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A systematic review and meta-analysis of tests to predict wound healing in diabetic foot

      Background

      This systematic review summarized the evidence on noninvasive screening tests for the prediction of wound healing and the risk of amputation in diabetic foot ulcers.

      Methods

      We searched MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Scopus from database inception to October 2011. We pooled sensitivity, specificity, and diagnostic odds ratio (DOR) and compared test performance.

      Results

      Thirty-seven studies met the inclusion criteria. Eight tests were used to predict wound healing in this setting, including ankle-brachial index (ABI), ankle peak systolic velocity, transcutaneous oxygen measurement (TcPo2), toe-brachial index, toe systolic blood pressure, microvascular oxygen saturation, skin perfusion pressure, and hyperspectral imaging. For the TcPo2 test, the pooled DOR was 15.81 (95% confidence interval [CI], 3.36-74.45) for wound healing and 4.14 (95% CI, 2.98-5.76) for the risk of amputation. ABI was also predictive but to a lesser degree of the risk of amputations (DOR, 2.89; 95% CI, 1.65-5.05) but not of wound healing (DOR, 1.02; 95% CI, 0.40-2.64). It was not feasible to perform meta-analysis comparing the remaining tests. The overall quality of evidence was limited by the risk of bias and imprecision (wide CIs due to small sample size).

      Conclusions

      Several tests may predict wound healing in the setting of diabetic foot ulcer; however, most of the available evidence evaluates only TcPo2 and ABI. The overall quality of the evidence is low, and further research is needed to provide higher quality comparative effectiveness evidence.
      In 2010, there were 25.8 million people in the United States with diabetes.
      Centers for Disease Control and Prevention
      National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011.
      As a major cause of morbidity, 15% of these patients would develop diabetic foot ulcers (DFUs) resulting from diabetic neuropathy or peripheral arterial disease.
      • Reiber G.E.
      • Vileikyte L.
      • Boyko E.J.
      • del Aguila M.
      • Smith D.G.
      • Lavery L.A.
      • et al.
      Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings.
      Inappropriately treated or untreated DFUs can lead to severe consequences, including lower extremity amputation and even death.
      Predicting wound healing is an essential step in the management of DFUs. It is estimated that early detection and appropriate treatments may prevent up to 85% of amputations.
      • Edmonds M.
      Experience in a multidisciplinary diabetic foot clinic.
      A range of noninvasive tests have been proposed in the literature to predict wound healing, including ankle-brachial index (ABI), toe-brachial index (TBI), transcutaneous oxygen measurement (TcPo2), and toe systolic blood pressure (TBP).
      Other tests have also been studied. Because in ischemic limbs blood moves at a much slower velocity in distal leg arteries (compared with nonischemic limbs), one other test is the ankle peak systolic velocity (APSV), which is estimated as the mean of the peak velocities measured across the distal tibial artery at the ankle level.
      • Bishara R.A.
      • Taha W.
      • Akladious I.
      • Allam M.A.
      Ankle peak systolic velocity: new parameter to predict nonhealing in diabetic foot lesions.
      Hyperspectral imaging is a noninvasive diagnostic tool that quantifies tissue oxygenation and generates anatomically relevant maps of microcirculatory changes. The map is based on local molecular composition (as reflected by wavelength selection) of molecules such as oxyhemoglobin and deoxyhemoglobin.
      • Nouvong A.
      • Hoogwerf B.
      • Mohler E.
      • Davis B.
      • Tajaddini A.
      • Medenilla E.
      Evaluation of diabetic foot ulcer healing with hyperspectral imaging of oxyhemoglobin and deoxyhemoglobin.
      Microvascular oxygen saturation (Sao2) can be measured using a micro-lightguide spectrophotometer that sends light from a xenon lamp to the tissue, where it is scattered and then collected by surrounding fibers. Light signal is converted into an electrical signal, digitized, and analyzed in real time by comparing to pre-recorded spectra of fully deoxygenated and oxygenated hemoglobin spectra.
      • Rajbhandari S.M.
      • Harris N.D.
      • Tesfaye S.
      • Ward J.D.
      Early identification of diabetic foot ulcers that may require intervention using the micro lightguide spectrophotometer.
      Skin perfusion pressure (SPP) can be measured by a laser Doppler scanner that is secured in a blood pressure cuff with a transparent window and records perfusion pressure during deflation.
      • Castronuovo Jr., J.J.
      • Adera H.M.
      • Smiell J.M.
      • Price R.M.
      Skin perfusion pressure measurement is valuable in the diagnosis of critical limb ischemia.
      However, it is unclear which test has the best prognostic accuracy in detecting treatment outcomes.
      Hereby, we conducted a systematic review and meta-analysis to summarize the evidence of available tests and to compare the performance of eight noninvasive tests in predicting wound healing of DFUs. To our knowledge, this is the first meta-analysis on this topic.

      Methods

      The methodology and reporting of this systematic review are consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
      • Arsenault K.A.
      • McDonald J.
      • Devereaux P.J.
      • Thorlund K.
      • Tittley J.G.
      • Whitlock R.P.
      The use of transcutaneous oximetry to predict complications of chronic wound healing: a systematic review and meta-analysis.
      The protocol of this systematic review was developed by the Society for Vascular Surgery Committee tasked to develop guidelines for the management of diabetic foot.

       Study selection

      To be eligible for this review, studies had to be clinical trials or observational studies that used one of these eight noninvasive tests: ABI, APSV, TcPo2, TBI, TBP, microvascular Sao2, SPP, and hyperspectral imaging. Studies had to report the incidence of subsequent healing of DFUs or the need for subsequent amputation. DFU patients, regardless of age, gender, ethnicity, and underlying symptoms, were included in analysis. Studies that reported only pretreatment test results were excluded, as were editorials, letters, errata, notes, and commentaries. Clinical reviews (systematic and nonsystematic reviews) and medical guidelines were used to identify relevant studies.

       Literature search

      We conducted a broad search of six electronic databases, including Ovid MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Scopus, from database inception to October 2011. The appropriate database search terms were developed for the concept of DFUs and for the concept of each noninvasive test. The search terms were broad without language or country restrictions. The detailed search strategy is available in the Appendix (online only).

       Data abstraction

      Two independent reviewers screened the study titles and abstracts using a predefined protocol. Full texts of the relevant studies were further assessed for inclusion by the same pair of reviewers. All discrepancies between the reviewers were resolved through consensus.
      Two reviewers extracted study details independently, in duplicate, using a standardized pilot-tested form. The following data were abstracted: study design, patient characteristics (sex, age), sample size, diabetes type, baseline ulcer status, length of follow-up, tests, and outcomes. The outcomes of interest were the number of healed foot ulcers and the number of amputated limbs. The outcomes were extracted at the longest duration of complete follow-up. We extracted or calculated the number of healed vs nonhealed ulcers and amputated limbs vs nonamputated limbs and constructed contingency tables. Predefined thresholds were used (ABI, 0.8; TcPo2, 30 mm Hg). When data reported were unclear, the authors of the included studies were contacted for clarification.

       Risk of bias and methodologic quality assessment

      Considering that the included studies were either nonrandomized or randomized for purposes other than the goal of this systematic review, we applied the Newcastle and Ottawa quality assessment tool and evaluated representativeness of study samples, exposure ascertainment, blinding of outcome assessors, and loss to follow-up.
      • 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 nonrandomized studies in meta-analysis.
      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 evidence (ie, high certainty), and observational studies warrant low-quality evidence. Then 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]).

       Data synthesis

      To evaluate the effectiveness of each test in predicting outcomes of interest, we calculated sensitivity and specificity for each test using bivariate binominal mixed models.
      • Chu H.
      • Cole S.R.
      Bivariate meta-analysis of sensitivity and specificity with sparse data: a generalized linear mixed model approach.
      • Reitsma J.B.
      • Glas A.S.
      • Rutjes A.W.
      • Scholten R.J.
      • Bossuyt P.M.
      • Zwinderman A.H.
      Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews.
      Developed by Reitsma et al and later refined by Chu and Cole, the bivariate binominal mixed model assumes independent exact binomial distributions of number of true positives and number of true negatives conditional on sensitivity and specificity for each study and constructs a bivariate normal model on the logit transforms of sensitivity and specificity between studies. This model accounts for within- and between-study variability and uses correlation between the studies to adjust an implicit threshold effect. The results, mean logit transforms of sensitivity and specificity, and related standard errors were back transformed and constructed 95% CI. We calculated the diagnostic odds ratio (DOR) based on the estimates of pooled sensitivity and specificity. DOR is a single global measure for diagnostic accuracy, used for general estimation of discriminative power of diagnostic procedures, and helps in comparing two or more diagnostic tests. DOR of a test is the ratio of the odds of positivity in subjects with disease relative to the odds in subjects without disease. We also pooled difference of test score across the included studies and constructed random-effects models using the DerSimonian and Laird method.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      The effect size, standardized mean difference (SMD), was calculated using Hedges' adjusted g measure.
      • Hedges L.V.
      Distribution theory for Glass's estimator of effect size and related estimators.
      SMD is used when we compare tests that used different units. The results are standardized (ie, expressed in standard deviation units) to allow comparison between tests.
      We assessed heterogeneity across individual studies using the I2 statistic and Cochran Q test. Publication bias was assessed by the Begg adjusted rank correlation test.
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      All statistical analyses were conducted using Stata version 12 (StataCorp, College Station, Tex).

       Sensitivity analysis

      We constructed multivariate nested random-effects meta-regression models across all included studies to further compare prognostic accuracy of clinical tests.
      • Freemantle N.
      • Cleland J.
      • Young P.
      • Mason J.
      • Harrison J.
      β Blockade after myocardial infarction: systematic review and meta regression analysis.
      To compare the regression coefficients between different tests in the model, we standardized the coefficients with one standard deviation. Thus, the standardized coefficients represent the standard deviation change of an outcome associated with one standard deviation increase of a test score. The higher value suggests the better discriminant test performance. The sensitivity analysis provided an alternative method to evaluate the findings.

      Results

      Our searches identified 229 potential studies; 95 were retrieved for full-text screening, and 37 met our inclusion criteria and thus were included in this systematic review (Fig 1). Among them, 32 were observational studies and 5 were randomized controlled trials (RCTs). As the five RCTs were not initiated for evaluating diagnostic tests and were not prognostically balanced between test group and comparison group, we considered them observational studies in this review. The characteristics of the included studies are listed in Table I.
      Table ICharacteristics of the included studies
      Study IDStudy designPtsDM typeAge, years ± SDMale, %Duration of DM, years ± SDUlcer description (baseline)Follow-up, months
      ABI
       Ballard,
      • Ballard J.L.
      • Eke C.C.
      • Bunt T.J.
      • Killeen J.D.
      A prospective evaluation of transcutaneous oxygen measurements in the management of diabetic foot problems.
      1995
      Obs55Type 2: 40%

      Type 1: 60%
      67 ± 1362Nonhealing ulcer: 91%8
       Castronuovo,
      • Castronuovo Jr., J.J.
      • Adera H.M.
      • Smiell J.M.
      • Price R.M.
      Skin perfusion pressure measurement is valuable in the diagnosis of critical limb ischemia.
      1997
      Obs5371 ± 1062
       Chen,
      • Chen G.P.
      • Gu J.P.
      • Lou W.S.
      • He X.
      • Chen L.
      • Su H.B.
      • et al.
      Diabetic peripheral arterial disease: lower limb angiography results and one year outcomes of interventional treatment.
      2010
      Obs3869 ± 94213 ± 312
       Edelman,
      • Edelman D.
      • Hough D.M.
      • Glazebrook K.N.
      • Oddone E.Z.
      Prognostic value of the clinical examination of the diabetic foot ulcer.
      1997
      RCT6466 ± 6115 ± 96
       Faglia,
      • Faglia E.
      • Favales F.
      • Quarantiello A.
      • Calia P.
      • Brambilla G.
      • Rampoldi A.
      • et al.
      Feasibility and effectiveness of peripheral percutaneous transluminal balloon angioplasty in diabetic subjects with foot ulcers.
      1996
      Obs8061 ± 970Ulcer Wagner grade: II, 15%; III, 20%; IV, 65%12
       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
      RCT7063 ± 106918 ± 10Ulcer Wagner grade: II, 13%; III, 25%; IV, 62%2
       Faglia,
      • Faglia E.
      • Mantero M.
      • Caminiti M.
      • Caravaggi C.
      • De Giglio R.
      • Pritelli C.
      • et al.
      Extensive use of peripheral angioplasty, particularly infrapopliteal, in the treatment of ischaemic diabetic foot ulcers: clinical results of a multicentric study of 221 consecutive diabetic subjects.
      2002
      Obs22170 ± 96320 ± 6Ulcer Wagner grade: I, 19%; II, 25%; III, 17%; IV, 38%; V, 1%14
       Hamalainen,
      • Hamalainen H.
      • Ronnemaa T.
      • Halonen J.P.
      • Toikka T.
      Factors predicting lower extremity amputations in patients with type 1 or type 2 diabetes mellitus: a population-based 7-year follow-up study.
      1999
      RCT733Type 2: 54%

      Type 1: 46%
      47 ± 1912 ± 984
       Hanna,
      • Hanna G.P.
      • Fujise K.
      • Kjellgren O.
      • Feld S.
      • Fife C.
      • Schroth G.
      • et al.
      Infrapopliteal transcatheter interventions for limb salvage in diabetic patients: importance of aggressive interventional approach and role of transcutaneous oximetry.
      1997
      Obs2962 ± 34112
       Huang,
      • Huang P.
      • Li S.
      • Han M.
      • Xiao Z.
      • Yang R.
      • Han Z.C.
      Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes.
      2005
      RCT28Type 2: 71%

      Type 1: 29%
      71 ± 66412 ± 8Texas wound classification: I C, 32%; I D, 32%; II C, 14%; II D, 14%; III C, 0%; III D, 7%3
       Johansen,
      • Johansen O.E.
      • Birkeland K.I.
      • Jorgensen A.P.
      • Orvik E.
      • Sorgard B.
      • Torjussen B.R.
      • et al.
      Diabetic foot ulcer burden may be modified by high-dose atorvastatin: a 6-month randomized controlled pilot trial.
      2009
      RCT13Type 2: 85%

      IDDM: 15%
      6477186
       Kalani,
      • Kalani M.
      • Brismar K.
      • Fagrell B.
      • Ostergren J.
      • Jorneskog G.
      Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.
      1999
      Obs5061 ± 127526 ± 1412
       Lee,
      • Lee S.S.
      • Chen C.Y.
      • Chan Y.S.
      • Yen C.Y.
      • Chao E.K.
      • Ueng S.W.
      Hyperbaric oxygen in the treatment of diabetic foot infection.
      1997
      Obs3163 ± 1050
       Londahl,
      • Londahl M.
      • Katzman P.
      • Hammarlund C.
      • Nilsson A.
      • Landin-Olsson M.
      Relationship between ulcer healing after hyperbaric oxygen therapy and transcutaneous oximetry, toe blood pressure and ankle-brachial index in patients with diabetes and chronic foot ulcers.
      2011
      RCT75Type 2: 71%

      Type 1: 29%
      69 ± 10Ulcer size (cm2): 3.1 (1.2-6.4)12
       Nather,
      • Nather A.
      • Bee C.S.
      • Huak C.Y.
      • Chew J.L.
      • Lin C.B.
      • Neo S.
      • et al.
      Epidemiology of diabetic foot problems and predictive factors for limb loss.
      2008
      Obs202Type 2: 95%

      Type 1: 5%
      60541-48Gangrene: 32%

      Infection: 29%

      Ulcer: 28%

      Cellulitis: 6%

      Necrotizing fasciitis: 4%

      Charcot osteoarthropathy: 2%
       Prochazka,
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      2010
      Obs9665 ± 9814
       Redlich,
      • Redlich U.
      • Xiong Y.Y.
      • Pech M.
      • Tautenhahn J.
      • Halloul Z.
      • Lobmann R.
      • et al.
      Superiority of transcutaneous oxygen tension measurements in predicting limb salvage after below-the-knee angioplasty: a prospective trial in diabetic patients with critical limb ischemia.
      2011
      Obs28Type 269 ± 88220 ± 10Critical limb ischemia and severe infrapopliteal peripheral vascular disease12
       Rigatelli,
      • Rigatelli G.
      • Cardaioli P.
      • Dell'Avvocata F.
      • Giordan M.
      • Lisato G.
      • Mollo F.
      Endovascular management of patients with coronary artery disease and diabetic foot syndrome: a long-term follow-up.
      2011
      Obs22079 ± 165137
       Winkley,
      • Winkley K.
      • Stahl D.
      • Chalder T.
      • Edmonds M.E.
      • Ismail K.
      Risk factors associated with adverse outcomes in a population-based prospective cohort study of people with their first diabetic foot ulcer.
      2007
      Obs253Type 2: 83%

      Type 1: 17%
      62 ± 146413.2Duration of ulcer: 3.1 ± 3.6 months Ulcer size (cm2): ≤1, 48.6%; >1, 51.4%18
       Xu,
      • Xu Y.
      • Zhu Y.Q.
      • Zhao J.G.
      • Wang J.B.
      • Tan H.Q.
      • Cheng Y.S.
      • et al.
      Subintimal angioplasty for below-the-ankle arterial occlusion in diabetic patients with chronic critical limb ischemia [Chinese].
      2011
      Obs37Type 2: 73%

      Type 1: 35%
      71 ± 96518 ± 69
      TcPo2
       Ay,
      • Ay H.
      • Yildiz Ş.
      The evaluation of TcPo2 and TcPco2 measurement as a follow up criteria in diabetic foot treated with HBO therapy.
      2004
      Obs5058 ± 86616 ± 31
       Ballard,
      • Ballard J.L.
      • Eke C.C.
      • Bunt T.J.
      • Killeen J.D.
      A prospective evaluation of transcutaneous oxygen measurements in the management of diabetic foot problems.
      1995
      Obs55Type 2: 40%

      Type 1: 60%
      67 ± 1362Nonhealing ulcer: 91%8
       Caselli,
      • Caselli A.
      • Latini V.
      • Lapenna A.
      • Di Carlo S.
      • Pirozzi F.
      • Benvenuto A.
      • et al.
      Transcutaneous oxygen tension monitoring after successful revascularization in diabetic patients with ischaemic foot ulcers.
      2005
      Obs43Type 2: 95%

      Type 1: 5%
      735820Ulcer Wagner grade IV, 100%11
       Ezio,
      • Ezio F.
      • Giacomo C.
      • Maurizio C.
      • Antonella Q.
      • Vincenzo C.
      • Francesco S.
      Evaluation of feasibility of ankle pressure and foot oxymetry values for the detection of critical limb ischemia in diabetic patients.
      2010
      Obs26173 ± 96718 ± 12Ulcer Wagner grade: 0, 6%; I, 30%; II, 10%; III, 7%; IV, 46%
       Faglia,
      • Faglia E.
      • Favales F.
      • Quarantiello A.
      • Calia P.
      • Brambilla G.
      • Rampoldi A.
      • et al.
      Feasibility and effectiveness of peripheral percutaneous transluminal balloon angioplasty in diabetic subjects with foot ulcers.
      1996
      Obs8061 ± 970Ulcer Wagner grade: II, 15%; III, 20%; IV, 65%12
       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
      RCT7063 ± 106918 ± 10Ulcer Wagner grade: II, 13%; III, 25%; IV, 62%2
       Faglia,
      • Faglia E.
      • Mantero M.
      • Caminiti M.
      • Caravaggi C.
      • De Giglio R.
      • Pritelli C.
      • et al.
      Extensive use of peripheral angioplasty, particularly infrapopliteal, in the treatment of ischaemic diabetic foot ulcers: clinical results of a multicentric study of 221 consecutive diabetic subjects.
      2002
      Obs22170 ± 96320 ± 6Ulcer Wagner grade: I, 19%; II, 25%; III, 17%; IV, 38%; V, 1%14
       Faglia,
      • Faglia E.
      • Dalla Paola L.
      • Clerici G.
      • Clerissi J.
      • Graziani L.
      • Fusaro M.
      • et al.
      Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003.
      2005
      Obs99370 ± 96718 ± 11Texas wound classification: 0 C, 12%; I C, 8%; I D, 7%; II C, 6%; II D, 13%; III C, 3%; III D, 50%26
       Faglia,
      • Faglia E.
      • Clerici G.
      • Caminiti M.
      • Quarantiello A.
      • Curci V.
      • Morabito A.
      Predictive values of transcutaneous oxygen tension for above-the-ankle amputation in diabetic patients with critical limb ischemia.
      2007
      Obs56470 ± 106517 ± 11Ulcer Wagner grade: 0, 16%; I, 15%; II, 14%; III, 10%; IV, 46%64
       Ferraresi,
      • Ferraresi R.
      • Centola M.
      • Ferlini M.
      • Da Ros R.
      • Caravaggi C.
      • Assaloni R.
      • et al.
      Long-term outcomes after angioplasty of isolated, below-the-knee arteries in diabetic patients with critical limb ischaemia.
      2009
      Obs10166 ± 98415 ± 535
       Hanna,
      • Hanna G.P.
      • Fujise K.
      • Kjellgren O.
      • Feld S.
      • Fife C.
      • Schroth G.
      • et al.
      Infrapopliteal transcatheter interventions for limb salvage in diabetic patients: importance of aggressive interventional approach and role of transcutaneous oximetry.
      1997
      Obs2962 ± 34112
       Ichioka,
      • Ichioka S.
      • Yokogawa H.
      • Sekiya N.
      • Kouraba S.
      • Minamimura A.
      • Ohura N.
      • et al.
      Determinants of wound healing in bone marrow-impregnated collagen matrix treatment: impact of microcirculatory response to surgical debridement.
      2009
      Obs756567
       Jacqueminet,
      • Jacqueminet S.
      • Hartemann-Heurtier A.
      • Izzillo R.
      • Cluzel P.
      • Golmard J.L.
      • Van Ha G.
      • et al.
      Percutaneous transluminal angioplasty in severe diabetic foot ischemia: outcomes and prognostic factors.
      2005
      Obs32Type 2: 84%

      Type 1: 16%
      67 ± 108522 ± 1212
       Kalani,
      • Kalani M.
      • Brismar K.
      • Fagrell B.
      • Ostergren J.
      • Jorneskog G.
      Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.
      1999
      Obs5061 ± 127526 ± 1412
       Khodabandehlou,
      • Khodabandehlou T.
      • Le Devehat C.
      Hemorheological disturbances as a marker of diabetic foot syndrome deterioration.
      2004
      Obs38Type 2: 71%

      Type 1: 29%
      68 ± 816 ± 1112
       Kim,
      • Kim H.R.
      • Han S.K.
      • Rha S.W.
      • Kim H.S.
      • Kim W.K.
      Effect of percutaneous transluminal angioplasty on tissue oxygenation in ischemic diabetic feet.
      2011
      Obs2369 ± 77420 ± 10Ischemic diabetic ulcer20
       Londahl,
      • Londahl M.
      • Katzman P.
      • Hammarlund C.
      • Nilsson A.
      • Landin-Olsson M.
      Relationship between ulcer healing after hyperbaric oxygen therapy and transcutaneous oximetry, toe blood pressure and ankle-brachial index in patients with diabetes and chronic foot ulcers.
      2011
      RCT75Type 2: 71%

      Type 1: 29%
      69 ± 10Ulcer size (cm2): HBOT, 3.1 (1.2-6.4)12
       Nouvong,
      • Nouvong A.
      • Hoogwerf B.
      • Mohler E.
      • Davis B.
      • Tajaddini A.
      • Medenilla E.
      Evaluation of diabetic foot ulcer healing with hyperspectral imaging of oxyhemoglobin and deoxyhemoglobin.
      2009
      Obs66Type 2: 57%

      Type 1: 43%
      52 ± 98813 ± 9Ulcer size (cm2): healed, 3.2 ± 3.9; nonhealed, 5.8 ± 6.26
       Prochazka,
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      2010
      Obs9665 ± 9814
       Redlich,
      • Redlich U.
      • Xiong Y.Y.
      • Pech M.
      • Tautenhahn J.
      • Halloul Z.
      • Lobmann R.
      • et al.
      Superiority of transcutaneous oxygen tension measurements in predicting limb salvage after below-the-knee angioplasty: a prospective trial in diabetic patients with critical limb ischemia.
      2011
      Obs28Type 269 ± 88220 ± 10Critical limb ischemia and severe infrapopliteal peripheral vascular disease12
       Rigatelli,
      • Rigatelli G.
      • Cardaioli P.
      • Dell'Avvocata F.
      • Giordan M.
      • Lisato G.
      • Mollo F.
      Endovascular management of patients with coronary artery disease and diabetic foot syndrome: a long-term follow-up.
      2011
      Obs22079 ± 165137
       Uccioli,
      • Uccioli L.
      • Gandini R.
      • Giurato L.
      • Fabiano S.
      • Pampana E.
      • Spallone V.
      • et al.
      Long-term outcomes of diabetic patients with critical limb ischemia followed in a tertiary referral diabetic foot clinic.
      2010
      Obs510Type 2: 93%

      Type 1: 7%
      70 ± 16420 ± 120
       Wattel,
      • Wattel F.
      • Mathieu D.
      • Coget J.M.
      • Billard V.
      Hyperbaric oxygen therapy in chronic vascular wound management.
      1990
      Obs11Chronic arterial insufficiency ulcers: 82%12
       Weng,

      Weng H, Yan L, Yang C, Chen LH, Yin GS, Xu MT, et al. Predictive values of transcutaneous oxygen pressure measurement for outcome of diabetic foot ulcers. Diabetes Conference: 69th Annual Meeting of the American Diabetes Association; New Orleans, La; June 5-9, 2009.

      2009
      Obs61
       Zgonis,
      • Zgonis T.
      • Garbalosa J.C.
      • Burns P.
      • Vidt L.
      • Lowery C.
      A retrospective study of patients with diabetes mellitus after partial foot amputation and hyperbaric oxygen treatment.
      2005
      Obs35Type 2: 97%

      Type 1: 3%
      7
      SPP
       Castronuovo,
      • Castronuovo Jr., J.J.
      • Adera H.M.
      • Smiell J.M.
      • Price R.M.
      Skin perfusion pressure measurement is valuable in the diagnosis of critical limb ischemia.
      1997
      Obs5371 ± 1062
       Prochazka,
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      2010
      Obs9665 ± 9814
      TBI
       Kalani,
      • Kalani M.
      • Brismar K.
      • Fagrell B.
      • Ostergren J.
      • Jorneskog G.
      Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.
      1999
      Obs5061 ± 127526 ± 1412
       Prochazka,
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      2010
      Obs9665 ± 9814
      TBP
       Kalani,
      • Kalani M.
      • Brismar K.
      • Fagrell B.
      • Ostergren J.
      • Jorneskog G.
      Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.
      1999
      Obs5061 ± 127526 ± 1412
       Prochazka,
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      2010
      Obs9665 ± 9814
      APSV
       Bishara,
      • Bishara R.A.
      • Taha W.
      • Akladious I.
      • Allam M.A.
      Ankle peak systolic velocity: new parameter to predict nonhealing in diabetic foot lesions.
      2009
      Obs6263 ± 668
      Microvascular Sao2
       Rajbhandari,
      • Rajbhandari S.M.
      • Harris N.D.
      • Tesfaye S.
      • Ward J.D.
      Early identification of diabetic foot ulcers that may require intervention using the micro lightguide spectrophotometer.
      1999
      Obs14Type 2: 86%

      Type 1: 14%
      67 ± 109314 ± 6Duration of ulcers: 12 ± 10 weeks9
      Hyperspectral imaging
       Nouvong,
      • Nouvong A.
      • Hoogwerf B.
      • Mohler E.
      • Davis B.
      • Tajaddini A.
      • Medenilla E.
      Evaluation of diabetic foot ulcer healing with hyperspectral imaging of oxyhemoglobin and deoxyhemoglobin.
      2009
      Obs66Type 2: 57%

      Type 1: 43%
      52 ± 98813 ± 9Ulcer size (cm2): 4.06
      ABI, Ankle-brachial index; APSV, ankle peak systolic velocity; DM, diabetes mellitus; HBOT, hyperbaric oxygen therapy; IDDM, insulin-dependent diabetes mellitus; Obs, observational study; Pts, patients; RCT, randomized controlled trial; Sao2, oxygen saturation; SD, standard deviation; SPP, skin perfusion pressure; TBI, toe-brachial index; TBP, toe blood pressure; TcPo2, transcutaneous oxygen measurement; Type 2, non-insulin-dependent diabetes mellitus.

       Risk of bias

      Fig 2 reports the quality indicators of the included studies. The quality of the included studies was generally adequate. Blinding of outcome assessors was the quality indicator most absent; 13 of the 37 studies did not meet the criterion or did not provide sufficient information for evaluation. Because of the limited number of studies evaluating each test, it was inappropriate to conduct statistical tests to assess publication bias for almost all of the screening tests.
      • Ioannidis J.P.
      • Trikalinos T.A.
      The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey.
      The only exception was the TcPo2 test. We found no evidence of publication bias in the outcomes of interest using the Begg adjusted rank correlation test (P > .05). In summary, the risk of bias within the studies is medium.
      Figure thumbnail gr2
      Fig 2Risk of bias assessment of the included studies. High risk: studies do not meet quality criteria. Unclear: not enough information to judge study quality. Low risk: studies meet quality criteria.

       Predictive ability of tests

      Meta-analysis was possible on studies of ABI and TcPo2. Because of the limited number of available studies on other tests, we were unable to pool prognostic accuracy of SPP, TBP, TBI, APSV, Sao2, and hyperspectral imaging.

       ABI

      Twenty studies evaluated ABI values with a total of 2376 patients (range, 13-733). The patients were observed for an average of 15 months (range, 2-84). The pooled ABI values were significantly higher in the healed ulcer group than in the nonhealed group (SMD, 0.42; 95% CI, 0.05-0.79; I2 = 15.7%; heterogeneity, P = .32). The combined difference between the amputated limb group and the nonamputated group was also significant (SMD, −0.99; 95% CI, −1.44 to −0.54; I2 = 44.5%; heterogeneity, P = .13).
      In terms of the ability of the test to predict healing, Table II summarizes the sensitivity, specificity, and DOR of ABI for predicting healed foot ulcers and limb amputations. In general, the prognostic accuracy of using the ABI for predicting healed foot ulcers was low, with the sensitivity of 0.48 (95% CI, 0.36-0.61) and the specificity of 0.52 (95% CI, 0.42-0.63). The overall DOR was 1.02 (95% CI, 0.40-2.64). In predicting limb amputations, the sensitivity was 0.52 (95% CI, 0.49-0.54) with the specificity of 0.73 (95% CI, 0.63-0.81). The DOR was 2.89 (1.65-5.05), suggesting a slightly better test performance for this outcome.
      Table IIPooled sensitivity, specificity, and diagnostic odds ratio (DOR) of ankle-brachial index (ABI) and transcutaneous oxygen measurement (TcPo2) tests
      OutcomeABITcPo2
      Estimate95% CIEstimate95% CI
      Complete ulcer healing
       Sensitivity0.480.36-0.610.720.61-0.81
       Specificity0.520.42-0.630.860.68-0.95
       DOR1.020.40-2.6515.813.36-74.45
      Limb amputation
       Sensitivity0.520.49-0.540.750.73-0.77
       Specificity0.730.63-0.810.580.52-0.64
       DOR2.891.65-5.054.142.98-5.76
      CI, Confidence interval.

       TcPo2

      Of the 37 included studies, 25 assessed TcPo2; 3789 patients (range, 11-993) were included in these studies. The average follow-up length was 16 months (range, 1-64). There was a significant difference of TcPo2 values between the healed group and the nonhealed group (SMD, 1.80; 95% CI, 1.06-2.54; I2 = 92.3%; heterogeneity, P < .001). The SMD was −2.26 (95% CI, −4.13 to −0.40) when the amputated-limb group was compared with the nonamputated group (I2 = 96.8%; heterogeneity, P < .001).
      In terms of the ability of the test to predict healing (Table II), the results suggested high accuracy of the TcPo2 test for predicting both ulcer healing and limb amputation. For ulcer healing, the combined sensitivity and specificity were 0.72 (95% CI, 0.61-0.81) and 0.86 (95% CI, 0.68-0.95), respectively. The DOR was 15.81 (95% CI, 3.36-74.45). For limb amputations, we found lower but still significantly better DOR with the combined estimate of 4.14 (95% CI, 2.98-5.76).

       SPP

      Two studies evaluated prognostic performance of the SPP test.
      • Castronuovo Jr., J.J.
      • Adera H.M.
      • Smiell J.M.
      • Price R.M.
      Skin perfusion pressure measurement is valuable in the diagnosis of critical limb ischemia.
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      Castronuovo et al
      • Castronuovo Jr., J.J.
      • Adera H.M.
      • Smiell J.M.
      • Price R.M.
      Skin perfusion pressure measurement is valuable in the diagnosis of critical limb ischemia.
      studied a convenience sample of 53 critical limb ischemia patients, 75% of whom had diabetes. Using the threshold of 30 mm Hg, they estimated that the sensitivity for healed ulcers was 85% with the specificity of 73%. The overall area under the receiver operating characteristic curve was 0.79. Prochazka et al
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      compared SPP values between the healed group and the nonhealed group and found a significant difference (111.19 mm Hg vs 68.57 mm Hg, respectively).

       TBP

      We identified two studies reporting TBP measurements in patients with DFUs.
      • Kalani M.
      • Brismar K.
      • Fagrell B.
      • Ostergren J.
      • Jorneskog G.
      Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      Kalani et al
      • Kalani M.
      • Brismar K.
      • Fagrell B.
      • Ostergren J.
      • Jorneskog G.
      Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.
      estimated that the sensitivity and specificity for TBP were 15% and 97%, respectively, using a cutoff point of 30 mm Hg. The positive predictive value and the negative predictive value were 67% and 77%, respectively. Prochazka et al
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      also found a significant difference on TBP values between the healed group and the nonhealed group (25.63 mm Hg vs 12.43 mm Hg, respectively).

       TBI

      Two studies evaluated TBI.
      • Kalani M.
      • Brismar K.
      • Fagrell B.
      • Ostergren J.
      • Jorneskog G.
      Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      Kalani et al
      • Kalani M.
      • Brismar K.
      • Fagrell B.
      • Ostergren J.
      • Jorneskog G.
      Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.
      found no significant difference between the healed group and the nonhealed group in terms of TBI measurements. Conversely, Prochazka et al
      • Prochazka V.
      • Gumulec J.
      • Jaluvka F.
      • Salounova D.
      • Jonszta T.
      • Czerny D.
      • et al.
      Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.
      reported that patients with healed wounds had higher TBI mean values at baseline than those who did not eventually heal.

       Microvascular Sao2

      One study measured serial microvascular Sao2 of 21 DFUs at the ulcer margin using a spectrophotometer. In healed ulcers, a significant reduction (P < .05) in Sao2 occurred with healing (Sao2 dropped from 58% at initial presentation to 45% just before healing). No such changes were noted on the control sites.
      • Rajbhandari S.M.
      • Harris N.D.
      • Tesfaye S.
      • Ward J.D.
      Early identification of diabetic foot ulcers that may require intervention using the micro lightguide spectrophotometer.
      The study concluded that serial microvascular oxygen measurements may be used to identify at an early stage those ulcers that are unlikely to heal and may require surgical intervention.

       APSV

      Bishara et al
      • Bishara R.A.
      • Taha W.
      • Akladious I.
      • Allam M.A.
      Ankle peak systolic velocity: new parameter to predict nonhealing in diabetic foot lesions.
      evaluated the performance of APSV. Using a sample of 100 limbs, the APSV value was significantly higher in the healed group than in the nonhealed group (53.0 cm/s vs 19.2 cm/s). The sensitivity, specificity, positive predictive value, and negative predictive value were 92.9%, 90.6%, 92.9%, and 90.6%, respectively. The authors concluded that APSV showed high accuracy in predicting the healing of DFUs.

       Hyperspectral imaging

      One study tested hyperspectral imaging of tissue oxyhemoglobin and deoxyhemoglobin in 73 DFUs.
      • Nouvong A.
      • Hoogwerf B.
      • Mohler E.
      • Davis B.
      • Tajaddini A.
      • Medenilla E.
      Evaluation of diabetic foot ulcer healing with hyperspectral imaging of oxyhemoglobin and deoxyhemoglobin.
      Nouvong et al estimated that the sensitivity for healing was 80%, the specificity was 74%, and the positive predictive value was 90%.

       Comparisons of tests

      We were able to pool prognostic performance only for ABI and TcPo2 because of the limited available evidence. As discussed before, TcPo2 more reliably predicted wound healing and limb amputation than ABI. The sensitivity analysis showed TcPo2 with larger standardized coefficients on healed ulcers (b = 0.311) and limb amputation (b = 0.408) than ABI (b = 0.287 and 0.334, respectively), also suggesting a better discriminatory performance of TcPo2 than ABI.

      Discussion

       Main findings

      We conducted a systematic review and meta-analysis to evaluate several available tests to predict wound healing in the setting of DFU and compared the prognostic accuracy of the tests. Eight tests, reported by 37 studies, were included in this study: ABI, APSV, TcPo2, TBI, TBP, microvascular Sao2, SPP, and hyperspectral imaging.
      We found that ABI had poor performance in predicting the healing of foot ulcers and modest performance in predicting limb amputations. TcPo2 was a better test for predicting both outcomes.
      With the limited number of the available studies, we were not able to quantitatively compare the prognostic accuracy of APSV, TBI, TBP, Sao2, SPP, and hyperspectral imaging. Our results are consistent with findings in other studies. A case-controlled study by Reiber et al
      • Reiber G.E.
      • Pecoraro R.E.
      • Koepsell T.D.
      Risk factors for amputation in patients with diabetes mellitus. A case-control study.
      showed transcutaneous oximetry to be the most associated with the risk of amputation in patients with DFU (compared with ankle-arm blood pressure index <0.45, absence of lower leg vibratory perception, and low levels of high-density lipoprotein subfraction 3).
      Our results in the DFU setting are consistent with a systematic review that evaluated transcutaneous oximetry to predict complications of chronic wound healing. It concluded that a periwound level below a cutoff of 20 mm Hg or 30 mm Hg was an independent predictor of chronic wound healing complications (odds ratio, 3.21; 95% CI, 1.07-9.69; I2 = 77%).
      • Arsenault K.A.
      • McDonald J.
      • Devereaux P.J.
      • Thorlund K.
      • Tittley J.G.
      • Whitlock R.P.
      The use of transcutaneous oximetry to predict complications of chronic wound healing: a systematic review and meta-analysis.

       Strengths and limitations

      The strengths of this systematic review include a comprehensive literature search, bias protection methods (reviewing and appraising evidence in duplicates), and both qualitative and quantitative summaries of the evidence. A sensitivity analysis was conducted to provide additional support for the findings.
      There are several limitations to our findings. First, 32 of the 37 included studies were observational ones. The five RCTs were not designed for assessing test performance; thus, the test and comparison groups were not balanced. All 37 studies are subject to high risk of bias due to baseline imbalance and potential outcome confounding. Second, ecologic bias may affect our conclusions (ie, the performance of different tests was compared across different studies, not within the same study). Third, various and arbitrary choices of threshold may exaggerate test performance.
      Thus, using the GRADE framework, the overall quality of this evidence (ie, confidence in the estimates) is low.
      • 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.

       Implications for practice and research

      Although we identified some evidence suggesting that TcPo2 has better prognostic accuracy than ABI in predicting wound healing of DFUs, each test has its own limitations in selected patients. ABI is not accurate when patients present with arterial wall calcification (medial calcinosis); TBI cannot be used to measure a toe when it is affected by ulcers or gangrene or has been amputated; SPP requires a cuff inflation to occlude capillary flow, which may be too painful for some patients and is not widely available. Such limitations along with cost, availability, and training factors need to be considered.

      Conclusions

      Several tests may predict wound healing in the DFU setting; however, most of the available evidence evaluates only TcPo2 and ABI. The overall quality of the evidence is low, and further research is needed to provide higher quality comparative effectiveness evidence.

      Author contributions

      Conception and design: ZW, RH, BF, TE, AT, LP, JM, MM
      Analysis and interpretation: ZW, MM
      Data collection: ZW, RH, BF, TE, AT, LP, MM
      Writing the article: ZW, LP, JM, MM
      Critical revision of the article: ZW, RH, BF, TE, AT, LP, JM, MM
      Final approval of the article: ZW, RH, BF, TE, AT, LP, JM, MM
      Statistical analysis: ZW, 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: tests for prediction of diabetic foot wound healing, limited to randomized and nonrandomized studies.

       Actual search strategy

       Ovid

      Databases: Embase 1988 to 2011 Week 40, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 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
      1((diabetic or diabetes) adj3 (foot or feet)).mp.14923
      2exp Diabetic Foot/11805
      31 or 214923
      4exp Ankle Brachial Index/3560
      5((ankle or toe) adj brachial adj2 (index or indices or ratio)).mp. [mp=ti, ab, sh, hw, tn, ot, dm, mf, dv, kw, ps, rs, nm, ui, tx, ct]7603
      64 or 57603
      7exp transcutaneous oxygen monitoring/1655
      8exp Blood Gas Monitoring, Transcutaneous/3814
      9“transcutaneous partial pressure of oxygen”.mp.111
      10tcpo2.mp.1665
      11hyperspectral imag*.mp.635
      12skin perfusion pressure*.mp.146
      13or/4-1212855
      143 and 13417
      15exp controlled study/3639965
      16exp evidence based medicine/518676
      17evidence-based.mp.175991
      18((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]4669099
      19meta analysis/87758
      20meta-analys$.mp.139569
      21exp “systematic review”/44105
      22systematic review$.mp.98690
      23exp Guideline/ or exp Practice Guideline/271941
      24guideline$.ti.87215
      25or/15-245188997
      26exp case study/1572995
      27exp Cohort Studies/1330764
      28exp longitudinal study/880349
      29exp retrospective study/628418
      30exp prospective study/532053
      31exp observational study/23108
      32exp comparative study/2198791
      33exp clinical trial/1477518
      34exp evaluation/1088304
      35exp twins/39276
      36exp validation study/28010
      37exp 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
      38((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.6826285
      39(“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]154865
      40or/26-3912888282
      4114 and (25 or 40)307
      4214417
      43limit 42 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]106
      4441 or 43311
      45limit 44 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]7
      4644 not 45304
      47from 14 keep 404-41714
      4846 or 47305
      49remove duplicates from 48221

       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((ankle w/1 brachial w/2 index) or (ankle w/1 brachial w/2 indicies) or (ankle w/1 brachial w/2 ratio) or (toe w/1 brachial w/2 index) or (toe w/1 brachial w/2 indicies) or (toe w/1 brachial w/2 ratio) or “transcutaneous partial pressure of oxygen” or (“transcutaneous oxygen” w/3 monitor*) or tcpo2 or “hyperspectral imag*” or “skin perfusion pressure*”)
      • 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

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