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Predicting foot ulcers in patients with diabetes: a systematic review and meta-analysis

F. Crawford, M. Inkster, J. Kleijnen, T. Fahey
DOI: http://dx.doi.org/10.1093/qjmed/hcl140 65-86 First published online: 3 February 2007

Abstract

Clinical guidelines recommend that all patients with diabetes should be screened annually to establish their risk of foot ulceration. The aim of this systematic review was to quantify the predictive value of diagnostic tests, physical signs and elements from the patient's history in relation to diabetic foot ulcers. Observational studies were identified from: electronic databases (MEDLINE, EMBASE and CINAHL); bibliographies of studies meeting the inclusion criteria; review articles and clinical guidelines; direct contact with authors. Published reports of cohort and case-control studies were considered for inclusion. Pooled estimates were calculated from absolute numbers as weighted mean differences, standard mean differences or odds ratios. Adjusted odds ratios from published reports were also extracted. We identified five case-control and 11 cohort studies. The incidence of foot ulcers ranged from 8% to 17% in the cohort studies, with varying lengths of follow-up. Diagnostic tests and physical signs that detect peripheral neuropathy (biothesiometry, monofilaments and absent ankle reflexes), and those that detect excessive plantar pressure (peak plantar pressure and joint deformity) were all significantly associated with future diabetic foot ulceration. However, there was a paucity of evidence concerning the predictive value of symptoms and signs. Further research is needed to establish the independent factors associated with diabetic foot ulceration, particularly elements from a patient's history and physical examination.

Introduction

The prevalence of foot ulceration among patients with diabetes mellitus ranges from 1.3% to 4.8% in the community, to as high as 12% in hospital.1 This represents considerable patient morbidity, and is associated with substantial health-care costs. The pathophysiology of diabetic foot ulceration is multifactorial, but peripheral neuropathy is thought to be responsible for most cases.

To prevent foot ulceration and amputation, clinical guidelines recommend early identification of risk, based on annual foot screening of all diabetic patients, with targeting of preventive and treatment interventions to ‘high risk’ individuals.2–4 Key to this preventive strategy is a structured clinical assessment that incorporates diagnostic tests alongside a thorough history and examination.

Current guidelines have not integrated data from primary studies that relate to the prognostic importance of diagnostic tests, physical signs and patient history (alone or in combination), the indicators that underlie any structured approach to preventive risk stratification in diabetic patients. We therefore undertook a systematic review to determine the predictive values of such features in estimating the risk of diabetic foot ulceration.

Methods

We followed recommended guidance concerning the conduct of systematic reviews.5

Search strategy

Electronic search strategies were used to identify studies which assessed the predictive value of diagnostic tests, signs and symptoms using MEDLINE (1966–February 2005), EMBASE (1980–March 2005), CINAHL1982–February 2005. The electronic search strategy was developed from clinical MeSH headings and text words. The search strategy is available from authors. We searched the bibliographies of included studies, review articles and national clinical guidelines.

Inclusion criteria

(i) Published reports of cohort or case-control studies that evaluated the factors used to predict diabetic foot ulceration. (ii) All study participants free of active foot ulceration at the time of study entry. (iii) All study participants in either study design had a diagnosis of diabetes (either type I or type II). The outcome (reference standard) was foot ulceration.

Definitions and explanations for the predictive factors assessed in the review are presented in Box 1.

Box 1 Descriptions of the index tests used to predict those at risk of diabetic foot ulceration

Graphic

Quality assessment

Assessment of methodological quality was used items adapted from the QUADAS tool, recommendations for methodological standards for clinical prediction rules and a checklist for assessment of the methodological quality both of randomized and non-randomized studies of health-care interventions.6–8 Quality assessment was done independently by two reviewers (FC, MI), and the results were used for descriptive purposes to provide an overall evaluation of the included studies. Disagreements were resolved by discussion, and information not available in the reports was sought from the corresponding authors of the primary study.

Data extraction

Data were extracted from the studies as absolute numbers and as means with SDs to permit the re-calculation of data as weighted or standardized mean differences and 95%CIs. Where data were available, they were re-calculated as pooled estimates of the effect of the predictive factors. All odds ratios and risk ratios presented in the included studies were also extracted from the published reports.

Statistical analyses

Data from the two different study designs are presented separately. We only present estimates of effectiveness where there were two or more reports for individual predictive factors. A complete list of estimates of all predictive factors is available from the authors.

As the review focused on a single outcome (diabetic foot ulceration) groups of patients were categorized into those who ulcerated and those who did not. Continuous outcomes, expressed as means and SDs, were pooled as weighted mean differences (WMD). Peak plantar pressure was measured using different dynamic platform-based equipment systems, and consequently a standardized mean difference (SMD) was used to pool data. Tests for heterogeneity were performed, and where heterogeneity was evident, a random effects model was used.9

Findings are presented using the following structure for potential predictive factors; diagnostic tests, physical signs and patient history.

Results

Characteristics of included studies

After independent assessment by two reviewers, 16 studies were judged to have met all inclusion criteria (Figure 1), with disagreements being resolved by discussion. Details of the study population and aspects of diagnostic tests, physical signs and patient history are presented in Tables 1 and 2. Five studies used a case-control design,10–14 and eleven a cohort design,15–25 (Tables 1 and 2). A conference abstract of unpublished data was also identified by the search.26

View this table:
Table 1

Study interventions and outcomes: case-control studies

Author, year Study design, setting, and sample sizeDiagnostic tests (with thresholds if appropriate)Signs, symptoms and other risk factorsDefinition of ulceration (outcome)
Bennett, 199610Peripheral nerve function assessed using two tests: biothesiometer; and Semmes-Weinstein monofilaments.AgeNot stated.
Sex
Secondary care; diabetic units, Brisbane, AustraliaPeripheral joint flexibility.Duration of diabetes
27 cases, 50 controlsAnkle joint dorsiflexion range of motion, measured with goniometer.Type of diabetes
BMI
Pressure of plantar aspect of foot, measured using a Musgrave Footprint system. Dynamic pressure recordings made of six foot prints with highest and lowest pressure prints discarded and average foot pressure obtained from the remaining four prints.HbA1c
Boulton 198611VPT measured with a biothesiometer (three readings on each side).AgeFoot ulcer was defined as an open lesion that was present below the level of the malleolus.
Secondary care diabetic foot clinic or emergency room, Miami Florida.Duration of diabetes
API was defined as ratio of posterior tibial artery systolic pressure to the brachial systolic pressures and values <0.8 were considered abnormal.BMI
HbA1c
86 cases, 49 controlsLimited joint mobility
Lavery 199812Peripheral sensory neuropathy assessed using vibration perception threshold testing at the distal great toe with a biothesiometer.AgeNot stated.
Sex
Texas diabetes institute, USADuration of diabetes
76 cases, 149 controlsPeripheral vascular disease of lower extremities evaluated using the Rose Intermittent Claudication Scale, the absence of palpable dorsalis pedis and posterior tibial pulses in the foot, transcutaneous oxygen tension on the dorsal aspect of the first intermetatarsal space (<30 mmHg), and the ankle-brachial systolic blood pressure index (<0.8).Diabetes type Education
HbA1c
BMI

Neuropathy
Three measurements of the first metatarsophalangeal joint, the subtalar joint, and ankle joint range of motion were averaged to assess limited joint mobility of the forefoot, rearfoot, and ankle.Previous amputation
Lower extremity bypass
Tobacco use
Evaluation of foot for presence of hallux valgus, toe contractures, subluxation or dislocation of the metatarsophalangeal joints, and prominent metatarsal heads on the sole of the foot.Alcohol abuse
Intermittent claudication
Retinopathy
EMED pressure platform system used to evaluate dynamic barefoot pressures on the sole of the foot. An average of pressures from three midgait steps was used for the purposes of analysis.
McNeely 199513Distal vibratory sensation by vibrating 128 Hz tuning fork. If unable to perceive vibration at any of three sites on either foot, then vibratory sensation was considered absent.% MenFoot ulcer graded as Seattle Wound Class 2.0 through 6.0.
Veterans affairs medical centre USAAge
Caucasian
46 cases, 322 controlsAesthesiometry by Semmes-Weinstein monofilament on eight standardized plantar sites and one mid-dorsal site of each foot. Inability to perceive the 5.07 monofilament at any of the nine sites on either foot was classified as insensate.BMI
Married
Education
Cigarette use
Achilles tendon reflexes were graded as present or absent for each ankle.

Ankle-arm BP index computed as the highest ankle (dorsalis pedis or posterior tibial) BP divided by the highest brachial BP (right or left) for each side.
Alcohol use
Diabetes type
Ankle-arm BP index computed as the highest ankle (dorsalis pedis or posterior tibial) BP divided by the highest brachial BP (right or left) for each side.Current
diabetes
Cutaneous circulation by measuring transcutaneous oxygen tension on mid-dorsum of each foot.treatment
Duration of diabetes
For all variables measured bilaterally, the lower of the two readings (right or left) was used in the analysis.Any formal diabetes education
Random serum glucose
Medical history
Sriussadaporn 199714Ratio of ankle to brachial systolic BP of same side was calculated as ankle-brachial systolic index (ABI).SexFoot ulcers defined as full-thickness disruption
Marital status
55 cases, 110 controlsPeripheral vascular insufficiency was diagnosed when ABI was <0.9. ABI of >1.2 suggested the presence of medial arterial calcification.Religionof skin below mid-calf level with one or more of themore of the following features: duration of the ulcer >14 days, presence of severe infection, necrosis or gangrene.
Living area
Peripheral nerve disorders were diagnosed on basis of short-latency somatosensory evoked potentials (SSEPs) following stimulation of the tibial nerve, recorded by Neuromatic 2000°C.Occupations
EducationDiabetic patients in either group who had a past history of foot ulcer as defined by above criteria, lower limb amputation, chronic venous ulcer, cerebrovascular disease, or spinal cord disease were not included in this study.
Economic status
Two questionnaires used to evaluate patients' knowledge of diabetes and foot-care behaviour.Smoking
Alcohol consumption
Diabetes duration
BMI
BP
Visual acuity
Diabetic knowledge score
Foot-care score
View this table:
Table 2

Study interventions and outcomes: cohort studies

Author, year Study setting, duration and sample sizeDiagnostic tests (with thresholds if appropriate)Signs, symptoms and other risk factorsDefinition of ulceration (outcome)Incidence of ulceration
Armstrong 200415Daily activity accelerometer/pedometer (measures the number of steps taken over a period of time, and records the time of day each step taken).Age 68.5 (10)Not stated8/100 (8%).
Texas, USASex 95.0
Duration = mean follow-up 37.1 (12.3) weeksDuration of diabetes 13.7 (9.3)
n = 100VPT meter threshold >25 V defined as neuropathyFoot risk category 68/32
BMI 30.0 (3.0)
Boyko 199916Sensory testing performed at nine locations on each foot using Semmes-Weinstein monofilament. Inability to detect 10 g monofilamentWeightFoot ulcer was defined as a full-thickness skin defect that required >14 days to heal.162 ulcers developed over 5442.6 cumulative person-years (3.0/100 person-years).
Ambulatory general internal medicine clinic patients at a veterans affairs medical centre Seattle, USAHeight
Diabetes duration
Vibration sensation measured using a 128 Hz tuning fork. VPT graded present/absent.Type 2 diabetes
Insulin useOutcome was defined as the first ulcer occurrence on the foot.
Duration not reportedCardiovascular autonomic neuropathy: mean heart rate variability on a continuous electrocardiogram, and immediate systolic BP response to standing from a supine position.Random glucose
n= 900HbA1cFollow-up on both limbs was terminated when the first ulcer occurred on either during the follow-up period.
Erythrocyte sedimentation rate
Lower-limb transcutaneous O2 tension with TCM-3 monitors. TC PO2 flow measure in perfusion unitsSerum creatinine
TcPO2 dorsal foot
Laser Doppler flowmetry on dorsal foot.Claudication <1 block
Standard Doppler techniques for brachial and lower-limb arterial BP. BP measured in mmHg.Peripheral vascular disease.
History of laser photocoagulation treatment
Hallux BP measured using a penile cuff and hand-held Doppler.Vision <20/40
History of ulceration
Random blood sample for plasma glucose (glucose oxidase method), serum creatinine and erythrocyte sedimentation rate.Previous amputation
Foot numbness and pain
Kastenbauer 200117X-ray taken of both feet to assess bone deformities and calcification of the media.SexFoot ulcers defined as full-thickness neuropathic plantar or lateral forefoot ulcerations penetrating the cutis and subcutis.18 forefoot ulcerations in 10 patients out of a total of 187 patients.
Diabetes centre at the third medical department, Hospital Lainz, Vienna, AustriaAge
Diabetes duration
Questionnaire for evaluating symptoms of peripheral neuropathy.Insulin use
Duration = 4 yearsHbA1c
n = 187Peripheral nerve conduction velocity, cardiorespiratory reflexes and orthostatic drop of systolic BP measured.Serum creatinine
Body weight
PVD determined using palpability of foot pulses and ankle-arm index.BMI
History of MI
VPT measured using a biothesiometer three times at the pulp of both great toes.History of angiography
Smoking
Perception of 10 g monofilament tested at eight plantar sites on each foot: insensate to 2/8 regarded as abnormal.Daily alcohol intake
Lavery 200318Lower extremity sensory examination using 10 g Semmes-Weinstein monofilament. Abnormality defined as inability to detect 10 sites evaluated with monofilament on each footAgeNot stated.263 patients (15.8%) developed an ulcer during 24 months follow-up.
In-patient and out-patient clinics in Texas, USA%Male
Weight
Duration = 2 yearsDuration of diabetes
n = 1666VPT using biothesiometer, abnormal reading >25 V.
Lower-extremity vascular status assessed by palpitating dorsalis pedis and posterior tibial pulses.
Peak foot pressures assessed using Novel EMED force-plate gait analysis system.
Litzelman 199719Lower-extremity oedema assessed by pressing thumb over pretibial area for 5 s.RaceResponse variable was the existence of any foot wound at time of follow-up assessment.63/704 (8.9%)
Primary care, Indiana USA.%Women
Duration = 1 yearSensortek Thermal Sensitivity Testing apparatus and Semmes-Weinstein monofilament used as objective measures of neuropathy.Age
n = 352Annual income

<$10 000
Thermal sensation was defined as abnormal if detection of temperature change from a reference of 25°C was >2 SDs from the mean sensitivity threshold for a group of healthy people without diabetes.Education level (years)Rated using the Seattle Wound Classification System, which ranges from a grade 1.1, signifying absence of lesions, to grade 10, where the entire foot or leg is gangrenous.
BMI
Duration of diabetes
Touch pressure sensation tested with a single 10 g Semmes-Weinstein monofilament.Taking insulin
Taking oral hypoglycaemic agents.
Abnormal pressure anaesthesiometry, defined as the absence of sensation at one or more of three sites tested on the plantar surface of each foot.Outcome was then dichotomized and separately analysed at two thresholds of severity.
Murray 199620Neuropathy deficit score: sensations of pain, light touch, vibration and cold tested in both lower limbs and scored to the level up to which sensation was impaired.MaleUlcers were classed as intrinsic if they occurred on the plantar surface of the foot and were not associated with external trauma, extrinsic if they occurred as a result of shoe pressure or trauma (typically dorsal). Only intrinsic ulcers were considered in the analysis.Seven intrinsic plantar ulcers documented in six patients.
Age
Secondary care diabetes centre and Manchester Foot Hospital, UKType 1 DM
Duration = not reportedVPT measured at both great toes by biothesiometer and compared with age-matched ‘normal’ measurements. Mean of three measurements used for each great toe.Duration of diabetes
n = 63History of intrinsic ulcers
Foot pressures measured using a dynamic optical pedobarograph.Total of 63 patients in study.
Peters 200121Plantar peak pressures measured with NovelAgeUlcers were defined as skin lesions distal to the ankle.54 follow-up ulcers. Unclear from paper if this was in 213 patients or if analysis was based on the number of feet.
Texas Health Science Center, San Antonio, USAEMED-SF platform system (average of three steps used for analysis). Elevated plantar pressures defined as a peak plantar pressure of >70 N/cm2.Diabetes duration
Follow-up
Duration = 3.5 yearsBMI
n = 213Several vascular parameters evaluated: TcPO2 <40 mmHg, probe temp. of 45°C; ABI of <0.8; absence of dorsal pedal and posterior tibial artery pulsations; incompressibility of pedal arteries (ABI >1.2).HbA1c
Female
Type 2 diabetes
Previous or present drinke
PVD defined as ABI <0.8 or any non-palpable pedal pulsation.Present or previous tobacco use
VPT measured with biothesiometer, voltage of >25 V defined as loss of protective sensation.Nephropathy
Retinopathy
10 g SWM applied to 10 areas of foot, impaired sensation defined as one or more unnoticed pinpricks with SWM or VPT of >25 V.HbA1c > 9%Subjects who received an amputation as a direct result of their initial ulceration were disqualified from further analysis.
Amputation history
Joint mobility assessed by averaging three measurements from first metatarsal phalangeal joint, subtalar joint and ankle.
CAGE questionnaire
Pham 200022Neuropathy symptom score NSS assessed by: patient questioned about nocturnal cramps, numbness, abnormal temperature sensation, burning, aching pain, irritation from bed clothes.AgeNot stated95 feet (19%). 73 patients (29%). 22 (9%) developed bilateral ulcers.
Multi centre study.Primary foot care clinic, Israel. Primary foot care clinicSex
BMI
Massachusetts, USA. University of Texas Health Science Center, San Antonio, Texas. California College of podiatric Medicine, San Francisco, USA.Neuropathic disability score based on examination of tendon reflexes and sensory modalities (pin prick, light touch, temperature perception) all at different levels in the lower limb (toes, midfoot, heel and lower leg).Duration of diabetes
Duration = follow-up 30 months
n = 248Vibration perception threshold measured using a biothesiometer.History of foot amputation
8 SWF monofilaments (1g to 100 g) used at the plantar aspect of the hallux.Type of diabetes
Maximal plantar foot pressure. F scan mat system, measuring dynamic pressure.
Peripheral vascular disease (PVD) based on absent foot pulses.
Rith-Najarian 199223Sensation status determined by applying the 5.07 monofilament to eight points on the plantar surface of each foot at time A or time B when the patient was blinded. Patients who failed to perceive the monofilament on one or more areas of either foot were retested twice before they were classified as insensate.AgeUlcerations were defined as any full thickness penetration of the dermis on the plantar aspect of the foot.41 ulcers from 358 patients (11.5%)
Primary care, Minnesota, USADuration of diabetes
Duration = 3 yearsSex
n = 358
Subset of patients had AAI calculated from measurements of right brachial artery and both posterior tibial arteries, obtained with a mercury manometer and a 2 MHz portable Doppler.
Veves 199224Neuropathy deficit score (NDS) used to diagnose neuropathy, based on reduced or absent ankle reflexes and reduced or absent sensation to pain, touch and vibration.AgeUlcers were classified as plantar when they occurred on plantar surface of foot and as dorsal if they occurred anywhere else on the foot15/86 with plantar ulceration and high pressures at baseline (17.4%)
Secondary care; clinics at diabetes centre, Manchester, UK.Gender
Diabetes type
Duration = 30 monthsFoot pressures measured by optical pedobarography. Peak pressures >12.3 kg/cm2 considered abnormal.Duration of diabetes
n = 86VPT measured at the great toe by biothesiometry. Upper threshold of normality was taken from established data based on measurements of a large number of healthy subjects.
Young 199425VPT was assessed by biothesiometry. Mean of three readings used to derive the value for each foot.SexNot stated.First ulcers = 8/469 patients (10.2%)
Secondary care, diabetes centre and foot clinic Manchester,Age
Diabetes type
UK Duration = 4 yearsDuration of diabetes
n = 469HbA1c
Creatinine
Figure 1.

Flow diagram of studies in the review.

Data from nine studies were available to calculate pooled estimates.10–14,16–18,,22 The incidence of foot ulceration developed by patients in cohort studies ranged from 8% to 17%, but with lengths of follow-up varying from 12 weeks to 4 years (Table 2).

Quality assessment (Tables 3 and 4)

Case-control studies

All five studies used statistical methods to adjust for confounding factors in the analysis (Table 1).10–14 In two studies, insufficient detail was given about the index tests to permit the presentation of data.12,,13

View this table:
Table 3

Case-control studies: quality assessment

Authors …Bennett 199610Boulton 198611Lavery 199812McNeeley 199513Sriussadaporn 199714
Hypothesis clearly defined?YYYYY
Patient characteristics clearly described?YYYYY
Predictive factors clearly described?YYYYY
Main outcome measure defined?YYYYY
Patients selected consecutively?NCNCYYNC
Patients representative of those who receive the test in practice?YYYYY
Context representative of the treatment majority of patients receive?YYYYY
Index tests (PF) reproducible?YNNNY
Adjustment made for confounders?YYYYY
Same clinical data available when test results (PF) interpreted?YYYYY
Assessment of outcome blind to the results of the index test (PF)?NANAYNANA
Uninterpretable/intermediate test results (PF) reported?NNNANN
Sample size adequate for number of outcome events?YYYYY
Statistical tests for main outcomes adequate?YYYYY
Study sought to measure and report adverse events?NNNNN
View this table:
Table 4

Cohort studies: quality assessment

Authors …Armstrong 200415Boyko 199916Kastenbauer 200117Lavery 200318Litzelman 199719Murray 199620Peters 200121Pham 200022Rith-Najarian 199223Veves 199224Young 199425
Hypothesis clearly defined?YYYYYYYYYYY
Patient characteristics clearly described?YYYYYYYYYYY
Predictive factors clearly described?YYYYYYYYYYY
Main outcome measure defined?YYYNYYYNYNN
Patients selected consecutively?YYYYNANCYYYNY
Patients representative of those who receive the test in practice?YYYYYYYYYYY
Whole sample or random selection of the sample's outcome verified?YNYYNYYYYYY
Characteristics of the patients lost to follow-up described?NANNNANNCNNNYNA
Context representative of the treatment majority of patients receive?YYYYYYYYYYY
Index tests (PF) reproducible?YNNYYYNYNYY
Treatment given between index tests and outcome?YYYYYYYYNYY
Adjustment made for confounders?NYNNCYNNYNNY
Length of follow-up the same for all participants?YNNYYNNNNNNC
Same clinical data available when test results (PF) interpreted?YYYYYYYYYYY
Assessment of outcome blind to the results of the index test (PF)?NCNAYNANCNNYNNNC
Uninterpretable/intermediate test results (PF) reported?NNNNNNNCNNNNC
Withdrawals for the study explained?NANYNANNANCYNYNA
Sample size adequate for number of outcome events?YYYYYYYYYYY
Statistical tests for main outcomes adequate?NYYYYNNYNNY
Study sought to measure and report adverse events?NNNNNNNNNNN

Cohort studies

Seven studies reported adjusted estimates for potential confounding factors (Table 2).15–17,19,21,22,,25 Patients received treatment between the index tests and the outcome (assessment of foot ulceration) in all except one study.23

Quantitative estimates concerning the predictive value of diagnostic tests, patient history, symptoms and signs

Unadjusted and adjusted estimates of effect of all predictive factors—diagnostic tests, physical signs and patient history—are summarized in Table 5. Pooled estimates (weighted and standardized mean differences) concerning the predictive value of diagnostic tests (peak plantar pressures, vibration perception threshold and HbA1c) and the duration of diabetes are presented in Figure 2.

View this table:
Table 5

Summary of pooled estimates for predictive value of diagnostic tests, physical signs and patient history in relation to diabetic foot ulceration

Pooled estimates WMD/SMD (95%CI)Unadjusted risk/OR (95%CI)Adjusted risk/OR (95%CI)
Case-controlCohortCase-controlCohort**Case-controlCohort**
Diagnostic tests
Peak plantar pressure10,12,17,18,20,22 (kg/cm2 or N/cm2)SMD 0.98 (0.63–1.33)10,12SMD 0.47 (0.24–0.70)18,203.6 (p < 0.001)123.2 (2.0–5.1)224.8 kg/cm2 (1.44–16.3)106.3 (1.2–32.7)*17
4.7 (1.2–18.9)*205.9 (p < 0.001)122 (1.4–2.9)18
2.0 kg/cm2 (1.2–3.3)22
Vibration perception threshold10–13,16,17,22,25WMD 20.00 (11.81–28.20)10,12WMD 17.07 (13.89–20.26)17,2210.77 (4.59–25.73)118.2 (7.4–18.4)224.9 (1.0–24.0)1025.4 (3.1–205)*17
32.5 (p < 0.001)127.99 (3.65–17.5)2515.2 (p < 0.001)123.4 (1.7–6.8)22
7.38 (2.52–21.66)132.33 (1.66–3.28)1618.42 (3.83–88.47)136.82 (2.75–16.92)25
Transcutaneous oxygen tension <30 mmHg12,13,181.1 (p = 0.85) 121.35 (1.18–1.56)*1657.87 (5.08–658.9)131.25 (1.08–1.45)*16
26.9 (3.03–218.99)13
HbA1c10–12,14–16,190.95 (−0.33 to 2.23)10,11,12,14,1 (0.46–1.5)163.0 (p < 0.001)121.26 (1.11–1.43)*161.69 (0.96 to 2.99)10
2.99 (0.49–8.99) 141.08 (0.94–1.24)193.2 (p < 0.03)12
Fasting blood glucose14,19 (mmol increase)1.00 (1.00 to1.00)191.01 (1.00–1.02)14
Ankle brachial index11,13,161.16 (0.40–3.33)131.25 (1.05–1.47)*161.20 (1.04–1.37)*16
2.84 (p = 0.08)11
Serum creatinine16,191.16 (1.04–1.29)*16
Physical signs
Monofilament (SWF)13,16,19,21–239.99 (3.50–28.49)133.37 (2.45–4.63)*162.17 (52–3.08)*17
5.46 (2.39–12.45)195.23 (2.26–12.13)19
5.4 (2.6–11.6)2233.2 (5.6–181.6)21
9.9 (4.8–21.0)242.4 (1.1–5.3)22
Visual acuity <20/2014 (<20/40)162.31 (1.72–3.09)*160.223 per unit decrease in decimal visual acuity (0.005–0.39)141.93 (1.42–2.63)*16
Lower limb oedema16,191.52 (1.12–2.06)*16
0.88 (0.37–2.10)19
Absent reflexes13,164.58 (2.11–9.94)131.40 (1.03–1.90)*166.48 (2.37–18.06)13
Limited subtalar joint motion12,22 (ROM degrees)2.1 (p < 0.009)121.03 (1.00–1.05)22
Limited 1st metatarsal-phalangeal motion11,12,16,223.57 (1.71–7.46)111.30 (1.11–1.54)*16
(ROM degrees)4.6 (p < 0.001)121.05 (1.01–1.03)22
Patient history
Gender12,225.7 (p < 0.001)122.27 (1.43–3.70)222.7 (p < 0.05)12
Duration of diabetes10–14,16,222.62 (−0.75 to 5.99)10–141.0 (0.57–1.62)161.18 (1.05–1.32)*161.0 (0.97–1.06)10
1.03 (1.00–1.05)223.0 (<0.04)12
Alcohol use12,171.8 (p = 0.19)125.1 (1.1–24.0)*17
Previous ulceration16,20–222.46 (1.84–3.29)*161.63 (1.17–2.26)*16
5.11 (3.17–8.24)224.2 (1.1–16.7) 21
56.8 (13.4–241.2)*20
Previous amputation12,1640.5 (p < 0.001)123.99 (2.71–5.87)*1610.0 (p < 0.02)122.81(1.84–4.29)*16
Lower limb bypass12,163.0 (p < 0.04)122.51 (1.53–4.10)*16
  • *Data reported as relative risk rather than odds ratio in these cohort studies. **Reciprocal of relative risk reported in some cohort studies, so that reference category remained consistent for all comparisons. WMD, weighted mean differences; SMD, standardized mean differences; –, pooled estimate not calculated.

Figure 2.

Forest plots of pooled data for the predictive value of a peak plantar pressure, b vibration perception threshold, c HbA1c and d duration of diabetes, for foot ulceration in diabetes. Continues overleaf.

Diagnostic tests

Peak plantar pressures (Figure 2a, Table 5)

Two case-control studies and four cohort studies measured peak plantar pressure, using four different dynamic measuring systems (Musgrave,10 F-scan,22 EMED12,18,,21 and a pedobarograph20,,24). High plantar pressures constitute a risk of ulceration: SMD 0.98 N/cm2 (95%CI 0.63–1.33)10,,12 for case-control studies, and SMD 0.47 N/cm2 (95%CI 0.24–0.70) for cohort studies.18,,22

Vibration perception threshold (VPT) (Figure 2b, Table 5)

Four case-control10–13 and six cohort studies16,17,20–22,,25 found patients with foot ulcerations to have significantly higher VPT than those who did not: WMD 20.00 V (95%CI 11.81–28.20)10,,12 for case-control studies and WMD 17.07 V (95%CI 13.89–20.26)17,,22 for cohort studies.

Transcutaneous oxygen tension (Table 5)

Two case-control studies and one cohort study categorized patient measurements into groups (⩽30 mmHg and 31–60 mmHg). Transcutaneous pO2 ⩽ 30 mmHg was more strongly associated with the development of a foot ulcer, compared with pO2 31–60 mmHg.12,,13,16

HbA1c (Figure 2c, Table 5)

In pooled results from four case-control studies, patients who developed foot ulcers had higher levels of HbA1c than those who did not, but the effect did not reach statistical significance: WMD 0.95% (95%CI −0.33 to 2.23).10–12,,14 Data from one cohort study did demonstrate a statistically significant effect: WMD 1.1% (95%CI 0.57–1.61).16

Ankle brachial indices (ABI) (Table 5)

Four cohort16,17,21,,23 and four case control studies11–14 measured blood pressure at the ankle and arm. Only one cohort study found an effect which remained evident after an adjustment for confounding.16

Fasting blood glucose and serum creatinine (Table 5)

There was inconsistent evidence that increasing levels of blood sugar (mmol/l)14,,19 and creatinine (μmol/l) were associated with increased risk of ulceration.16,,19

Physical signs

Cutaneous sensation (monofilaments) (Table 5)

One case-control study and five cohort studies all found statistically significant differences in the rate of foot ulceration between people whose feet were insensate to ⩽5.07 monofilaments (⩽10 g pressure) and those who were not, with ORs ranging from 2 to 10.13,16,19,21–23

Absent ankle reflexes (Table 5)

Absent ankle reflexes were predictive of a higher risk of foot ulceration in one case-control13 and one cohort study,16 with unadjusted ORs of 4.9 and 1.4, respectively.

Visual acuity (Table 5)

Patients with lower mean visual acuity were at greater risk of foot ulceration in one case-control and one cohort study (adjusted RR 1.9).14,,16

Patient history

Duration of diabetes (Figure 2d, Table 5)

In five case-control studies, patients who developed foot ulcers had diabetes for longer than those who did not, but this effect was not statistically significant: WMD 2.62 (95%CI −0.75 to 5.99).10–14 Combined data from two cohort studies did find a statistically significant effect: WMD 1.88 (95%CI 0.48–3.28).16,,22

History of foot ulceration, amputation and history of lower limb bypass (Table 5)

In four cohort studies investigating the risk associated with a history of foot ulceration,16,20–22 patients who had previous ulceration were more likely to develop diabetic foot ulcers (adjusted ORs ranging from 1.6 to 4.2). One case-control study and one cohort study found a history of amputation to be a risk factor for foot ulceration.12,,16 These two studies also found that a history of lower limb bypass operation predicted future foot ulceration.

Discussion

Summary of findings

We found evidence to support the use of diagnostic tests and physical signs that detect peripheral neuropathy, the principal cause of diabetic foot ulceration. High vibration perception thresholds (VPTs) using a biothesiometer or a tuning fork, high plantar pressure and 10 g monofilaments appear reliable methods to identify those at risk of future ulceration. Absent ankle reflexes, and limited joint motion at both the first metatarsal-phalangeal joint and the subtalar joint were also found to increase the risk of foot ulceration. These findings were evident across different study designs, pooled, unadjusted and adjusted estimates of effect. Established vascular disease, in the form of a history of previous amputation, ulceration or lower limb bypass procedures, was also consistently associated with risk of future ulceration.

None of the published studies reported on the predictive value of signs associated with foot trauma, such as inappropriate footwear and improperly cut toenails.

Evidence concerning the predictive value of ‘contributory’ factors in diabetic foot ulceration, such as some physical signs and elements from the patient's history, was less clear. For example, HbA1c and ankle brachial indices (ABI, ABPI, or AAI) produced inconsistent and contradictory findings (Table 5). The length of time that a person had diabetes was marginally predictive in two cohort studies,16,,22 although in five methodologically weaker case-control studies, the association was not statistically significant.10–14

Shortcomings of this review

Synthesized evidence from this review does support the predictive value of most conventional diagnostic tests used to assess the risk of foot ulceration in people with diabetes. However, only a minority of primary studies assessed the independent predictive value of diagnostic tests in addition to physical signs and elements from a patient's history. Furthermore, different cut-points have been used for many of the diagnostic tests, making comparisons between studies difficult. Some diagnostic tests require a standardized procedure when being carried out. For example, ankle brachial index studies (ABI, ABPI, or AAI) were difficult to interpret because of the lack of detail disclosed as to the position of the patient when blood pressure was measured. Ankle systolic pressure is affected by posture; 1 mmHg higher for each inch the ankle is below the heart.27 This detail was missing from three case-control and four cohort studies, and prevented us from pooling data. Only one cohort study found <0.8 ABI to be predictive of future ulcer risk.16 The value of this procedure in that ulceration risk assessment is yet to be established.

The review included studies that assessed multiple potential predictive factors, and there is a risk of false positive findings in the estimates reported from the primary studies.28 The pooled estimates of nearly all predictive factors showed evidence of significant heterogeneity. This is a consequence of the different and varied definitions for some of the predictive factors, that different cut-points were used, different methods with ascertaining diabetic ulceration and different lengths of follow-up (Tables 1 and 2). Standardizing diagnostic tests and the cut-offs used would be helpful for both research and practice.

Context of other studies

A previous systematic review assessing some of the methods advocated for preventing diabetic foot ulceration suggested that monofilaments, biothesiometer, tuning fork and peak plantar pressure were useful screening tests.29 Our results are consistent with these findings. We also identified eight additional studies that have provided more evidence of the predictive value of tests, and a more integrated approach has permitted data to be pooled.

National and international clinical guidelines also suggest that previous foot amputation and foot ulceration are useful criteria for the identification of patients at ‘high risk’ of foot ulceration.2–4 These guidelines are supported by the findings from this systematic review. However, some recommendations in clinical guidelines do not appear to be based on any firm evidence. For example, we could find no convincing data to support that ‘absent leg or pedal pulses’ is a risk factor for diabetic foot ulceration, despite the suggestion that this clinical sign is a key indicator of risk.3,,4 Few studies adopted a comprehensive approach to the evaluation of predictive factors, and some variables that could predispose to foot ulceration, such as levels of exercise, the presence of callus, Charcot deformity or adequate footwear, have not been subject to extensive evaluation. There is a clear need for further research to address these clinical uncertainties.

Generalizability of findings

The incidence of foot ulcerations in the cohort studies varied from 8% to 17% (Table 2). These are much higher levels of ulceration than those cited in UK national clinical guidelines (5–7%), diabetes text books (7%) and in a national survey (5%).3,.4,.30,.31 This observed difference in incidence may imply that patients included in the studies had more severe disease than those in the general diabetic population. Most of these patients were recruited from hospital diabetes clinics and dedicated foot clinics.

Future studies

Future observational studies need to include the characteristics of patients who were lost to follow-up, and should also attempt to explain the reasons for patients’ withdrawal from studies. None of the sixteen studies included in the review measured adverse events from any of the diagnostic tests evaluated.

The predictive value of relatively simple clinical signs such as the presence or absence of leg and pedal pulses, skin colour, skin texture, hairlessness of the lower legs and condition of the toenails are not known. Clinical signs are potentially more cost-effective than more complex diagnostic tests, and are more feasible in community settings. Given that there are quite marked differences in cost between different tests, any new evidence about cost-effectiveness would deserve consideration. A diagnostic rule, based on elements of the clinical history, examination and available diagnostic tests needs to be developed, validated and tested to establish the effectiveness and cost-effectiveness of using such an approach when assessing the risk of diabetic foot ulceration in community settings.32

Conclusions

Diagnostic tests and clinical signs are helpful in predicting the risk of diabetic foot ulceration. Evidence concerning the predictive value of simpler elements from the clinical history and examination is less clear. Future studies should assess the independent predictive value of all elements of patient history, physical signs and diagnostic tests when assessing the risk of diabetic foot ulceration.

Acknowledgements

The authors thank Ms Julie Glanville, the Centre for Reviews and Dissemination at the University of York and Mr Donald Orrock, Ninewells Hospital Library at the University of Dundee, for their help with the development of the electronic search strategies. Also Professors Armstrong, Boyko, Boulton, Kastenbauer, Rith Najarian and Veves, who provided additional information about the primary studies. Fay Crawford and Melanie Inkster are funded by the Chief Scientist Office, The Scottish Executive, Edinburgh.

References

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