Understanding Perfusion Evaluation in Critical Limb Ischemia: Mission Possible

As per the 2016 American Heart Association/American College of Cardiology (AHA/ACC) guidelines on the management of patients with lower extremity peripheral artery disease (PAD), critical limb ischemia (CLI) was defined as “a condition characterized by chronic (≥2 week) ischemic rest pain, nonhealing wound/ulcers, or gangrene in 1 or both legs attributable to objectively proven arterial occlusive disease.”¹ Unfortunately, the latter part often appears harder to prove than it should be, therefore CLI can be misdiagnosed, or is sometimes even overlooked because ischemia may not have been considered in the differential. Goodney et al. showed that 54% of 20,464 Medicare-insured patients with PAD who underwent above or below the knee amputation did not have a diagnostic angiogram or revascularization performed in the preceding year.² Similarly, and in a more contemporary analysis, Reinecke et al. showed that out of 4,298 patients with CLI and leg amputation, more than 1,650 never had a vascular procedure in the previous 24 months.³ While there are many possible explanations including geographic, patient and practice-level disparities, insufficient knowledge about the interpretation and/or appropriate selection of hemodynamic tests leading to underrating of the underlying ischemia is probably a key factor. As just one of many examples, Shishehbor et al. analyzed 237 IN.PACT DEEP trial-patients with CLI Rutherford class 4-6 which was validated clinically along with a core-lab adjudicated evidence of significant angiographic infrapopliteal disease and found that only 6% and 16% had met the CLI diagnostic criteria applying the societal guidelines-suggested cutoffs for ankle-brachial index (ABI) and systolic ankle pressure, respectively.⁴ If these cutoffs were to be used in the studies by Dr. Goodney and Dr. Reinecke to grade the severity of PAD, then even less patients would have been classified as having severe ischemia and probably more would have undergone primary amputation without any further vascular investigation. CLI has a dreadful path with only half of the patients reaching the 6-month mark alive with preserved limbs.⁵

To improve the outcomes of CLI, earlier detection and advancement in treatment are both necessary. The second part has been relatively static with timely revascularization still being the mainstay of therapy which is totally dependent on early detection. AHA has realized that an accurate limb perfusion assessment is the cornerstone in appropriately identifying, treating, and following patients with CLI. Subsequently, a team of experts was designated to prepare an AHA Scientific Statement titled: “Perfusion Assessment in Critical Limb Ischemia: Principles for Understanding and the Development of Evidence and Evaluation of Devices” (REFS). The authors should be congratulated on this extremely well-written, timely, and much needed practical document. This AHA statement does not provide an algorithm for order of testing in CLI, but rather a forum for diverse perspectives through an in-depth discussion of all limb perfusion modalities available, from simple bedside techniques to novel tools, their diagnostic accuracy, prognostic value, limitations, knowledge gaps, and their impact on public health and future directions. More importantly, it highlights the critical role of perfusion assessment not just in making the correct diagnosis and following patients post intervention, but also during procedures to guide and ensure an adequate revascularization.

CLI is a disease of both macro and microcirculation, and thus it is very important to evaluate the two when encountering such patients, especially those with tissue loss. Ironically, the most frequently ordered test in CLI, the ABI, is the one most likely to be falsely reassuring. However, it is simple, cheap, and can be done in the office with a hand-held Doppler device and appropriate blood pressure cuffs. When calculating ABI, using the affected angiosome-related systolic ankle pressure, rather than the highest systolic ankle pressure, would likely increase the sensitivity of this test in a disease where false negatives are unaffordable. Knowing ABI limitations, if an ABI is not diagnostic in a patient with a non-healing wound, then it is recommended to proceed with other tests that can evaluate both circulations such as toe-brachial index (TBI), skin perfusion pressure (SPP), or transcutaneous oxygen tension (TcPO2).1 It is crucial to maintain high clinical suspicion for CLI regardless of the trigger, as not every case starts as a CLI but it may end as one. In trauma or even pressure heel ulcers, the blood flow might have been already reduced at baseline but sufficient enough to keep the skin intact; however, and after the development of an ulcer, the pressure requirement for ulcer healing is now higher and therefore evaluation for CLI would be indicated if other conservative measures like offloading and wound care fail. Accordingly, the authors emphasized the dynamic nature of the perfusion test cutoffs as different wounds may require different perfusion pressures to heal depending on other characteristics like the presence of infection, wound size and depth, and the control of contributing factors including diabetes, dyslipidemia, edema, malnutrition, just to name a few. Other perfusion assessment tools, namely perfusion computed tomography (CT), perfusion magnetic resonance imaging (MRI), and hyperspectral imaging, are limited to large academic centers and have a limited role in daily CLI practice. Nonetheless, they may help improve our understanding of CLI pathophysiology, evaluate response to new treatment options like stem cell therapy, and finally explain the variations in presentation, response to traditional treatment, and outcomes seen across different populations. While more research is needed to prove the efficacy of novel non-invasive techniques like FlowMet-R in guiding intraprocedural revascularization and predicting wound healing in CLI, intra-procedural wound blush score might be promising.⁶

Proper perfusion assessment is critical in CLI, yet it can be challenging. There is no single perfect test and indeed these tools evaluate different aspects of limb perfusion with each providing unique information. Therefore, it is important to understand this AHA statement in order to be able to choose wisely among available tests, depending on the purpose of the evaluation, and to interpret their results accurately. In addition, more attention needs to be paid to certain higher risk groups for complications, particularly women and blacks.