Critical limb ischemia (CLI) is synonymous with “end-stage” peripheral artery disease (PAD) and ultimately develops when the capillary beds are inadequately perfused and unable to sustain tissue viability. Several clinical and noninvasive criteria have been used to determine which CLI patients would benefit from revascularization . These include Rutherford categories 4–6, systolic ankle pressure <50 mmHg, non-pulsatile plethysmographic tracing, and/or transcutaneous oxygen pressure <30 mmHg [1, 2]. The European Consensus Conference has also included the need for analgesia for more than 2 weeks as part of the definition [3]. Anatomically, CLI is characterized by multilevel and multivessel infrainguinal and tibial arterial stenoses and occlusions that create a severe imbalance between supply and demand of oxygen in the affected tissues, compromising its viability and threatening limb loss. Although CLI encompasses <5 % of all cases of PAD, its prognosis is poor. The 1-year mortality and major amputation rates range from 20 to 50 % [4–6]. Under less severe circumstances, compensatory mechanisms such as angiogenesis and arteriogenesis [7] are sufficient to overcome the increased demand imposed by the lack of adequate tissue perfusion ; however, in patients with CLI, these mechanisms have been exhausted and/or are defective. Inadequate perfusion of the skin and surrounding tissues leads to endothelial dysfunction, chronic inflammation [8], and muscle damage [9–11]. The clinical manifestations of these molecular changes are ischemic rest pain, non-healing ulcerations, and gangrene. A staggering 20–25 % of patients with CLI will undergo primary amputation, 50–60 % undergo revascularization (surgical and/or endovascular), and 25 % are treated medically [12]. The 5-year mortality rate for populations with CLI is 60 % [13]. Among CLI patients who do not undergo revascularization , approximately 40 % will undergo a major amputation within 6 months and 20 % will die [8]. Observational studies indicate that only about 50 % will be alive without a major amputation at 1 year, 25 % will have died, and 25 % will have required a major amputation. PAD is usually a manifestation of systemic atherosclerosis and is associated with substantial morbidity and mortality both from PAD itself and other atherosclerotic diseases such as myocardial infarction (MI) and stroke. Significant coronary artery disease has been demonstrated in 60–80 % of patients with PAD [14], and hemodynamically significant carotid artery stenoses (by duplex ultrasound) have been demonstrated in 12–25 % [15–17]. The increased risk of MI, stroke, and cardiovascular mortality in patients with PAD is explained by the diffuse nature of the atherosclerotic process, which expands across most, if not all, arterial beds. The annual overall major cardiovascular event rate (MI, ischemic stroke, and vascular death) is approximately 5–7 %. The risk of MI is increased by 20–60 %, whereas the risk of death from coronary artery disease is increased two- to sixfold. The presence of PAD is associated with a 40 % increase in the risk of stroke [18–22].

CLI represents the “point of no return” in the clinical spectrum of the patient with PAD. Medical management has a role in the treatment of risk factors for secondary prevention of cardiovascular disease end points, which are highly prevalent among these patients. However, the role of medical management in treating the symptoms and complications of severe limb hypoperfusion is less well established. Surgery and more recently percutaneous endovascular treatments have become the mainstays of management of CLI, but pharmacological agents can have a role as adjuncts or alternatives in patients who are unsuitable for revascularization or those who have suboptimal results. Newer techniques such as the use of growth factors, gene therapy, and stem cells are being investigated. Management of novel risk factors and new applications of technology such as spinal cord stimulators are being studied, and the findings of these studies are likely to increase treatment options in the future.

The treatment of patients with CLI is rather complex and the issue is further complicated by the current paradigm. Although the purpose of this chapter is to discuss the long-term care of the patient with CLI, it must be emphasized that the contemporary management of CLI should include a combination of endovascular and surgical revascularization as the mainstay of therapy, complemented by a host of noninterventional therapies. This newly proposed, combined approach should be delivered in a “continuum of care” model, represented by a chain whereby patient care is carried by each one of its links or team members. One of the greatest weaknesses, perhaps the “Achilles heel” of our current approach to CLI, is the reigning “disjointment” of the pieces that should conform to the “CLI continuum of care.” In this proposed multidisciplinary approach (see Fig. 58.1), the patient first enters “the chain” through any of its constituent links. The first member of the team sees and evaluates the patient and then proceeds with a simultaneous referral to the remainder of the team. In this model, the patient is evaluated by the primary care physician (sometimes an endocrinologist), an infectious disease specialist, a wound care specialist, a podiatrist, occasionally an orthotics specialist as well as a “vascular rehabilitation specialist,” and, last but not least, the vascular specialist (either a vascular surgeon with endovascular training and experience, an interventional cardiologist, or an interventional radiologist). The patient then undergoes a series of noninvasive vascular tests in order to diagnose the extent of disease, to plan the therapeutic revascularization strategy, and to serve as baseline for future surveillance studies. Once the patient undergoes complete revascularization (in many instances, this could require up to three or four interventions in the threatened limb), the continuum of care perpetuates. The patient should continue to be followed by all the members of the team to ensure complete healing. Each member should participate in the follow-up and surveillance and should keep a high index of suspicion and an aggressive approach with prompt referral for repeat revascularization , which is of paramount importance since these patients live on a very delicate balance where perfusion is barely able to keep the metabolic needs of “healed” tissue, but will become insufficient if there is another insult to the skin barrier . The currently working system is not designed to function in this manner. Generally, the patient is only referred to the vascular specialist after months of failed wound therapy or repetitive visits to the podiatrist for serial debridements . Only after these traditional modalities have failed is the patient referred to the vascular specialist, in many instances too late. Another weakness of this approach has been the traditional referral to specialists who are not trained in the latest revascularization techniques, and these patients frequently undergo amputations without even to have undergone an angiographic evaluation. In the best of scenarios, the patient is properly referred to a vascular specialist, undergoes appropriate noninvasive and invasive testing, and finally receives adequate revascularization therapy. Among these (unfortunately the minority), only a very small fraction returns for follow-up with the vascular specialist or with any of the other members of the team. Many times they do follow-up with a “wound clinic” which is not affiliated with the system where the vascular specialist performed the intervention and therefore is not familiar with the latest techniques and advances. Thanks to the disjointment, there is no communication of the progress of the patient, and many times when the patient comes back, the situation is worse than it was at the first encounter. Overall, there is a widespread lack of knowledge and attachment to the old ways that needs to be overcome. Unfortunately, data-driven clinical studies to evaluate strategies for surveillance, use, and duration of antiplatelets, anticoagulants, and other risk factor-modifying agents, as well as the use of noninvasive testing, and indications for repeat revascularization in these patients do not exist. Current data has been derived from retrospective studies, with inconsistent reporting standards leading to a paucity of evidence, especially following endovascular revascularization in CLI [23].

Noninterventional therapies have a role as primary treatment in patients who have failed to improve symptoms (despite revascularization) and in patients who are unsuitable or unfit for revascularization, as adjuvant treatment after revascularization procedures, and to reduce the incidence of cardiovascular events.

The goals and pillars of CLI treatment are:

The medical goals are tasks that should be led by the primary care physician and endocrinologists. The interventional goals require the active participation of podiatrists, wound care and infectious disease specialists, vascular specialists, and vascular rehabilitation and orthotics specialists. The surveillance goals should be a task of all the members of the team.

Noninterventional therapies for the management of CLI comprise the use of preventive measures, wound care, pharmacotherapy (primary, to treat CLI, and adjuvant, to reduce major adverse cardiovascular events and to improve post-interventional outcomes), biotherapies (cell and gene therapy), and mechanical therapies designed to achieve the goals aforementioned. The stakeholders involved are the patients and the members of the CLI continuum of care, all of whom represent an integral part, a link of the chain that has to be in place in order to improve outcomes.