Diabetic foot ulcers (DFUs) and the resulting lower-extremity amputations (LEAs) are a common, complex, costly, and disabling complication of diabetes.1,2
According to the International Working Group on the Diabetic Foot, a DFU is a full-thickness wound penetrating through the dermis (the deep vascular and collagenous inner layer of the skin) located below the ankle in a diabetes patient.3–5
The diabetic foot is biologically compromised. This results from multiple contributing factors. The major underlying causes are noted to be peripheral neuropathy and ischemia from peripheral arterial disease (PAD). In the presence of these factors, even moderate ischemia can cause ulcers and impair healing.
Diabetic foot ulcers can be categorized as purely neuro-pathic, purely ischemic, or a combination of the two, namely, neuroischemic.6,7
The estimated current prevalence of each is 35%, 15%, and 50%, respectively.8
Foot tissues can become ischemic because of macrovascular disease (atherosclerosis) but can also be complicated by associated microvascular disease.9,10
The relationship between DFU and PAD has been explored in detail.11
Previously published DFU research often ignored PAD as a potential risk factor and/or important cause. Ischemia has gained recognition as a significant cause of DFUs, with increasing prevalence in developed countries.
Based on an analysis conducted at the Diabetic Foot Clinic, King's College Hospital in London, there is some preliminary evidence that the prevalence of neuroischemic ulcers has been rising since the 1990s from approximately one-third of patients to over 50%, therefore becoming the most common etiology of DFUs.12
Risk for ulcers and ultimately amputations can be likened to a stairway, where each factor above contributes deleteriously to the etiologic foundation below (
Additional works by Morbach and coworkers13
identified the increasing prevalence of PAD in patients with DFU. In their study, comparing centers in the developed and developing world, they identified nearly half of the population with concomitant PAD from cohorts of patients from 1998–1999. Despite these data being in existence since the late 1990s and a large, multinational prospective cohort confirming these data several years later (with data collection from 2003 to 2004),14,15
clinical studies focusing on infection and healing in people with DFUs have systematically excluded what now is likely a majority of the patients under care in centers across the developed world.
Outcomes in Neuroischemic versus Neuropathic Diabetic Foot Ulcers
The presence or absence of ischemia and PAD largely impacts the outcomes in the treatment of DFUs. Peripheral arterial disease in DFUs is associated with the most severe adverse outcomes, including lower probability of healing, longer healing times, higher probability of ulcer recurrence, greater risk of toe as well as major amputations, and potentially higher mortality.
A compelling study published by Moulik and colleagues16
provides outcomes for patients with all three types of DFUs. Those with ischemic or neuroischemic disease have a much higher probability of amputation, with ischemic patients showing numerically higher mortality (
Figure 2 Cumulative amputation rates for foot ulcers of various etiologies (reproduced with permission from Diabetes Care16).
Figure 3 Cumulative survival rates for foot ulcers of various etiologies (reproduced with permission from Diabetes Care16).
The EURODIALE study14
was one of the few large prospective, international studies on outcome and deter-minants of outcome in diabetic foot disease. This study has shown that, when stratifying patients according to the presence or absence of PAD, significantly fewer wounds with PAD healed than in those without PAD (69% versus 84%, respectively). Furthermore, significant differences in clinical characteristics, outcome, and predictors of out-come in patients with and without PAD and the different pathophysiology and treatment of PAD and non-PAD ulcers led the authors to consider that DFU with and without PAD should potentially be defined as two separate disease states. Finally, the EURODIALE study confirmed that infection was significantly associated to nonhealing in individuals with PAD compared with non-PAD patients. Peripheral vascular insufficiency was previously shown to be associated with a two-fold increase of foot infection.17
Patients with infection and ischemia are nearly 90 times more likely to receive a midfoot or higher amputation compared with patients in less advanced wound stages (76.5% versus 3.5%; p
A study commissioned by the United States Agency for Healthcare Research and Quality has shown that, among U.S. Medicare beneficiaries, the prevalence of LEA in the subpopulation of patients with diabetes and PAD was approximately three times as high as in the corresponding diabetes baseline population. This prevalence of LEA was even nearly seven times higher in nonelderly diabetes patients with PAD—many of whom likely have end-stage renal disease—compared with the prevalence in the Medicare population with diabetes.18
Outcomes of Mild/Moderate Ischemia in Diabetic Foot Ulcer Patients
The severity of PAD itself increases the risks of adverse outcomes, specifically nonhealing ulcers, amputation, and mortality. In a large cohort Swedish study, primary healing, amputation rates, and mortality were linked to the severity of the vascular insufficiency, measured by ankle or toe pressure.19
In a prospective population-based cohort study of adults with type 1 and type 2 diabetes mellitus presenting with their first foot ulcer (excluding those with severe ischemia), moderate ischemia was associated with mortality [hazard ratio = 2.74; 95% confidence interval (CI) 1.46–5.14]. Micro-vascular complications were the only explanatory factor associated with recurrent ulceration (hazard ratio = 3.34; 95% CI 1.17–9.56).20
This latter finding may have to do with skin and structural changes to the skin secondary to microvascular disease leading to a viscoelastically less robust integument less able to respond to repetitive normal and shear stress.
In a cohort of patients with vascular insufficiency, but not candidates for revascularization, Marston and associates21
have shown a clear correlation between the severity of ischemia and the risk of limb loss. While all patients with vascular insufficiency might initially be considered candidates for revascularization, severe comorbidities, patient consent, or anatomic/technical factors might obviate revascularization in favor of nonsurgical care. This population has been largely ignored from study in the medical literature but may be one that is important to address in future works.
Taylor and coworkers22
reported on the management and outcomes of 917 neuropathic ulcers in 706 patients over 5 years. The population was divided into three groups: neuropathic, ischemic with revascularization, and ischemic without revascularization. The latter can be considered patients with mild to moderate ischemia, for whom a revascularization procedure was not justified. Out of these three groups, the ischemic patients without revasculariza-tion had the worst outcomes. Outcomes for neuropathic, ischemia (revascularized), and ischemia (not revascularized), respectively, included 5-year limb salvage of 80%, 61%, and 51% (p
< .001); survival of 47%, 37%, and 24% (p
= .03); amputation-free survival of 37%, 28%, and 17% (p
< .001); maintenance of ambulation of 74%, 55%, and 55% (p
< .001); and maintenance of independence of 82%, 72%, and 58% (p
Mortality in Ischemic Patients
Armstrong and colleagues23
discussed the relatively high 5-year mortality rates for patients with neuropathic and ischemic DFUs and diabetes-related amputations compared with serious medical conditions, including several common types of cancer, using data gathered from multiple sources. By 5 years, 45% to 55% of patients with neuropathic and ischemic DFUs, respectively, will die. These common complications of diabetes have higher mortality rates than cancers of the prostate, breast, and colon, as well as Hodgkin's disease (
Relative 5-year mortality rates and comparison to major forms of cancer.