Pilot Assessment of the Repeatability of Indocyanine Green Fluorescence Imaging and Correlation with Traditional Foot Perfusion Assessments.

BACKGROUND: Ankle brachial index (ABI), toe pressures (TP), and transcutaneous oxygen pressure (TcPO2) are traditionally used in the assessment of critical limb ischemia (CLI). Indocyanine green (ICG) fluorescence imaging can be used to evaluate local circulation in the foot and to evaluate the severity of ischemia. This prospective study analyzed the suitability of a fluorescence imaging system (photodynamic eye [PDE]) in CLI. MATERIAL AND METHODS: Forty-one patients with CLI were included. Of the patients, 66% had diabetes and there was an ischemic tissue lesion in 70% of the limbs. ABI, toe pressures, TcPO2 and ICG-fluorescence imaging (ICG-FI) were measured in each leg. To study the repeatability of the ICG-FI, each patient underwent the study twice. After the procedure, foot circulation was measured using a time-intensity curve, where T1/2 (the time needed to achieve half of the maximum fluorescence intensity) and PDE10 (increase of the intensity during the first 10 s) were determined. A time-intensity curve was plotted using the same areas as for the TcPO2 probes (n=123). RESULTS: The mean ABI was 0.43, TP 21 mmHg, TcPO2 23 mmHg, T1/2 38 s, and PDE10 19 AU. Time-intensity curves were repeatable. In a Bland-Altman scatter plot, the 95% limits of agreement of PDE10 was 9.9 AU and the corresponding value of T1/2 was 14 s. Correlation between ABI and TP was significant (R=.73, p<.001), and it was weaker in diabetic patients (R=.47, p=.048) compared with non-diabetic patients (R=.89, p=.002). Correlations between ABI and TcPO2 and TP and TcPO2 were weak (R=.37, p=.05 and R=.43, p=.037, respectively). Correlation between TcPO2 and PDE10 was strong in diabetic patients (R=.70, p=.003). CONCLUSIONS: According to this pilot study, ICG-FI with PDE can be used in the assessment of blood supply in the ischemic foot.

Strategies for free flap transfer and revascularisation with long-term outcome in the treatment of large diabetic foot lesions.

OBJECTIVE/BACKGROUND: To analyse the impact of ischaemia and revascularisation strategies on the long-term outcome of patients undergoing free flap transfer (FFT) for large diabetic foot lesions penetrating to the tendon, bone, or joint. METHODS: Foot lesions of 63 patients with diabetes (median age 56 years; 70% male) were covered with a FTT in 1991-2003. Three groups were formed and followed until 2009: patients with a native in line artery to the ulcer area (n = 19; group A), patients with correctable ischaemia requiring vascular bypass (n = 32; group B), and patients with uncorrectable ischaemia lacking a recipient vessel in the ulcer area (n = 12; group C). RESULTS: The respective 1, 5, and 10 year amputation free survival rates were 90%, 79%, and 63% in group A; 66%, 25%, and 18% in group B; and 50%, 42%, and 17%, in group C. The respective 1, 5, and 10 year leg salvage rates were 94%, 94%, and 87% in group A; 71%, 65%, and 65% in group B; and 50%, 50%, and 50% in group C. In 1 year, 43%, 45%, and 18% of the patients in groups A, B, and C, respectively, achieved stable epithelisation for at least 6 months. The overall amputation rate was associated with smoking (relative risk [RR] 3.09, 95% confidence interval [CI] 1.8-5.3), heel ulceration (RR 2.25, 95% CI 1.1-4.7), nephropathy (RR 2.24, 95% CI 1.04-4.82), and an ulcer diameter of >10 cm (RR 2.08, 95% CI 1.03-4.48). CONCLUSION: Despite diabetic comorbidities, complicated foot defects may be covered by means of an FFT with excellent long-term amputation free survival, provided that a patent native artery feeds the ulcer area. Ischaemic limbs may also be salvaged with combined FFT and vascular reconstruction in non-smokers and in the absence of very extensive heel ulcers. Occasionally, amputation is avoidable with FFT, even without the possibility of direct revascularisation.

Compression therapy versus surgery in the treatment of patients with varicose veins: A RCT.

OBJECTIVE: Superficial venous reflux and varicose veins are common. The aim of this randomized controlled trial was to assess effectiveness of compression therapy compared with surgery for superficial venous reflux. METHODS: 153 patients with CEAP class C2-C3 and superficial venous reflux were randomized to receive either conservative treatment (compression stockings) (n = 77) or surgery (n = 76). Clinical examination including duplex ultrasound (DUS) was performed at entry and 1 and 2 years after randomization (compression group) or surgery (surgery group). Venous Clinical Severity Score without compression stockings (VCSS-S), Venous Segmental Disease Score (VSDS), Venous Disability Score (VDS), and health-related quality of life (HRQoL) were assessed at entry and at the follow-ups. Data were analysed on an intention-to-treat basis and according to the actual treatment performed. RESULTS: At 2 years, 70/76 patients in the surgery group and 11/77 patients in the compression group had been operated on. VCSS-S decreased from 4.6 to 3.5 in the compression group (p < .01) and from 4.8 to 0.6 in the surgery group (p < .001). VSDS decreased from 7.7 to 7.0 in the compression group and from 8.2 to 0.9 in the surgery group (p < .0001). HRQoL did not change in the compression group, but improved significantly in the surgery group. CONCLUSION: The surgical elimination of non-complicated superficial venous reflux is an effective treatment when compared with providing compression stockings only.

Doppler ultrasound examination of multiple sclerosis patients and control participants: inter-observer agreement and association with disease.

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) has been proposed as a major risk factor for multiple sclerosis (MS). The aim of this study was to assess inter-observer agreement between two ultrasound examiners and to compare findings in MS patients and control participants. METHODS: A prospective, blinded, controlled study of MS patients diagnosed within 2 years (MS ≤ 2, n = 39), patients diagnosed more than 10 years ago (MS > 10, n = 43) and age- and sex-matched control participants (n = 40). Ultrasound examinations were performed by two independent examiners. CCSVI criteria 1, 3, 4 and 5 as proposed by Zamboni were explored: (1) reflux in the internal jugular (IJV) and vertebral veins (VV), (3) IJV cross-sectional area (CSA) ≤0.3 cm(2), (4) absence of flow in IJV and VV, and (5) reverted postural control of venous outflow. RESULTS: Criteria 1, 4 and 5 were met in less than 10% of the MS patients and control participants as studied by both examiners. The level of inter-observer agreement was poor for all parameters except assessment of the CSA of IJV at the thyroid level. Findings meeting CCSVI criterion 3 (CSA ≤ 0.3 cm(2)) were observed in 18/40 (45%) of the control participants, in 24/37 (65%) of MS ≤ 2 patients (p = 0.09 vs. control participants) and in 30/43 (70%) of the MS > 10 patients (p = 0.022 vs. control participants). CONCLUSIONS: The feasibility of the CCSVI criteria for common use is questionable because of low inter-observer agreement. Small-calibre IJVs meeting the CCSVI criterion 3 appear common in both Finnish control participants and MS patients, but the clinical significance of this finding is questionable.

The natural course of abdominal aortic aneurysms that meet the treatment criteria but not the operative requirements.

INTRODUCTION: Abdominal aortic aneurysms (AAAs) of 55 mm diameter or growth >5 mm in 6 months are commonly accepted treatment criteria. The aim of this study was to establish the outcome of aneurysms that met the treatment criteria but not the operative requirements. MATERIAL AND METHODS: Patients (n = 154) who were declined from operative care of AAA in Helsinki University Central Hospital (HUCH) during 2000-2010 were retrospectively analysed. Reasons for exclusion were identified. The follow-up period extended until the end of April 2012. The rupture rate and mortality were determined. The patients were analysed according to the aneurysm diameter: 55-60, 61-70 and >70 mm. RESULTS: The reasons for exclusion from operative treatment were cardiorespiratory co-morbidities in 33%, cancer in 8%, overall condition in 33% and patient's choice in 21% of the patients. Regardless of the size of the aneurysm, the cause of death was aneurysm rupture in 43%, which was confirmed either in hospital or in autopsy for 76% of the patients. Of the ruptured aneurysms, 12 were operated of which five survived. CONCLUSIONS: A ruptured aneurysm is the most common cause of death among patients unfit for surgery; this should be considered in the preoperative evaluation process, especially since 5 of the 12 patients survived the ruptured AAA (RAAA) operation.

Predictors of failure of endovascular revascularization for critical limb ischemia.

BACKGROUND AND AIMS: To characterize predictors of failure when treating critical limb ischemia (CLI) patients with an endovascular intervention as the first-line strategy. PATIENTS AND METHODS: This retrospective, registry-based study included 217 consecutive patients with 240 chronic critically ischemic limbs treated with infrainguinal percutaneous trans-luminal angioplasty (PTA) during 2006-2007 at Helsinki University Central Hospital, Finland. The primary outcome measures were death, major (above-ankle) amputation, and the need for surgical re-intervention within 6 months after the primary procedure. The secondary out-come measures were overall major amputation and survival rates as well as the overall need for surgical or any other (surgical or endovascular) type of re-intervention. Predictors of outcome endpoints were identified with a univariate screen, and a Cox regression model was used in the multivariate analysis. RESULTS: Compared to ulcer, gangrene was significantly more strongly associated with amputation within 6 months post-procedurally as well as during the whole follow-up period (p ≤ 0.028). The patient's inability to walk upon hospital arrival was a significant predictor of death, amputation and surgical re-intervention. Mediasclerotic ankle-brachial index (ABI) was an independent predictor of amputation as well as endovascular re-interventions. CONCLUSIONS: The strong predictors of poor outcome after endovascular revascularization for patients with CLI are cardiac morbidity, the inability to ambulate upon hospital arrival, and gangrene as a manifestation of CLI. The risk of amputation seems to be significantly higher for gangrene than for ulcer and this matter should be taken into account in the clinical classifications for CLI.

Decreasing the delay to carotid endarterectomy in symptomatic patients with carotid stenosis--outcome of an intervention.

OBJECTIVES: Surgical treatment of carotid stenosis after the onset of ischaemic symptoms should be performed within 2 weeks. This aim was accomplished only in 11% during the years 2007-2008 in the Helsinki University Central Hospital (HUCH) region. Since then, special efforts have been made in order to shorten the delay. The aim of this study was to find out how these changes affected the symptom-to-knife time (SKT). MATERIALS AND METHODS: All symptomatic patients (n = 144) who had carotid endarterectomy (CEA, n = 145) in HUCH in 2010 were retrospectively analysed and the SKT was determined. RESULTS: Of the operations, 37% (n = 53) were performed within the recommended 2 weeks. The median SKT was 19 days (1-183). Of the patients who came to HUCH on an emergency basis (n = 80), 55% (n = 45) were operated within 2 weeks and their median SKT was 13 days (1-148). CONCLUSIONS: The changes that were made in 2008-2009 have significantly shortened the delay in the treatment of carotid stenosis, but the desired time frame of 2 weeks was reached far too seldom. The greatest benefit from preventive CEA is achieved when patients are referred emergently to a clinic where neurologist, imaging resources and vascular surgeon are available.

End-stage renal disease and critical limb ischemia: a deadly combination?

OBJECTIVES: This study was planned to evaluate the prognostic impact of end-stage renal disease (ESRD) in patients with critical leg ischemia (CLI) undergoing infrainguinal revascularization. MATERIALS AND METHODS: 1425 patients who underwent infrainguinal revascularization for CLI were the subjects of the present analysis. Ninety-five patients had ESRD (eGFR < 15 ml/min/m²), and of them 66 (70%) underwent percutaneous transluminal angioplasty and 29 (30%) underwent bypass surgery. RESULTS: ESRD patients had significantly lower overall survival (at 3-year, 27.1% vs. 59.7%, p < 0.0001), leg salvage (at 3-year, 57.7% vs. 83.0%, p < 0.0001), and amputation free survival (at 3-year, 16.2% vs. 52.9%, p < 0.0001) than patients with no or less severe renal failure. The difference in survival was even greater between 86 one-to-one propensity matched pairs (at 3-year, 23.1% vs. 67.3%, p < 0.0001). ESRD was an independent predictor of all-cause mortality (RR 2.46, 95%CI 1.85-3.26). Logistic regression showed that age ≥ 75 years was the only independent predictor of 1-year all-cause mortality (OR 4.92, 95%CI 1.32-18.36). Classification and regression tree analysis showed that age ≥ 75 years and, among younger patients, bypass surgery for leg ulcer and gangrene were associated with significantly higher 1-year mortality CONCLUSIONS: Lower limb revascularization in patients with CLI and end-stage renal failure is associated with favourable leg salvage. However, these patients have a very poor survival and this may jeopardize any attempt of revascularization. Further studies are needed to identify ESRD patients with acceptable life expectancy and who may benefit from lower limb revascularization.

The path from art to evidence in treating critical limb ischaemia--reflections on 35 years' experience.

Despite numerous attempts, chronic critical limb ischaemia (CLI) has not been unequivocally defined as yet. Its epidemiology is poorly investigated and its prevalence probably higher than anticipated. It is accompanied by high mortality and morbidity irrespective of the way it is treated. Its management is very expensive. Additionally, the prevailing diabetes epidemic is increasing the need for revascularizations although there is a clear lack of evidence as to when to revascularize an ulcerated diabetic foot. The fast development of endovascular techniques blurs the vision as the window of opportunity for gathering proper evidence keeps narrowing. The notion of endovascular artistry prevails, but attempts to conduct proper studies with clear definitions, strict criteria and appropriate outcome measures in a standardised manner should continue--preferably using propensity scoring if randomised controlled trials are not possible. This review highlights some of the steps leading from art to evidence and illustrates the difficulties encountered along the path. In parallel with this overview, the progress of the treatment for CLI in Finland is described from the perspective of the work concluded at Helsinki University Central Hospital.

The ulcerated leg: when to revascularize.

The role of peripheral arterial disease in ulcerated diabetic feet has long been underestimated. Progressive claudication, rest pain and the extent of irreversible tissue loss have frequently been indications for revascularization for neuroischaemic ulcers in diabetic patients. These typical ischaemic symptoms are warning signs that are less frequent in diabetic individuals with ischaemia than those without diabetes. Consequently, 30-50% of individuals with diabetes and foot ulcers already have gangrene at admission and are therefore often considered unsuitable for revascularization. Furthermore, the healing of a neuroischaemic ulcer is worsened by microvascular dysfunction, causing arteriovenous shunting, capillary ischaemia, leakage and venous pooling. Therefore, the threshold of revascularizing neuroischaemic ulcers should be lower than that of purely ischaemic ulcers. Comorbidity, ulcer characteristics and infection affect the decision as to when to intervene, as do the severity and extent of occlusive arterial lesions. The window of opportunity for vascular intervention in the neuroischaemic diabetic foot should not be missed, and the need for early vascular intervention as an integrated part of a strategy to achieve healing should be emphasized. Noninvasive vascular testing should be performed on all individuals with an ulcerated diabetic foot. The arterial tree should be imaged if noninvasive tests indicate ischaemia or when mild or questionable ischaemia is diagnosed and conservative treatment does not promote ulcer healing in 6 weeks. Revascularization should be performed whenever feasible to repair distal perfusion to achieve ulcer healing.

A systematic review of the effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral arterial disease.

In several large recent observational studies, peripheral arterial disease (PAD) was present in up to 50% of the patients with a diabetic foot ulcer and was an independent risk factor for amputation. The International Working Group on the Diabetic Foot therefore established a multidisciplinary working group to evaluate the effectiveness of revascularization of the ulcerated foot in patients with diabetes and PAD. A systematic search was performed for therapies to revascularize the ulcerated foot in patients with diabetes and PAD from 1980-June 2010. Only clinically relevant outcomes were assessed. The research conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the Scottish Intercollegiate Guidelines Network methodological scores were assigned. A total of 49 papers were eligible for full text review. There were no randomized controlled trials, but there were three nonrandomized studies with a control group. The major outcomes following endovascular or open bypass surgery were broadly similar among the studies. Following open surgery, the 1-year limb salvage rates were a median of 85% (interquartile range of 80-90%), and following endovascular revascularization, these rates were 78% (70.5-85.5%). At 1-year follow-up, 60% or more of ulcers had healed following revascularization with either open bypass surgery or endovascular revascularization. Studies appeared to demonstrate improved rates of limb salvage associated with revascularization compared with the results of medically treated patients in the literature. There were insufficient data to recommend one method of revascularization over another. There is a real need for standardized reporting of baseline demographic data, severity of disease and outcome reporting in this group of patients.

Diagnosis and treatment of peripheral arterial disease in diabetic patients with a foot ulcer. A progress report of the International Working Group on the Diabetic Foot.

The International Working Group on the Diabetic Foot (IWDGF) has produced in 2011 a guideline on the diagnosis and treatment of peripheral arterial disease in patients with diabetes and a foot ulcer. This document, together with a systematic review that provided the background information on management, was produced by a multidisciplinary working group of experts in the field and was endorsed by the IWDGF. This progress report is based on these two documents and earlier consensus texts of the IWDGF on the diagnosis and management of diabetic foot ulcers. Its aim is to give the clinician clear guidance on when and how to diagnose peripheral arterial disease in patients with diabetes and a foot ulcer and when and which treatment modalities should be considered, taking both risks and benefits into account.

Chapter II: Diagnostic methods.

Non-invasive vascular studies can provide crucial information on the presence, location, and severity of critical limb ischaemia (CLI), as well as the initial assessment or treatment planning. Ankle-brachial index with Doppler ultrasound, despite limitations in diabetic and end-stage renal failure patients, is the first-line evaluation of CLI. In this group of patients, toe-brachial index measurement may better establish the diagnosis. Other non-invasive measurements, such as segmental limb pressure, continuous-wave Doppler analysis and pulse volume recording, are of limited accuracy. Transcutaneous oxygen pressure (TcPO(2)) measurement may be of value when rest pain and ulcerations of the foot are present. Duplex ultrasound is the most important non-invasive tool in CLI patients combining haemodynamic evaluation with imaging modality. Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are the next imaging studies in the algorithm for CLI. Both CTA and MRA have been proven effective in aiding the decision-making of clinicians and accurate planning of intervention. The data acquired with CTA and MRA can be manipulated in a multiplanar and 3D fashion and can offer exquisite detail. CTA results are generally equivalent to MRA, and both compare favourably with contrast angiography. The individual use of different imaging modalities depends on local availability, experience, and costs. Contrast angiography represents the gold standard, provides detailed information about arterial anatomy, and is recommended when revascularisation is needed.

Chapter III: Management of cardiovascular risk factors and medical therapy.

Critical limb ischaemia (CLI) is a particularly severe manifestation of lower limb atherosclerosis posing a major threat to both limb and life of affected patients. Besides arterial revascularisation, risk-factor modification and administration of antiplatelet therapy is a major goal in the treatment of CLI patients. Key elements of cardiovascular risk management are smoking cessation and treatment of hyperlipidaemia with dietary modification or statins. Moreover, arterial hypertension and diabetes mellitus should be adequately treated. In CLI patients not suitable for arterial revascularisation or subsequent to unsuccessful revascularisation, parenteral prostanoids may be considered. CLI patients undergoing surgical revascularisation should be treated with beta blockers. At present, neither gene nor stem-cell therapy can be recommended outside clinical trials. Of note, walking exercise is contraindicated in CLI patients due to the risk of worsening pre-existing or causing new ischaemic wounds. CLI patients are oftentimes medically frail and exhibit significant comorbidities. Co-existing coronary heart and carotid as well as renal artery disease should be managed according to current guidelines. Considering the above-mentioned treatment goals, interdisciplinary treatment approaches for CLI patients are warranted. Aim of the present manuscript is to discuss currently existing evidence for both the management of cardiovascular risk factors and treatment of co-existing disease and to deduct specific treatment recommendations.

Chapter I: Definitions, epidemiology, clinical presentation and prognosis.

The concept of chronic critical limb ischaemia (CLI) emerged late in the history of peripheral arterial occlusive disease (PAOD). The historical background and changing definitions of CLI over the last decades are important to know in order to understand why epidemiologic data are so difficult to compare between articles and over time. The prevalence of CLI is probably very high and largely underestimated, and significant differences exist between population studies and clinical series. The extremely high costs associated with management of these patients make CLI a real public health issue for the future. In the era of emerging vascular surgery in the 1950s, the initial classification of PAOD by Fontaine, with stages III and IV corresponding to CLI, was based only on clinical symptoms. Later, with increasing access to non-invasive haemodynamic measurements (ankle pressure, toe pressure), the need to prove a causal relationship between PAOD and clinical findings suggestive of CLI became a real concern, and the Rutherford classification published in 1986 included objective haemodynamic criteria. The first consensus document on CLI was published in 1991 and included clinical criteria associated with ankle and toe pressure and transcutaneous oxygen pressure (TcPO(2)) cut-off levels <50 mmHg, <30 mmHg and <10 mmHg respectively). This rigorous definition reflects an arterial insufficiency that is so severe as to cause microcirculatory changes and compromise tissue integrity, with a high rate of major amputation and mortality. The TASC I consensus document published in 2000 used less severe pressure cut-offs (≤ 50-70 mmHg, ≤ 30-50 mmHg and ≤ 30-50 mmHg respectively). The thresholds for toe pressure and especially TcPO(2) (which will be also included in TASC II consensus document) are however just below the lower limit of normality. It is therefore easy to infer that patients qualifying as CLI based on TASC criteria can suffer from far less severe disease than those qualifying as CLI in the initial 1991 consensus document. Furthermore, inclusion criteria of many recent interventional studies have even shifted further from the efforts of definition standardisation with objective criteria, by including patients as CLI based merely on Fontaine classification (stage III and IV) without haemodynamic criteria. The differences in the natural history of patients with CLI, including prognosis of the limb and the patient, are thus difficult to compare between studies in this context. Overall, CLI as defined by clinical and haemodynamic criteria remains a severe condition with poor prognosis, high medical costs and a major impact in terms of public health and patients' loss of functional capacity. The major progresses in best medical therapy of arterial disease and revascularisation procedures will certainly improve the outcome of CLI patients. In the future, an effort to apply a standardised definition with clinical and objective haemodynamic criteria will be needed to better demonstrate and compare the advances in management of these patients.

Chapter IV: Treatment of critical limb ischaemia.

Recommendations stated in the TASC II guidelines for the treatment of peripheral arterial disease (PAD) regard a heterogeneous group of patients ranging from claudicants to critical limb ischaemia (CLI) patients. However, specific considerations apply to CLI patients. An important problem regarding the majority of currently available literature that reports on revascularisation strategies for PAD is that it does not focus on CLI patients specifically and studies them as a minor part of the complete cohort. Besides the lack of data on CLI patients, studies use a variety of endpoints, and even similar endpoints are often differentially defined. These considerations result in the fact that most recommendations in this guideline are not of the highest recommendation grade. In the present chapter the treatment of CLI is not based on the TASC II classification of atherosclerotic lesions, since definitions of atherosclerotic lesions are changing along the fast development of endovascular techniques, and inter-individual differences in interpretation of the TASC classification are problematic. Therefore we propose a classification merely based on vascular area of the atherosclerotic disease and the lesion length, which is less complex and eases the interpretation. Lesions and their treatment are discussed from the aorta downwards to the infrapopliteal region. For a subset of lesions, surgical revascularisation is still the gold standard, such as in extensive aorto-iliac lesions, lesions of the common femoral artery and long lesions of the superficial femoral artery (>15 cm), especially when an applicable venous conduit is present, because of higher patency and limb salvage rates, even though the risk of complications is sometimes higher than for endovascular strategies. It is however more and more accepted that an endovascular first strategy is adapted in most iliac, superficial femoral, and in some infrapopliteal lesions. The newer endovascular techniques, i.e. drug-eluting stents and balloons, show promising results especially in infrapopliteal lesions. However, most of these results should still be confirmed in large RCTs focusing on CLI patients. At some point when there is no possibility of an endovascular nor a surgical procedure, some alternative non-reconstructive options have been proposed such as lumbar sympathectomy and spinal cord stimulation. But their effectiveness is limited especially when assessing the results on objective criteria. The additional value of cell-based therapies has still to be proven from large RCTs and should therefore still be confined to a research setting. Altogether this chapter summarises the best available evidence for the treatment of CLI, which is, from multiple perspectives, completely different from claudication. The latter also stresses the importance of well-designed RCTs focusing on CLI patients reporting standardised endpoints, both clinical as well as procedural.

Chapter V: Diabetic foot.

Ulcerated diabetic foot is a complex problem. Ischaemia, neuropathy and infection are the three pathological components that lead to diabetic foot complications, and they frequently occur together as an aetiologic triad. Neuropathy and ischaemia are the initiating factors, most often together as neuroischaemia, whereas infection is mostly a consequence. The role of peripheral arterial disease in diabetic foot has long been underestimated as typical ischaemic symptoms are less frequent in diabetics with ischaemia than in non-diabetics. Furthermore, the healing of a neuroischaemic ulcer is hampered by microvascular dysfunction. Therefore, the threshold for revascularising neuroischaemic ulcers should be lower than that for purely ischaemic ulcers. Previous guidelines have largely ignored these specific demands related to ulcerated neuroischaemic diabetic feet. Any diabetic foot ulcer should always be considered to have vascular impairment unless otherwise proven. Early referral, non-invasive vascular testing, imaging and intervention are crucial to improve diabetic foot ulcer healing and to prevent amputation. Timing is essential, as the window of opportunity to heal the ulcer and save the leg is easily missed. This chapter underlines the paucity of data on the best way to diagnose and treat these diabetic patients. Most of the studies dealing with neuroischaemic diabetic feet are not comparable in terms of patient populations, interventions or outcome. Therefore, there is an urgent need for a paradigm shift in diabetic foot care; that is, a new approach and classification of diabetics with vascular impairment in regard to clinical practice and research. A multidisciplinary approach needs to implemented systematically with a vascular surgeon as an integrated member. New strategies must be developed and implemented for diabetic foot patients with vascular impairment, to improve healing, to speed up healing rate and to avoid amputation, irrespective of the intervention technology chosen. Focused studies on the value of predictive tests, new treatment modalities as well as selective and targeted strategies are needed. As specific data on ulcerated neuroischaemic diabetic feet are scarce, recommendations are often of low grade.