Caroline McIntosh

Review Paper: Basic Concepts to Novel Therapies: A Review of the Diabetic Foot:

Diabetes mellitus is a global epidemic. Peripheral neuropathy and peripheral vascular disease are complications of diabetes mellitus and the primary causative factors for foot ulceration. Foot ulceration is the leading cause of hospitalization in people with diabetes mellitus. The burden of foot ulceration on health care systems and individual patients is immense. Despite conventional treatment, there persists a high incidence of amputation. A multidisciplinary approach is required to prevent ulcers. This review describes the etiology and risk factors for diabetic foot ulceration and a system for evaluating the diabetic foot. The assessment of neuropathy and the grading of foot ulcers are critically examined. This is important to allow for standardization in clinical trials. The management of diabetic foot syndrome is reviewed. The treatments to ensure vascular supply to the lower limb and control of infection as well as novel therapies, which are becoming available to treat nonhealing, “no-option” diabetic ulcers, are discussed.

Cryotherapy versus salicylic acid for the treatment of plantar warts (verrucae): a randomised controlled trial.

Objective To compare the clinical effectiveness of cryotherapy versus salicylic acid for the treatment of plantar warts. Design A multicentre, open, two arm randomised controlled trial. Setting University podiatry school clinics, NHS podiatry clinics, and primary care in England, Scotland, and Ireland. Participants 240 patients aged 12 years and over, with a plantar wart that in the opinion of the healthcare professional was suitable for treatment with both cryotherapy and salicylic acid. Interventions Cryotherapy with liquid nitrogen delivered by a healthcare professional, up to four treatments two to three weeks apart. Patient self treatment with 50% salicylic acid (Verrugon) daily up to a maximum of eight weeks. Main outcome measures Complete clearance of all plantar warts at 12 weeks. Secondary outcomes were (a) complete clearance of all plantar warts at 12 weeks controlling for age, whether the wart had been treated previously, and type of wart, (b) patient self reported clearance of plantar warts at six months, (c) time to clearance of plantar wart, (d) number of plantar warts at 12 weeks, and (e) patient satisfaction with the treatment. Results There was no evidence of a difference between the salicylic acid and cryotherapy groups in the proportions of participants with complete clearance of all plantar warts at 12 weeks (17/119 (14%) v 15/110 (14%), difference 0.65% (95% CI –8.33 to 9.63), P=0.89). The results did not change when the analysis was repeated but with adjustment for age, whether the wart had been treated previously, and type of plantar wart or for patients’ preferences at baseline. There was no evidence of a difference between the salicylic acid and cryotherapy groups in self reported clearance of plantar warts at six months (29/95 (31%) v 33/98 (34%), difference –3.15% (–16.31 to 10.02), P=0.64) or in time to clearance (hazard ratio 0.80 (95% CI 0.51 to 1.25), P=0.33). There was also no evidence of a difference in the number of plantar warts at 12 weeks (incident rate ratio 1.08 (0.81 to 1.43), P=0.62). Conclusions Salicylic acid and the cryotherapy were equally effective for clearance of plantar warts. Trial registration Current Controlled Trials ISRCTN18994246, National Research Register N0484189151.

EVerT: cryotherapy versus salicylic acid for the treatment of verrucae – a randomised controlled trial

OBJECTIVE To compare the clinical effectiveness and cost-effectiveness of cryotherapy using liquid nitrogen versus patient daily self-treatment with 50% salicylic acid for the treatment of verrucae (plantar warts). DESIGN A multicentre, pragmatic, open, two-armed randomised controlled trial with an economic evaluation. Randomisation was simple, with the allocation sequence generated by a computer in a 1 : 1 ratio. SETTING Podiatry clinics, university podiatry schools and primary care in England, Scotland and Ireland. PARTICIPANTS Patients were eligible if they presented with a verruca which, in the opinion of the health-care professional, was suitable for treatment with both salicylic acid and cryotherapy, and were aged 12 years and over. INTERVENTIONS Cryotherapy using liquid nitrogen delivered by a health-care professional compared with daily patient self-treatment with 50% salicylic acid (Verrugon, William Ransom & Son Plc, Hitchin, UK) for a maximum of 8 weeks. MAIN OUTCOME MEASURES The primary outcome was complete clearance of all verrucae at 12 weeks. Secondary outcomes were complete clearance of all verrucae at 12 weeks, controlling for age, whether or not the verrucae had been previously treated and type of verrucae, with a second model to explore the effect of patient preferences, time to clearance of verrucae, clearance of verrucae at 6 months, number of verrucae at 12 weeks and patient satisfaction with the treatment. RESULTS In total, 240 eligible patients were recruited, with 117 patients allocated to the cryotherapy group and 123 to the salicylic acid group. There was no evidence of a difference in clearance rates between the treatment groups in the primary outcome [17/119 (14.3%) in the salicylic acid group vs 15/110 (13.6%) in the cryotherapy group; p = 0.89]. The results of the study did not change when controlled for age, whether or not the verrucae had been previously treated and type of verrucae, or when patient preferences were explored. There was no evidence of a difference in time to clearance of verrucae between the two groups [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.51 to 1.25; p = 0.33] or in the clearance of verrucae at 6 months (33.7% cryotherapy vs 30.5% salicylic acid). There was no evidence of a difference in the number of verrucae at 12 weeks between the two groups (incidence rate ratio 1.08, 95% CI 0.81 to 1.43; p = 0.62). Nineteen participants reported 28 adverse events, 14 in each group, with two treatment-related non-serious adverse events in the cryotherapy group. Cryotherapy was also associated with higher mean costs per additional healed patient (£101.17, 95% bias-corrected and accelerated CI £85.09 to £117.26). The probability of cryotherapy being cost-effective is 40% for a range of willingness-to-pay thresholds of £15,000-30,000 per patient healed. CONCLUSIONS There is no evidence for a difference in terms of clearance of verrucae between cryotherapy and salicylic acid (at both 12 weeks and 6 months), number of verrucae at 12 weeks and time to clearance of verrucae. Cryotherapy was associated with higher mean costs per additional healed patient compared with salicylic acid. TRIAL REGISTRATION Current Controlled Trials ISRCTN18994246. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 32. See the HTA programme website for further project information.

Lower Extremity Wounds

Foreword (David Gray). Introduction (Karen Ousey and Caroline McIntosh). 1 The Need for a Multiprofessional Approach in Wound Care (Caroline McIntosh and Karen Ousey). 2 Physiology of Wound Healing (Karen Ousey and Caroline McIntosh). 3 Skin Changes in the At-Risk Limb (Caroline McIntosh and Kimberley Martin). 4 Infected Wounds (Nicoletta Frescos and Tabatha Rando). 5 Leg Ulcers (Adrienne Taylor). 6 Surgical Wounds (Jacqui Fletcher). 7 Pressure Ulcers (Karen Ousey and Caroline McIntosh). 8 Diabetic Foot Ulcers (Caroline McIntosh and Veronica Newton). 9 Foot Ulceration in Rheumatoid Arthritis (Deborah Turner, Jill Firth and Heidi Davys). 10 Nail Surgery Wounds (Caroline McIntosh and Steve Hancox). Editor and Author Biographies. Index.

A prospective study of risk factors for foot ulceration: The West of Ireland Diabetes Foot Study

BACKGROUND This is the first study to examine risk factors for diabetic foot ulceration in Irish general practice. AIM To determine the prevalence of established risk factors for foot ulceration in a community-based cohort, and to explore the potential for estimated glomerular filtration rate (eGFR) to act as a novel risk factor. DESIGN A prospective observational study. METHODS Patients with diabetes attending 12 (of 17) invited general practices were invited for foot screening. Validated clinical tests were carried out at baseline to assess for vascular and sensory impairment and foot deformity. Ulcer incidence was ascertained by patient self-report and medical record. Patients were re-assessed 18 months later. RESULTS Of 828 invitees, 563 (68%) attended screening. On examination 23-25% had sensory dysfunction and 18-39% had evidence of vascular impairment. Using the Scottish Intercollegiate Guidelines Network risk stratification system we found the proportion at moderate and high risk of future ulceration to be 25% and 11%, respectively. At follow-up 16/383 patients (4.2%) developed a new foot ulcer (annual incidence rate of 2.6%). We observed an increasing probability of abnormal vascular and sensory test results (pedal pulse palpation, doppler waveform assessment, 10 g monofilament, vibration perception and neuropathy disability score) with declining eGFR levels. We were unable to show an independent association between new ulceration and reduced eGFR [Odds ratio 1.01; P = 0.64]. CONCLUSION Our data show the extent of foot complications in a representative sample of diabetes patients in Ireland. Use of eGFR did not improve identification of patients at risk of foot ulceration.

The REFORM study protocol: a cohort randomised controlled trial of a multifaceted podiatry intervention for the prevention of falls in older people.

Introduction Falls and fall-related injuries are a serious cause of morbidity and cost to society. Foot problems and inappropriate footwear may increase the risk of falls; therefore podiatric interventions may play a role in reducing falls. Two Cochrane systematic reviews identified only one study of a podiatry intervention aimed to reduce falls, which was undertaken in Australia. The REFORM trial aims to evaluate the clinical and cost-effectiveness of a multifaceted podiatry intervention in reducing falls in people aged 65 years and over in a UK and Irish setting. Methods and analysis This multicentre, cohort randomised controlled trial will recruit 2600 participants from routine podiatry clinics in the UK and Ireland to the REFORM cohort. In order to detect a 10% point reduction in falls from 50% to 40%, with 80% power 890 participants will be randomised to receive routine podiatry care and a falls prevention leaflet or routine podiatry care, a falls prevention leaflet and a multifaceted podiatry intervention. The primary outcome is rate of falls (falls/person/time) over 12 months assessed by patient self-report falls diary. Secondary self-report outcome measures include: the proportion of single and multiple fallers and time to first fall over a 12-month period; Short Falls Efficacy Scale—International; fear of falling in the past 4 weeks; Frenchay Activities Index; fracture rate; Geriatric Depression Scale; EuroQoL-five dimensional scale 3-L; health service utilisation at 6 and 12 months. A qualitative study will examine the acceptability of the package of care to participants and podiatrists. Ethics and dissemination The trial has received a favourable opinion from the East of England—Cambridge East Research Ethics Committee and Galway Research Ethics Committee. The trial results will be published in peer-reviewed journals and at conference presentations. Trial registration number Current Controlled Trials ISRCTN68240461assigned 01/07/2011.

Cohort Randomised Controlled Trial of a Multifaceted Podiatry Intervention for the Prevention of Falls in Older People (The REFORM Trial)

Background Falls are a major cause of morbidity among older people. A multifaceted podiatry intervention may reduce the risk of falling. This study evaluated such an intervention. Design Pragmatic cohort randomised controlled trial in England and Ireland. 1010 participants were randomised (493 to the Intervention group and 517 to Usual Care) to either: a podiatry intervention, including foot and ankle exercises, foot orthoses and, if required, new footwear, and a falls prevention leaflet or usual podiatry treatment plus a falls prevention leaflet. The primary outcome was the incidence rate of self-reported falls per participant in the 12 months following randomisation. Secondary outcomes included: proportion of fallers and those reporting multiple falls, time to first fall, fear of falling, Frenchay Activities Index, Geriatric Depression Scale, foot pain, health related quality of life, and cost-effectiveness. Results In the primary analysis were 484 (98.2%) intervention and 507 (98.1%) control participants. There was a small, non statistically significant reduction in the incidence rate of falls in the intervention group (adjusted incidence rate ratio 0.88, 95% CI 0.73 to 1.05, p = 0.16). The proportion of participants experiencing a fall was lower (49.7 vs 54.9%, adjusted odds ratio 0.78, 95% CI 0.60 to 1.00, p = 0.05) as was the proportion experiencing two or more falls (27.6% vs 34.6%, adjusted odds ratio 0.69, 95% CI 0.52 to 0.90, p = 0.01). There was an increase (p = 0.02) in foot pain for the intervention group. There were no statistically significant differences in other outcomes. The intervention was more costly but marginally more beneficial in terms of health-related quality of life (mean quality adjusted life year (QALY) difference 0.0129, 95% CI -0.0050 to 0.0314) and had a 65% probability of being cost-effective at a threshold of £30,000 per QALY gained. Conclusion There was a small reduction in falls. The intervention may be cost-effective. Trial Registration ISRCTN ISRCTN68240461

Cost-effectiveness of cryotherapy versus salicylic acid for the treatment of plantar warts: economic evaluation alongside a randomised controlled trial (EVerT trial)

BackgroundPlantar warts (verrucae) are extremely common. Although many will spontaneously disappear without treatment, treatment may be sought for a variety of reasons such as discomfort. There are a number of different treatments for cutaneous warts, with salicylic acid and cryotherapy using liquid nitrogen being two of the most common forms of treatment. To date, no full economic evaluation of either salicylic acid or cryotherapy has been conducted based on the use of primary data in a pragmatic setting. This paper describes the cost-effectiveness analysis which was conducted alongside a pragmatic multicentre, randomised trial evaluating the clinical effectiveness of cryotherapy versus 50% salicylic acid of the treatment of plantar warts.MethodsA cost-effectiveness analysis was undertaken alongside a pragmatic multicentre, randomised controlled trial assessing the clinical effectiveness of 50% salicylic acid and cryotherapy using liquid nitrogen at 12 weeks after randomisation of patients. Cost-effectiveness outcomes were expressed as the additional cost required to completely cure the plantar warts of one additional patient. A NHS perspective was taken for the analysis.ResultsCryotherapy costs on average £101.17 (bias corrected and accelerated (BCA) 95% CI: 85.09-117.26) more per participant over the 12 week time-frame, while there is no additional benefit, in terms of proportion of patients healed compared with salicylic acid.ConclusionsCryotherapy is more costly and no more effective than salicylic acid.Trial registrationCurrent Controlled Trials ISRCTN18994246 [controlled-trials.com] and National Research Register N0484189151.

An optimised patient information sheet did not significantly increase recruitment or retention in a falls prevention study: an embedded randomised recruitment trial

BackgroundRandomised controlled trials are generally regarded as the ‘gold standard’ experimental design to determine the effectiveness of an intervention. Unfortunately, many trials either fail to recruit sufficient numbers of participants, or recruitment takes longer than anticipated. The current embedded trial evaluates the effectiveness of optimised patient information sheets on recruitment of participants in a falls prevention trial.MethodsA three-arm, embedded randomised methodology trial was conducted within the National Institute for Health Research-funded REducing Falls with ORthoses and a Multifaceted podiatry intervention (REFORM) cohort randomised controlled trial. Routine National Health Service podiatry patients over the age of 65 were randomised to receive either the control patient information sheet (PIS) for the host trial or one of two optimised versions, a bespoke user-tested PIS or a template-developed PIS. The primary outcome was the proportion of patients in each group who went on to be randomised to the host trial.ResultsSix thousand and nine hundred patients were randomised 1:1:1 into the embedded trial. A total of 193 (2.8%) went on to be randomised into the main REFORM trial (control n = 62, template-developed n = 68; bespoke user-tested n = 63). Information sheet allocation did not improve recruitment to the trial (odds ratios for the three pairwise comparisons: template vs control 1.10 (95% CI 0.77–1.56, p = 0.60); user-tested vs control 1.01 (95% CI 0.71–1.45, p = 0.94); and user-tested vs template 0.92 (95% CI 0.65–1.31, p = 0.65)).ConclusionsThis embedded methodology trial has demonstrated limited evidence as to the benefit of using optimised information materials on recruitment and retention rates in the REFORM study.Trial registrationInternational Standard Randomised Controlled Trials Number registry, ISRCTN68240461. Registered on 01 July 2011.

A new paradigm of electrical stimulation to enhance sensory neural function

The ability to improve peripheral neural transmission would have significant therapeutic potential in medicine. A technology of this kind could be used to restore and/or enhance sensory function in individuals with depressed sensory function, such as older adults or patients with peripheral neuropathies. The goal of this study was to investigate if a new paradigm of subsensory electrical noise stimulation enhances somatosensory function. Vibration (50Hz) was applied with a Neurothesiometer to the plantar aspect of the foot in the presence or absence of subsensory electrical noise (1/f type). The noise was applied at a proximal site, on a defined region of the tibial nerve path above the ankle. Vibration perception thresholds (VPT) of younger adults were measured in control and experimental conditions, in the absence or presence of noise respectively. An improvement of ∼16% in VPT was found in the presence of noise. These are the first data to demonstrate that modulation of axonal transmission with externally applied electrical noise improves perception of tactile stimuli in humans.