Appropriate diagnosis of critical limb ischemia (CLI) has been underappreciated. Although endovascular therapy has evolved around the world during the last decade, the endovascular community in both developed and developing Asian countries has distinct variations in clinical practice frameworks, device availability, regulations, and reimbursement. Consequently, there is a broad spectrum in maturity or dominancy of the endovascular specialty among cardiologists, vascular surgeons, and radiologists by county. In parallel with advancements in endovascular therapy, awareness of the importance of wound management still remains underdeveloped. Thus, dissemination of comprehensive approaches in different disciplines for treatment of CLI is urgently needed.

In 2010, the first meeting of the Endovascular Asia (formerly, Bay Area Endovascular Summit) took place as a grassroots forum for interaction between cardiologists, vascular surgeons, radiologists, orthopedic surgeons, plastic surgeons, vascular nurses, wound care nurses, vascular ultrasonography technologists, and clinical engineering technologists beyond national boundaries to appreciate the need for multidisciplinary practice and harmonize endovascular therapy and wound care. During Endovascular Asia 2017 in Osaka, the first Asian CLI meeting session called CLI Asia was convened on December 2, 2017, to generate Asian multidisciplinary expert consensus on the essential diagnostic and treatment strategy with participation by endovascular and wound specialists from Japan, Taiwan, South Korea, Hong Kong, India, Singapore, Thailand, and Malaysia. This article is intended to share the practical consensus statement based on the collaboration between endovascular therapy and wound care beyond specialty and country borders that reflect discussions at that meeting.

Asia comprises about 60% of the world population, with intercountry variations in economic status and health-care systems. Currently, there is a projected increase in the burden of peripheral artery disease (PAD) and diabetes in Asia [1, 2]. Asia has the highest incidence and prevalence of end-stage renal disease (ESRD) in the world [3]. Therefore, most Asian patients with PAD may also have diabetes or ESRD. CLI in the context of diabetes or ESRD is the most advanced and challenging subset of PAD (Fig. 1); given these pandemic conditions, this is an emerging public health issue in Asian countries. Diabetic and ESRD-related CLI has complex pathophysiology that includes dysfunction of the macrocirculation due to extensive atherosclerotic lesions, dysfunction of the microcirculation including arteriovenous shunting, bacterial infection, and diabetic foot deformity associated with neuropathy [4]. Diabetes mellitus and ESRD can change the nature of peripheral artery disease, especially infrapopliteal artery disease. Vessel calcification, endothelial dysfunction, subsequent thrombosis, and vasoconstriction can cause disturbances in the macrocirculation and microcirculation [5‐7]. Foot ischemia can be further impaired by neuropathy. Arteriovenous shunting due to autonomic neuropathy, exogenous factors such as excessive loading due to motor and sensory neuropathy, and diabetic foot deformity can cause neuroischemic ulcers or gangrene [8]. In addition, hyperglycemia and impaired immunological responses can increase susceptibility to bacterial infections of ischemic wounds. Subsequent infectious arteritis in the small arteries of the foot can exacerbate ischemia. Consequently, polymicrobial foot infections can range from minimal superficial infections to deep infections such as osteomyelitis; these infections can create a physical barrier against re-epithelialization and amplify the risk of sepsis. Therefore, compared to CLI patients without diabetes or ESRD, CLI patients with diabetes or ESRD have approximately twice the risk of wound healing failure, reintervention, and major amputation or death even after endovascular therapy [9, 10]. If CLI patients can meet the following conditions: less cardiovascular comorbidity, functional recovery expectancy after revascularization, good quality autogenous vein conduit, and an estimated life expectancy of 2 years or more, bypass-first strategy might be considered as an initial revascularization strategy [11, 12]. However, since most Asian countries have only a small group of dedicated vascular surgeons compared to Western countries [13], Asian CLI patients might have less chance to undergo bypass surgery. In consideration of Asian situations, endovascular therapy with sophisticated wound management is the mainstream approach for contemporary CLI.

Assessment of limb ischemia is integral to diagnosing CLI. Traditional measurements that assess the macrocirculation, such as the ankle–brachial index (ABI) and ankle pressure, can be falsely elevated due to excessive calcification of the tibial artery, which is common in diabetic or ESRD-related CLI [14], and do not reflect blood flow below the ankle. Given the limited utility of assessment of the macrocirculation (Fig. 2a), intense evaluation of the microcirculation with measures such as skin perfusion pressure (SPP) and transcutaneous oxygen pressure (TCPo2) is essential in the setting of CLI [15‐21]. In particular, SPP is a more reliable tool for detecting severe PAD involving calcified vessels and predicting healing of ischemic wounds than other methods for evaluating the macrocirculation and microcirculation (ABI, ankle pressure, toe–brachial index, toe pressure, and TCPo2) [15, 18, 22]. Indeed, given its simplicity and being approved for clinical use, SPP is widely used in most Japanese vascular centers. According to Castronuovo et al. [19], SPP values of 40–50 mmHg or higher at the proximal margin of the wound are associated with a high likelihood (90% and more) of wound healing in critically ischemic limbs (Fig. 2b). Thus, an SPP value less than 40–50 mmHg is the cutoff for diagnosing CLI; it is a strong indication for revascularization. In the clinical setting, even if macrocirculation indicators such as ABI are abnormal, SPP, a measure of the microcirculation, can be preserved in some patients, and vice versa. Therefore, evaluation of the microcirculation should be routine in patients with rest pain or tissue loss. When SPP measurement is unavailable, TCPo2 is an alternative.

Atherosclerotic PAD is a major cause of CLI. Critically ischemic wounds consist of dry and wet wound. Typically, dry wounds can be observed in traditional CLI such as nondiabetic or non ESRD-related CLI. Caution needs to be taken to prevent sepsis when dry wounds might change to wet wounds because of the development of local bacterial infection after revascularization. Wet wounds can be frequently observed in diabetic or ESRD-related CLI, suggesting a significantly underlying bacterial infection (Fig. 1). If microcirculation in the foot is preserved, the cause of wound might be toe circulation disorder such as typical diabetic foot even though significant arterial lesions are evident. Nonatherosclerotic PAD (NAPAD) is potentially contaminated in our daily practice (Fig. 3). Underdiagnosis or misdiagnosis of NAPAD can lead to serious adverse outcomes that may be avoided or minimized with awareness of its distinctive symptoms and signs [23‐28]. However, despite its common symptoms, NAPAD remains underappreciated compared to atherosclerotic PAD due to its low prevalence. Limb ischemia in younger patients warrants a high index of clinical suspicion for NAPAD. Even in older patients, most cases of NAPAD (e.g., infrapopliteal artery disease in patients without diabetes and renal failure) including vasculitis (e.g., scleroderma) and thrombophilia (e.g., antiphospholipid syndrome, essential thrombocytosis) might be misinterpreted as an atherosclerotic condition [29‐31]. There is no vascular imaging feature in nonatherosclerotic CLI. Therefore, a high clinical index of suspicion for NAPAD with physical examination and laboratory tests is an integral part of the diagnostic evaluation. In cases where the microcirculation of the foot is preserved, other disorders including cholesterol embolization syndrome, calciphylaxis, venous stasis, systemic disorders (e.g., paraneoplastic syndrome and myeloproliferative disorder), and adverse effects of medications might be considered because patients with nonatherosclerotic CLI or conditions other than CLI might require different specific treatments (Fig. 4). Thus, correctly diagnosing the etiology of arterial lesions is essential for appropriate treatment strategy.

Since the traditional categories of the Rutherford classification do not take into account coexistent bacterial infection in an ischemic wound, the WIFI classification has emerged in the context of wounds, ischemia, and infection [32]. More recently, with an awareness of the importance of concomitant foot deformity, the concept of arterial insufficiency, infection, and foot deformity (AID) concept has been proposed [33]. The extent to which ischemia, bacterial infection, neuropathy, and foot deformity are involved in each patient with CLI varies (Fig. 5).

Although this is the time to liberally embrace contemporary endovascular procedures, standalone endovascular therapy alone cannot facilitate clinical success because many patients present with severe ischemic wounds, often with ongoing bacterial infection that can involve cellulitis, abscess, osteomyelitis, gas gangrene, or necrotizing fasciitis (Fig. 6). Therefore, in parallel with the assessment of foot ischemia and revascularization, assessment of the range and depth of bacterial infection is crucial. The bottom line is proactive wound management that encompasses timely liberal removal of devitalized structures (necrotic infected tissue), empirical or sensitivity-based antibiotic treatment, glucose control, off-loading, and epithelialization-stimulating dressings (Fig. 5) [34].

An essential process of wound healing includes: bleeding and inflammation, which are reactions to revascularization; and granulation, epithelialization, and reconstitution, which reflect cell proliferation. In cases where bacterial wound infection develops after revascularization, urgent debridement is required to prevent the development of sepsis and accelerate the wound healing process. In addition, in cases of preexisting severe bacterial wound infection (e.g., malodorous, high CRP), primary urgent debridement followed by endovascular revascularization needs to be considered. In particular, gas gangrene and necrotizing fasciitis might need urgent surgical intervention such as debridement or major amputation because these soft tissue bacterial infections can rapidly spread and become life threatening. In cases of severe inflammation with cellulitis, abscess, and osteomyelitis before or after revascularization, the priority for treatment can be placed on temporary debridement or minor amputation to prevent sepsis (Figs. 7, 8). In cases of uncontrolled infected wounds, major amputation or palliative care can be considered for patients who are not eligible for any intensive care and revascularization. In addition, rehabilitation to prevent disuse muscle atrophy is indispensable in CLI practice for functional capacity after wound healing and limb salvage. Therefore, since an individualized approach including specialists (plastic surgeons, orthopedic surgeons, etc.) and nurses can translate into improved management of CLI, a qualified team that organizes the disciplines of endovascular therapy and wound care should be established in each institution or regional medical network.

Regular serial evaluation of the wound and microcirculation after revascularization until complete wound healing can facilitate early identification of wound worsening and timely clinically driven reintervention and debridement. Judging from the Japanese clinical experience, SPP evaluation or a similar technique on the day after the procedure, 2–3 days later, 7 days later, 1 month later, and every month thereafter might be a reasonable routine schedule [4]. In cases of unfavorable wound conditions (e.g., wound color, speed of granulation), temporary evaluation for severity of ischemia and infectious wound is recommended. Also, even if foot microcirculation is preserved, a couple of times of debridement or minor amputation might be needed to remove residual necrotic or infectious tissue and to control recurrence of infection in the wound until complete wound healing.

Increasing awareness of lower limb artery anatomical variations can improve patient care. Although a persistent sciatic artery is a well-recognized anatomical variant in the suprapopliteal artery segment, variants in the popliteal artery branching pattern consisting of aplasty or hypoplasty of the tibial artery, a high takeoff for the tibioperoneal artery, trifurcation, and anterior tibioperoneal trunk are also not uncommon [62]. Given that approximately 10% of infrapopliteal arteries have variants, with the type 3A variant characterized by an aplastic posterior tibial artery and a hypertrophied peroneal artery connected to the plantar artery being the most common, differentiating occlusion from anatomical variation is a challenging task in severe infrapopliteal artery disease. When an infrapopliteal variant is observed in one extremity, there is a 28–50% probability of the same pattern on the other side. Keeping in mind the possibility of underlying infrapopliteal variations is the key to their successful identification and outcomes [62‐64].

Amid a pandemic of PAD with diabetes and ESRD in Asia, endovascular therapy represents a paradigm shift in the treatment of CLI. However, from a clinical perspective, a comprehensive patient-oriented approach, rather than a one-size-fits-all approach, is the key to clinical success. Therefore, harmonization of revascularization and wound management into a coordinated multidisciplinary approach that goes beyond a specialty-based framework is vital for the treatment of CLI.