • Romanelli M.
      • Baccetti F.
      • Arvia C.
      • et al.
      Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial.
      1998
      ItalyHospital department foot clinicType 1 or 2 DM; mean HbA1c, 9.2%, DM for 17 years, with clinical neuropathy and ulcer >3 weeks416 (up to 11 in some patients)64NRNR
      Sherman,
      • Sherman R.A.
      Maggot therapy for treating diabetic foot ulcers unresponsive to conventional therapy.
      2003
      USAMaggot therapy service, Department of Pathology, University of California IrvineUlcer duration >2 weeks; most had peripheral venous or arterial disease18 (20 ulcers)>267NRAll: 9.8 cm2; conventional therapy: 6.3; MDT: 13.5
      Singh,
      • Singh A.
      Usage of ultrasound in wound management comparison between ultrasonic wound debridement and sharp debridement in diabetic foot ulcers: a randomized clinical trial. Thesis.
      2006
      MalaysiaUniversity of Malaya Medical CentreType 1 DM: 8.5%; type 2 DM: 91.5%.59 (60 ulcers)0.55755NR
      Vandeputte,

      Vandeputte G, Grayson L. Diabetic foot infection controlled by immuno-modulating hydrogel containing 65% glycerine. Presentation of a clinical trial at 6th European Conference on Advances in Wound Management. Amsterdam, The Netherlands; 1996:50-53.

      1996
      BelgiumWound-care departmentNR29NRNRNRNR
      Whalley,

      Whalley BA, Harding K, Van Acker K, Capillas R. Performance characteristics and safety of purilon gel versus intrasite using biatain non-adhesive dressing as secondary dressing in the treatment of diabetic foot ulcers. 11th European Tissue Repair Society Annual Conference Cardiff, Wales; 2001. p 49.

      2001
      UKProbably secondary care settingNR74 (66 evaluated)2.5 or until healingNRNRPurilon: 2.5; IntraSite: 2.4
      Yao,
      • Yao M.
      • Hasturk H.
      • Kantarci A.
      • Gu G.
      • Garcia-Lavin S.
      • Fabbi M.
      • et al.
      A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers.
      2014
      USAProbably secondary care setting83% type 2 DM; ulcer duration: 36.4 ± 24.8 weeks125 weeks40-72661.9, 2.1, and 2.5, for the 3 groups
      DM, Diabetes mellitus; HbA1c, glycated hemoglobin; NaCMC, sodium carboxymethylcellulose; MDT, maggot débridement therapy; NR, not reported; UK, United Kingdom; USA, United States of America.
      Table IIInclusion criteria and interventions in each study
      StudyInclusion criteriaExclusion criteriaIntervention 1Intervention 2
      Apelqvist,
      • Apelqvist J.
      • Larsson J.
      • Stenstrom A.
      Topical treatment of necrotic foot ulcers in diabetic patients: a comparative trial of DuoDerm and MeZinc.
      1990
      Diabetic patients with superficial full-thickness skin ulcer below the ankle, systolic toe pressure >45 mm Hg or absence of cutaneous erythema; only the largest in every patientClinical signs of cellulitis, positive patch test, inappropriate application of dressingAdhesive zinc oxide tapeOcclusive hydrocolloid dressing (DuoDerm)
      Armstrong,
      • Armstrong D.G.
      • Salas P.
      • Short B.
      • Martin B.R.
      • Kimbriel H.R.
      • Nixon B.P.
      • et al.
      Maggot therapy in “lower-extremity hospice” wound care: fewer amputations and more antibiotic-free days.
      2005
      Diabetic patients with single DFU, inability to walk without the use of a wheel chair or other device, diagnosis of peripheral vascular disease without surgical intervention, >6 months of follow-up informationNo clinically vascular disease; not grade C or D of University of Texas grading scaleMaggot débridementStandard wound care
      Bowling,
      • Bowling F.L.
      • Crews R.T.
      • Salgami E.
      • Armstrong D.G.
      • Boulton A.J.
      The use of superoxidized aqueous solution versus saline as a replacement solution in the versajet lavage system in chronic diabetic foot ulcers: a pilot study.
      2011
      Hospital and community adult patients with type 1 and type 2 DM who had chronic (>4 weeks) nonclinically infected DFUs where necrotic tissue was present and mechanical débridement was indicatedUlcers >25 cm2, grade 3 (University of Texas classification), osteomyelitis, peripheral arterial disease (absent pulses, ABI <0.8), use of anticoagulants, immunosuppressive drug treatment, known allergies to chlorine, clinically infected woundsSuperoxidized aqueous solutionSaline solution
      Caputo,
      • Caputo W.J.
      • Beggs D.J.
      • DeFede J.L.
      • Simm L.
      • Dharma H.
      A prospective randomised controlled clinical trial comparing hydrosurgery debridement with conventional surgical debridement in lower extremity ulcers.
      2008
      Patients with lower extremity ulcersNot reportedHydrosurgical débridementConventional surgical débridement
      D'Hemecourt,
      • d'Hemecourt P.A.
      • Smiell J.M.
      • Karim M.R.
      Sodium carboxymethylcellulose aqueous-based gel vs. becaplermin gel in patients with nonhealing lower extremity diabetic ulcers.
      1998
      The study had 3 arms; the third group (34 patients) was randomized to good wound care and becaplermin. Outcomes for this group were not available.
      Age ≥19 years, type 1 or type 2 DM, ≥1 full-thickness ulcer (stage 3 or 4), ulcer present 8 weeks before study, 1 cm2-10 cm2 postdébridement, TcPo2 >30 mm Hg, chronic diabetic ulcer of lower extremityOsteomyelitis, outside 1 cm2-10 cm2 range, patient had >3 ulcers, cause of ulcer was not diabetic (eg, electrical, chemical or radiation), patients with cancer, concomitant medication to affect wound healing, women who were pregnant, nursing, or of child-bearing potentialGood wound care and NaCMC hydrogelGood wound care consisted of daily dressing changes, sharp débridement of the ulcer when deemed necessary by the investigator, systemic control of infection if present, and off-loading of pressure
      Jensen,
      • Jensen J.L.
      • Seeley J.
      • Gillin B.
      Diabetic foot ulcerations. A controlled, randomized comparison of two moist wound healing protocols: Carrasyn Hydrogel Wound dressing and wet-to-moist saline gauze.
      1998
      Diabetic patients with an ulcer >1 cm diameter, no infection of ulcer or periwound tissue, Wagner grade 2 ulcer not involving tendon, joint, or bone, documented blood supply consistent with the ability to heal (palpable pulses, noninvasive vascular study), willingness to comply with protocolNot reportedCarrasyn hydrogel wound dressing (initially treated with sharp débridement, patients received custom-made healing sandals for pressure redistribution)Wet-to-moist saline gauze (initially treated with sharp débridement, patients received custom-made healing sandals for pressure redistribution)
      Markevich,
      • Markevich M.R.
      • Mousley M.
      • Melloy E.
      Maggot therapy for diabetic neuropathic foot wounds.
      2000
      Patients with DM, mean age 54, mean DM duration 16 years with neuropathic foot woundsNot reportedMaggot (green-bottle fly)Hydrogel
      Paul,
      • Paul A.G.
      • Ahmad N.W.
      • Lee H.L.
      • Ariff A.M.
      • Saranum M.
      • Naicker A.S.
      • et al.
      Maggot debridement therapy with Lucilia cuprina: a comparison with conventional debridement in diabetic foot ulcers.
      2009
      All patients aged 35-70 years, who were admitted for infected diabetic foot wounds (below ankle) to the orthopedics wards requiring repeat débridement or nonurgent primary débridementGangrenous wounds, necrotizing fasciitis, abscesses, wounds with exposed viable bones/viable tendons, wounds that were profusely bleeding, ischemic wounds ABSI <0.75); patients who had entomophobiaMaggot therapyConventional therapy (surgical débridement and dressing)
      Piaggesi,
      • Piaggesi A.
      • Schipani E.
      • Campi F.
      • Romanelli M.
      • Baccetti F.
      • Arvia C.
      • et al.
      Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial.
      1998
      New patients with painless ulcer(s) lasting ≥3 weeks, nonischemic, uncomplicated neuropathic ulcers with clinical characteristics of neuropathy; type 1 or 2 DM of at least 5 years' durationSymptomatic claudication or absence of foot pulses, recent ketoacidosis, renal failure, infection (perilesional edema and erythema, or pus, systemic symptoms, such as fever or leukocytosis, positive wound swab) congenital foot deformities or diabetic neuroarthropathy, BMI >30 kg/m2, clinical history of stroke, cardiac failure, cancer, HIV positivity, history of mental illness, subclinical macroangiopathy (ABPI <0.9), osteomyelitis or doubtful cases for osteomyelitisSurgical excision of the ulcer (débridement or removal of bone segments underlying the lesion, necessary, subsequent suture of the skin, and relief of weight-bearing for 4 weeks)Nonoperative treatment (initial débridement and medication of ulcer, relief of weight-bearing, regular dressings, and follow-up)
      Sherman,
      • Sherman R.A.
      Maggot therapy for treating diabetic foot ulcers unresponsive to conventional therapy.
      2003
      Nonhealing wounds, have contours that could be measured by planimetry, making them eligible for this studyPatients with osteomyelitis or rapidly advancing soft-tissue infectionMaggot therapy (Phaenicia or Lucilia sericata)Standard therapy (dry gauze or saline gauze)
      Singh,
      • Singh A.
      Usage of ultrasound in wound management comparison between ultrasonic wound debridement and sharp debridement in diabetic foot ulcers: a randomized clinical trial. Thesis.
      2006
      Type 1 or type 2 DM, with DFUs (grade 0, 1 or 2), sensate feet (based on Neuropathic Disability Score), and at least 1 (dorsalis pedis or posterior tibial) pulses palpableDFUs grade 3 or 4, patients whose ulcers were covered with a hard scab, patients with peripheral neuropathy based on modified Neuropathic Disability Score, those who did not have at least 1 of the foot pulses palpable (dorsalis pedis artery or posterior tibialis artery)Ultrasound-assisted wound débridementSharp débridement
      Vandeputte,

      Vandeputte G, Grayson L. Diabetic foot infection controlled by immuno-modulating hydrogel containing 65% glycerine. Presentation of a clinical trial at 6th European Conference on Advances in Wound Management. Amsterdam, The Netherlands; 1996:50-53.

      1996
      Diabetic patients with a wound (neuropathic or not); whether necrotic or infected woundsPatients under a systemic antibiotic regimenHydrogel dressingDry gauze
      Whalley,

      Whalley BA, Harding K, Van Acker K, Capillas R. Performance characteristics and safety of purilon gel versus intrasite using biatain non-adhesive dressing as secondary dressing in the treatment of diabetic foot ulcers. 11th European Tissue Repair Society Annual Conference Cardiff, Wales; 2001. p 49.

      2001
      Neuropathic uncomplicated DFUs (grade 1-2)Not reportedPurilon gelIntraSite gel
      Yao,
      • Yao M.
      • Hasturk H.
      • Kantarci A.
      • Gu G.
      • Garcia-Lavin S.
      • Fabbi M.
      • et al.
      A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers.
      2014
      Chronic nonhealing DFUsNot reportedNoncontact low-frequency ultrasound therapyDébridement, offloading and moist wound care
      ABI, Ankle-brachial index; ABPI, ankle-brachial pressure index; ABSI, ankle-brachial systolic index; BMI, body mass index; DFU, diabetic foot ulcers; DM, diabetes mellitus; TcPo2, transcutaneous oxygen pressure.
      a The study had 3 arms; the third group (34 patients) was randomized to good wound care and becaplermin. Outcomes for this group were not available.

       Methodologic quality and risk of bias

      The quality of the included studies ranged from fair to moderate. Randomization and allocation concealment were adequately described only in four and two of 11 RCTs, respectively. Patients and caregivers were blinded only in three studies. Lack of blinding is less of a concern for objective outcomes, such as amputation, but can introduce a significant bias for subjective or assessor-dependent outcomes such as wound healing. No baseline imbalances were mentioned in 60% of the studies, and almost half of the trials did not report loss of follow-up data. Overall quality of observational studies was moderate. The samples were representative in two studies; however, groups were comparable in all three of the studies. Moreover, follow-up was adequate, and all studies reported a 100% response rate. Nevertheless, none of them adjusted for potential confounders. Tables III and IV describe the quality of included studies.
      Table IIIMethodologic quality of randomized trials
      Study nameHow was the randomization done?Allocation concealmentBlindingBaseline imbalances.Efficient follow-upAdhere to treatmentPatients lost to follow-up, %Funding
      Apelqvist,
      • Apelqvist J.
      • Larsson J.
      • Stenstrom A.
      Topical treatment of necrotic foot ulcers in diabetic patients: a comparative trial of DuoDerm and MeZinc.
      1990
      NRNRNRMore men in DuoDerm groupWeekly multidisciplinary meetingsNRNRNR
      Bowling,
      • Bowling F.L.
      • Crews R.T.
      • Salgami E.
      • Armstrong D.G.
      • Boulton A.J.
      The use of superoxidized aqueous solution versus saline as a replacement solution in the versajet lavage system in chronic diabetic foot ulcers: a pilot study.
      2011
      Computer-generated block randomizationYes; sealed envelopesPatients, caregiversNoYes; weekly visitsYes0Includes for-profit sources
      Caputo,
      • Caputo W.J.
      • Beggs D.J.
      • DeFede J.L.
      • Simm L.
      • Dharma H.
      A prospective randomised controlled clinical trial comparing hydrosurgery debridement with conventional surgical debridement in lower extremity ulcers.
      2008
      NRYes; method not mentionedNRNoNRNRNRNR
      D'Hemecourt,
      • d'Hemecourt P.A.
      • Smiell J.M.
      • Karim M.R.
      Sodium carboxymethylcellulose aqueous-based gel vs. becaplermin gel in patients with nonhealing lower extremity diabetic ulcers.
      1998
      Unclear (patients were randomly assigned in a 2:2:1 ratio to 1 of 3 treatment groups)NRYes; patients, care givers and outcome assessorsYes; group size and ulcer characteristics (mean area, depth, and duration)NRNR0NR
      Jensen,
      • Jensen J.L.
      • Seeley J.
      • Gillin B.
      Diabetic foot ulcerations. A controlled, randomized comparison of two moist wound healing protocols: Carrasyn Hydrogel Wound dressing and wet-to-moist saline gauze.
      1998
      NRNRNRUlcer duration longer in Carrasyn groupYes; weekly visitsNR16Includes for-profit sources
      Markevich,
      • Markevich M.R.
      • Mousley M.
      • Melloy E.
      Maggot therapy for diabetic neuropathic foot wounds.
      2000 (abstract)
      NRNRDouble-blindedBaseline surface area bigger in hydrogel groupNRNRNRNR
      Piaggesi,
      • Piaggesi A.
      • Schipani E.
      • Campi F.
      • Romanelli M.
      • Baccetti F.
      • Arvia C.
      • et al.
      Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial.
      1998
      Table of randomizationNRNRNoYes; regular visitsYesNRNR
      Singh,
      • Singh A.
      Usage of ultrasound in wound management comparison between ultrasonic wound debridement and sharp debridement in diabetic foot ulcers: a randomized clinical trial. Thesis.
      2006
      Drawing lotsNRNRNoNRNRNR
      Vandeputte,

      Vandeputte G, Grayson L. Diabetic foot infection controlled by immuno-modulating hydrogel containing 65% glycerine. Presentation of a clinical trial at 6th European Conference on Advances in Wound Management. Amsterdam, The Netherlands; 1996:50-53.

      1996 (abstract)
      Preprepared randomization listingNRNRNoNRNRNRNR
      Whalley,

      Whalley BA, Harding K, Van Acker K, Capillas R. Performance characteristics and safety of purilon gel versus intrasite using biatain non-adhesive dressing as secondary dressing in the treatment of diabetic foot ulcers. 11th European Tissue Repair Society Annual Conference Cardiff, Wales; 2001. p 49.

      2001
      NRNRNRNoYes; regular visitsNRNRNR
      Yao,
      • Yao M.
      • Hasturk H.
      • Kantarci A.
      • Gu G.
      • Garcia-Lavin S.
      • Fabbi M.
      • et al.
      A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers.
      2014
      Block randomizationNRNRNoYes; regular visitsNR0NR
      NR, Not reported.
      Table IVMethodologic quality of cohort studies
      Study nameSample representativenessAre the 2 groups from the same population?Was the exposure properly verified?Adjustment for confoundersOutcome assessment between the 2 groupsAdequacy of follow-upResponse rate, %Source of study funding?
      Armstrong,
      • Armstrong D.G.
      • Salas P.
      • Short B.
      • Martin B.R.
      • Kimbriel H.R.
      • Nixon B.P.
      • et al.
      Maggot therapy in “lower-extremity hospice” wound care: fewer amputations and more antibiotic-free days.
      2005
      YesYesYesNoYes, quite similarYes100NR/unclear
      Paul,
      • Paul A.G.
      • Ahmad N.W.
      • Lee H.L.
      • Ariff A.M.
      • Saranum M.
      • Naicker A.S.
      • et al.
      Maggot debridement therapy with Lucilia cuprina: a comparison with conventional debridement in diabetic foot ulcers.
      2009
      YesYesYesNoYes, quite similarYes100NR/unclear
      Sherman,
      • Sherman R.A.
      Maggot therapy for treating diabetic foot ulcers unresponsive to conventional therapy.
      2003
      UnclearYesYesNoYes, quite similarYes100Not-for-profit source

       Meta-analysis

      Based on three RCTs, autolytic débridement was associated with a statistically significant increase in healing rates compared with standard wound débridement by gauze and conventional wound care (RR, 1.89; 95% CI, 1.35-2.64; P < .001), I2 = 0.00% (Fig 2). Autolytic débridement is applied by using hydrogel type dressings that promote a moist environment to enhance the function of naturally occurring enzymes and facilitate shedding of devitalized tissue.
      Figure thumbnail gr2
      Fig 2Autolytic débridement vs conventional wound care. The solid squares indicate the risk ratio and are proportional to the weights used in the meta-analysis. The diamond indicates the pooled risk ratio, and the lateral tips of the diamond indicate the associated 95% confidence intervals (CIs). The horizontal lines represent the 95% CIs.
      A meta-analysis of three comparative studies showed no significant difference in complete healing rates between larval débridement and conventional wound care (RR, 1.27; 95% CI, 0.84-1.91; P = .37), I2 = 34%. However, two of the studies also reported a significant reduction in the rate of amputation in favor of larval therapy (RR, 0.43; 95% CI, 0.21-0.88; P = .02), I2 = 0% (Fig 3). Larval therapy (also called therapeutic myiasis) is done using the larvae of the greenbottle fly (Lucilia sericata), which naturally feed on dead tissue, cellular debris, and serous drainage. Larval therapy is provided using a prefabricated foam or as free-range loose larvae applied directly to the wound and retained in place by a dressing.
      Figure thumbnail gr3
      Fig 3Larval débridement vs conventional wound care. The solid squares indicate the risk ratio and are proportional to the weights used in the meta-analysis. The diamond indicates the pooled risk ratio, and the lateral tips of the diamond indicate the associated 95% confidence intervals (CIs). The horizontal lines represent the 95% CIs.
      One RCT
      • Markevich M.R.
      • Mousley M.
      • Melloy E.
      Maggot therapy for diabetic neuropathic foot wounds.
      compared maggot-based débridement vs autolytic débridement with hydrogel and reported a significant difference in number of patients who achieved >50% reduction of the wound area after 10 days in favor of maggot therapy (51.1% vs 27.1%; RR, 1.89; 95% CI, 1.21-2.96; P = .005). However, the two interventions did not differ significantly in the number of patients who achieved complete wound healing (RR, 2.5; 95% CI, 0.50-12.46; P = .26).
      One RCT
      • Piaggesi A.
      • Schipani E.
      • Campi F.
      • Romanelli M.
      • Baccetti F.
      • Arvia C.
      • et al.
      Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial.
      compared surgical débridement vs conventional wound dressing and reported a healing rate of 95% (21 of 22 ulcers) in the surgical group vs 79.2% (19 of 24 ulcers) in the conventional group; however, the association was not statistically significant (RR, 1.2; 95% CI, 0.96-1.51; P = .10). The healing time was significantly shorter in the surgical group than in the conventional group (46.73 ± 38.94 vs 128.9 ± 86.60 days; P < .001). Infective complications occurred less often in the first group (1 of 22 [4.5%] vs 3 of 24 [12.5%]; RR, 0.36; 95% CI, 0.04-3.24; P = .36) as did relapses of ulcerations (3 vs 8; RR, 0.41; 95% CI, 0.12-1.35; P = .14); nevertheless, neither outcome reached statistical significance.
      Ultrasound débridement was compared with surgical débridement in two small RCTs published as a thesis.
      • Singh A.
      Usage of ultrasound in wound management comparison between ultrasonic wound debridement and sharp debridement in diabetic foot ulcers: a randomized clinical trial. Thesis.
      • Yao M.
      • Hasturk H.
      • Kantarci A.
      • Gu G.
      • Garcia-Lavin S.
      • Fabbi M.
      • et al.
      A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers.
      Low-frequency ultrasound is applied with a wound-treatment solution through the probe tip in a noncontact fashion. Both studies reported significantly smaller-sized wounds in the ultrasound group after 2 to 5 weeks. Data on complete wound healing were not available. The quality of evidence was downgraded due to indirectness of outcome and inadequate follow-up time.
      In one RCT,
      • Caputo W.J.
      • Beggs D.J.
      • DeFede J.L.
      • Simm L.
      • Dharma H.
      A prospective randomised controlled clinical trial comparing hydrosurgery debridement with conventional surgical debridement in lower extremity ulcers.
      a hydrosurgical débridement system—a device that concurrently cuts and aspirates soft tissue—was compared with a surgical débridement and reported similar clinical efficacy for the median time to complete wound healing (71 days in the hydrosurgical group vs 74 days in the surgical group; P = .733). The quality of the evidence was downgraded due to indirectness and high risk of bias.
      One RCT
      • Bowling F.L.
      • Crews R.T.
      • Salgami E.
      • Armstrong D.G.
      • Boulton A.J.
      The use of superoxidized aqueous solution versus saline as a replacement solution in the versajet lavage system in chronic diabetic foot ulcers: a pilot study.
      assessing the use of superoxidized aqueous solution vs saline for lavage in a hydrosurgical débridement system reported no significant change in wound size at week 4 (P = .4). The quality of evidence was low due to methodologic limitations of the study.
      Another study
      • Apelqvist J.
      • Larsson J.
      • Stenstrom A.
      Topical treatment of necrotic foot ulcers in diabetic patients: a comparative trial of DuoDerm and MeZinc.
      compared adhesive zinc oxide tape vs occlusive hydrocolloid dressing and reported a significant difference in complete disappearance or at least 50% reduction in the necrotic area in favor of adhesive zinc oxide (RR, 2.33; 95% CI, 1.11-4.89; P = .02) The quality of evidence was low due to methodologic limitations and imprecision.
      Finally, one study published in abstract form

      Whalley BA, Harding K, Van Acker K, Capillas R. Performance characteristics and safety of purilon gel versus intrasite using biatain non-adhesive dressing as secondary dressing in the treatment of diabetic foot ulcers. 11th European Tissue Repair Society Annual Conference Cardiff, Wales; 2001. p 49.

      compared two types of hydrogels used for autolytic débridement and reported that complete wound healing was achieved in 35% of patients in one group compared with 19% in the second group. The wounds reduced in size from (mean ± standard deviation) 2.5 ± 3.2 cm2 to 0.6 ± 1.1 cm2 in the first group and from 2.4 ± 2.9 cm2 to 1.0 ± 1.8 cm2 in the second group (the total number of patients was 66, and no statistical testing for significance was reported).

      Discussion

      We conducted a systematic review and meta-analyses to evaluate the comparative effectiveness of different débridement methods for diabetic foot ulcers. We found low to moderate quality evidence supporting benefits of autolytic débridement with hydrogel and surgical débridement, delivered with ultrasound assistance or other methods. The RCT that compared larva vs autolytic débridement reported a significant reduction in the wound size area in favor of larval therapy, but the number of completely healed ulcers between the groups was similar. When different hydrogels were compared in one RCT, no significant differences were found. Pooling of three controlled cohorts showed that there is no significant difference in the healing rate between larval débridement and conventional wound care but potentially a difference in the amputation rate.
      • Armstrong D.G.
      • Salas P.
      • Short B.
      • Martin B.R.
      • Kimbriel H.R.
      • Nixon B.P.
      • et al.
      Maggot therapy in “lower-extremity hospice” wound care: fewer amputations and more antibiotic-free days.
      • Paul A.G.
      • Ahmad N.W.
      • Lee H.L.
      • Ariff A.M.
      • Saranum M.
      • Naicker A.S.
      • et al.
      Maggot debridement therapy with Lucilia cuprina: a comparison with conventional debridement in diabetic foot ulcers.
      • Sherman R.A.
      Maggot therapy for treating diabetic foot ulcers unresponsive to conventional therapy.
      Overall, the number of included studies and number of events were quite low, making the available evidence imprecise and inconclusive. In addition, the comparison (control) group in the included studies received conventional wound care, the details of which were not well reported and likely varied across studies, particularly in dressing type, débridement type, frequency and intensity, and follow-up frequency.
      Our results are consistent with other evidence syntheses attempts. Tian et al
      • Tian X.
      • Liang X.M.
      • Song G.M.
      • Zhao Y.
      • Yang X.L.
      Maggot debridement therapy for the treatment of diabetic foot ulcers: a meta-analysis.
      conducted a systematic review and meta-analysis and reported that maggot débridement therapy was superior to the control group in diabetic foot ulcers to achieve full healing (RR, 1.8; 95% CI, 1.07-3.02), amputation rate (RR, 0.41; 95% CI, 0.20-0.85), time to healing (RR, −3.70, 95% CI, −5.76 to −0.64), and number of antibiotic-free days (126.8 ± 30.3 days vs 81.9 ± 42.1 days; P = .001); however, no significant change was noted in the incidence of infection after intervention (RR, 0.82; 95% CI, 0.65-1.04).
      • Tian X.
      • Liang X.M.
      • Song G.M.
      • Zhao Y.
      • Yang X.L.
      Maggot debridement therapy for the treatment of diabetic foot ulcers: a meta-analysis.
      Another systematic review did not find strong evidence to support a specific method of débridement due to sparse data and methodologic limitations of the studies; hence, they did not perform a meta-analysis.
      • Hinchliffe R.J.
      • Valk G.D.
      • Apelqvist J.
      • Armstrong D.G.
      • Bakker K.
      • Game F.L.
      • et al.
      A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes.
      A systematic review by the Cochrane collaboration included only RCTs and reported similar conclusions.
      • Edwards J.
      • Stapley S.
      Debridement of diabetic foot ulcers.
      The present systematic review expands on the previous findings and brings the evidence base up to date regarding RCTs and observational studies that evaluated all types of débridement.

       Clinical and practice implications

      The available evidence points toward putative benefits of autolytic, larval, and surgical débridement. However, our confidence in the difference between treatments is rather low and may change as future research accumulate. Therefore, the choice of débridement therapy remains a decision to be made based on patient preferences, clinical context, availability of surgical expertise and materials, and cost. A cost-effectiveness analysis highlighted the uncertainty about cost-effectiveness that likely differ based on analysis assumptions and the environment of care delivery.
      • Bennett H.
      • Sewell B.
      • Anderson P.
      • Rai M.
      • Goyal R.
      • Phillips C.
      Cost-effectiveness of interventions for chronic wound debridement: an evaluation in search of data.
      The accompanying guideline by the Society for Vascular Surgery will demonstrate the clinical implications and aid patients and surgeons in choosing the most suitable method.

      Conclusions

      The available literature supports the efficacy of several débridement methods, including surgical, autolytic, and larval débridement. Comparative effectiveness evidence between these methods and supportive evidence for other methods is of low quality due to methodologic limitations and imprecision. Hence, the choice of débridement method at the present time should be based on the available expertise, patient preferences, the clinical context, and cost.

      Author contributions

      Conception and design: TE, JD, GP, AT, MN, RF, RH, BF, LP, MM
      Analysis and interpretation: TE, MM
      Data collection: TE, JD, GP, AT, MN, RF, RH, BF, LP, MM
      Writing the article: TE, JD, GP, AT, MN, RF, RH, BF, LP, MM
      Critical revision of the article: TE, JD, GP, AT, MN, RF, RH, BF, LP, MM
      Final approval of the article: TE, JD, GP, AT, MN, RF, RH, BF, LP, 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: diabetic foot débridement, limited to randomized and nonrandomized studies.

       Actual search strategy

       OVID

      Databases: 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
      #SearchesResults
      1exp Debridement/28816
      2debridement.mp.43237
      31 or 243237
      4((diabetic or diabetes) adj3 (foot or feet)).mp.14923
      5exp Diabetic Foot/11805
      64 or 514923
      73 and 61582
      8exp controlled study/3639965
      9exp evidence based medicine/518676
      10Evidence-based.mp.176011
      11((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]4669205
      12meta analysis/87758
      13meta-analys$.mp.139596
      14exp “systematic review”/44105
      15systematic review$.mp.98714
      16exp Guideline/ or exp Practice Guideline/271941
      17Guideline$.ti.87231
      18or/8-175189162
      19exp case study/1572995
      20exp Cohort Studies/1330764
      21exp longitudinal study/880349
      22exp retrospective study/628418
      23exp prospective study/532053
      24exp observational study/23108
      25exp comparative study/2198792
      26exp clinical trial/1477519
      27exp evaluation/1088304
      28exp twins/39276
      29exp validation study/28010
      30exp 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/6878167
      31((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.6826566
      32(“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]154892
      33or/19-3212888585
      347 and (18 or 33)1023
      35from 7 keep 919-1503585
      36limit 35 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]105
      3734 or 361023
      38Limit 37 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, Ovid MEDLINE In-Process, CCTR, CDSR; records were retained]60
      3937 not 38963
      40from 7 keep 1504-158279
      4139 or 40992
      42remove duplicates from 41662

       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 (debridement)
      • 3
        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*))
      • 4
        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”)
      • 5
        1 and 2 and (3 or 4)
      • 6
        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*)
      • 7
        5 and not 6
      • 8
        DOCTYPE(le) or DOCTYPE(ed) or DOCTYPE(bk) or DOCTYPE(er) or DOCTYPE(no) or DOCTYPE(sh)
      • 9
        7 and not 8

      References

        • Margolis D.J.
        • Kantor J.
        • Berlin J.A.
        Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis.
        Diabetes Care. 1999; 22: 692-695
      1. Consensus development conference on diabetic foot wound care: 7-8 April 1999, Boston, Massachusetts. American Diabetes Association.
        Diabetes Care. 1999; 22: 1354-1360
        • Cornell R.S.
        • Meyr A.J.
        • Steinberg J.S.
        • Attinger C.E.
        Debridement of the noninfected wound.
        J Vasc Surg. 2010; 52: 31S-36S
        • Edwards J.
        • Stapley S.
        Debridement of diabetic foot ulcers.
        Cochrane Database Syst Rev. 2010; : CD003556
        • 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
      2. 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
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trial. 1986; 7: 177-188
        • 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
        • Markevich M.R.
        • Mousley M.
        • Melloy E.
        Maggot therapy for diabetic neuropathic foot wounds.
        Diabetologia. 2000; (Proceedings of the 36th Annual Meeting of the European Association for the Study of Diabetes): A15
        • Piaggesi A.
        • Schipani E.
        • Campi F.
        • Romanelli M.
        • Baccetti F.
        • Arvia C.
        • et al.
        Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial.
        Diabet Med. 1998; 15: 412-417
        • Singh A.
        Usage of ultrasound in wound management comparison between ultrasonic wound debridement and sharp debridement in diabetic foot ulcers: a randomized clinical trial. Thesis.
        Faculty of Medicine, University of Malaya, 2006
        • Yao M.
        • Hasturk H.
        • Kantarci A.
        • Gu G.
        • Garcia-Lavin S.
        • Fabbi M.
        • et al.
        A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers.
        Int Wound J. 2014; 11: 586-593
        • Caputo W.J.
        • Beggs D.J.
        • DeFede J.L.
        • Simm L.
        • Dharma H.
        A prospective randomised controlled clinical trial comparing hydrosurgery debridement with conventional surgical debridement in lower extremity ulcers.
        Int Wound J. 2008; 5: 288-294
        • Bowling F.L.
        • Crews R.T.
        • Salgami E.
        • Armstrong D.G.
        • Boulton A.J.
        The use of superoxidized aqueous solution versus saline as a replacement solution in the versajet lavage system in chronic diabetic foot ulcers: a pilot study.
        J Am Podiatr Med Assoc. 2011; 101: 124-126
        • Apelqvist J.
        • Larsson J.
        • Stenstrom A.
        Topical treatment of necrotic foot ulcers in diabetic patients: a comparative trial of DuoDerm and MeZinc.
        Br J Dermatol. 1990; 126: 787-792
      3. Whalley BA, Harding K, Van Acker K, Capillas R. Performance characteristics and safety of purilon gel versus intrasite using biatain non-adhesive dressing as secondary dressing in the treatment of diabetic foot ulcers. 11th European Tissue Repair Society Annual Conference Cardiff, Wales; 2001. p 49.

        • Armstrong D.G.
        • Salas P.
        • Short B.
        • Martin B.R.
        • Kimbriel H.R.
        • Nixon B.P.
        • et al.
        Maggot therapy in “lower-extremity hospice” wound care: fewer amputations and more antibiotic-free days.
        J Am Podiatr Med Assoc. 2005; 95: 254-257
        • Paul A.G.
        • Ahmad N.W.
        • Lee H.L.
        • Ariff A.M.
        • Saranum M.
        • Naicker A.S.
        • et al.
        Maggot debridement therapy with Lucilia cuprina: a comparison with conventional debridement in diabetic foot ulcers.
        Int Wound J. 2009; 6: 39-46
        • Sherman R.A.
        Maggot therapy for treating diabetic foot ulcers unresponsive to conventional therapy.
        Diabetes Care. 2003; 26: 446-451
        • Tian X.
        • Liang X.M.
        • Song G.M.
        • Zhao Y.
        • Yang X.L.
        Maggot debridement therapy for the treatment of diabetic foot ulcers: a meta-analysis.
        J Wound Care. 2013; 22: 462-469
        • Hinchliffe R.J.
        • Valk G.D.
        • Apelqvist J.
        • Armstrong D.G.
        • Bakker K.
        • Game F.L.
        • et al.
        A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes.
        Diabetes Metab Res Rev. 2008; 24: S119-S144
        • Bennett H.
        • Sewell B.
        • Anderson P.
        • Rai M.
        • Goyal R.
        • Phillips C.
        Cost-effectiveness of interventions for chronic wound debridement: an evaluation in search of data.
        Wounds UK. 2013; 9: 3-11
        • d'Hemecourt P.A.
        • Smiell J.M.
        • Karim M.R.
        Sodium carboxymethylcellulose aqueous-based gel vs. becaplermin gel in patients with nonhealing lower extremity diabetic ulcers.
        Wounds. 1998; 10: 69-75
        • Jensen J.L.
        • Seeley J.
        • Gillin B.
        Diabetic foot ulcerations. A controlled, randomized comparison of two moist wound healing protocols: Carrasyn Hydrogel Wound dressing and wet-to-moist saline gauze.
        Adv Wound Care. 1998; 11: 1-4
      4. Vandeputte G, Grayson L. Diabetic foot infection controlled by immuno-modulating hydrogel containing 65% glycerine. Presentation of a clinical trial at 6th European Conference on Advances in Wound Management. Amsterdam, The Netherlands; 1996:50-53.