Critical Limb Ischemia: Diagnosis and Current Management

Research Article Joseph Karam, MD Elliot J. Stephenson, MD From: Minneapolis Heart Institutet at Abbott Northwestern Hospital, Minneapolis, MN Address for correspondence: Joseph Karam, MD Minneapolis Heart Institutet at Abbott Northwestern Hospital 920 E 28th Street Suite 400 Minneapolis, MN 55415 E-mail: joseph.karam@allina. com Ó by the Minneapolis Heart Institute Foundation Critical Limb Ischemia: Diagnosis and Current Management ABSTRACT Critical limb ischemia is considered the end-stage of peripheral arterial disease. It presents a challenge to the treating physicians since no consensus exists on a classification system and treatment algorithm. Furthermore, the disease carries a high morbidity and mortality rate. Even with optimal medical therapy and appropriate wound care, treating these patients may require a combination of both open and endovascular procedures. KEY WORDS critical limb ischemia, peripheral artery disease n INTRODUCTION Critical limb ischemia (CLI) is considered the end-stage of peripheral arterial disease (PAD). CLI is defined by the international consensus as, A patient with chronic ischemic rest pain, ulcers, or gangrene attributable to objectively proven arterial occlusive disease. 1 The pathophysiology of CLI is that of chronic insufficiency in blood flow to match the oxygen demands of the distal tissues. This leads to a cascade of events that subsequently may result in rest pain or tissue loss. As its name implies, CLI is a chronic process and is not to be confused with acute limb ischemia, which refers to an acute occlusion of the distal arterial tree with its ensuing ischemic manifestations. However, an acute change to a chronic PAD patient may manifest as CLI either from a new wound or acute worsening of the arterial supply. The Fontaine and Rutherford classification have been used to create a uniform description of the stages of PAD based on clinical presentation (Table 1). CLI patients fall into the more severe ends of the classification of both: Fontaine stages III and IV or Rutherford grades 4 through 6. Although PAD is a common condition affecting 8 to 10 million Americans, only 10% of patients with this condition develop CLI. Approximately 1% of patients with PAD have CLI. This subset of patients carries a considerable rate morbidity and mortality with an overall morality approaching 50% at 5 years and 70% at 10 years. 2 4 Up to 25% of patient presenting with CLI will receive a primary amputation despite current treatment modalities. Even with advances in medical treatments and revascularization, only 25% of patients will have resolution of symptoms while preserving their limb. 1 The high amputation rate is partly due to the fact that most CLI patients are referred to vascular surgeons late in the course of their disease. Case Report #1: Endovascular Revascularization A 79-year-old male presented to the hospital with acute onset altered mental status and weakness. His medical history is notable for coronary bypass, congestive heart failure (CHF), diabetes mellitus (DM), and PAD. At time of presentation he had a leukocytosis and his left foot had gangrenous changes to the first 4 digits, concerning for source of his infection. He had normal femoral pulse, absent popliteal and pedal pulses, and monophasic Doppler signals in the left foot. Ankle brachial indices could not be measured due to noncompressible vessels. Toe-brachial indexes (TBIs) on the right were 0.36 and unobtainable on the left because of the gangrenous digits. Transcutaneous oximetry showed severely limited oxygenation. At initial angiogram, the superficial femoral artery (SFA) lesion was successfully stented and a popliteal lesion with extension into the tibioperoneal trunk and origin of the posterior tibial artery was identified. Distal to the occlusions, two-vessel runoff to the ankle was evident through the anterior tibial (AT) and posterior tibial (PT) arteries, although the 124 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 2 n Fall/Winter 2017

KARAM AND STEPHENSON TABLE 1 Classification systems for PAD. Classification Stage Clinical Description Fontaine I Asymptomatic IIa Mild claudication IIb Moderate to severe claudication III Rest pain IV Ulceration or gangrene Rutherford 0 Asymptomatic 1 Mild claudication 2 Moderate claudication 3 Severe claudication 4 Rest pain 5 Minor tissue loss 6 Severe tissue loss or gangrene AT has an occlusion at the ankle (Figure 1). Postangiogram oximetry revealed no significant improvement with SFA intervention. Surgical revascularization options were limited. Given his multiple comorbidities and lack of conduit, he was taken back to the angiography suite for additional endovascular revascularization. The PT was accessed at the ankle with a micropuncture needle and wire (Cook Medical, Bloomington, IN), the inner dilator was used to exchange for a V-18 control wire (Boston Scientific, Marlborough, MA) without a sheath. A 2.6-Fr catheter (CXI; Cook Medical) was placed over the V-18 wire for support. The occlusion was crossed with a 0.018-inch angled glidewire (Terumo Medical Corp., Somerset, NJ) and the support catheter (Cook Medical). The 0.018 glidewire, advanced from the antegrade femoral access site, was snared from above and then externalized through the contralateral femoral access. The popliteal occlusion was stented with a stent (Supera; Abbott Vascular, Santa Clara, CA; Figure 2). The PT lesion was angioplastied with a 2-mm balloon. The completed angiogram showed good flow through the PT to the ankle (Figure 3). Subsequently, the patient underwent a transmetatarsal amputation of his left foot with primary healing at 7 weeks. FIGURE 1 Angiogram showing occlusion of popliteal artery, with proximal reconstitution of AT and more distal reconstitution of the PT. Case Report #2: Hybrid Revascularization With Both Open and Endovascular Interventions A 71-year-old male was admitted to the hospital with right second toe gangrene and cellulitis. His past medical history was significant for poorly controlled DM, atrial fibrillation on chronic anticoagulation, CHF, hypertension and dyslipidemia, and PAD. A year prior to this presentation, he underwent a balloon angioplasty of the left SFA for a nonhealing ulcer of the left foot. His clinical exam on admission revealed a palpable bilateral femoral pulse with absent distal pulses on the right. Broad spectrum antibiotics were initiated. Angiography revealed a high-grade stenosis of the proximal popliteal artery (Figure 4) that was successfully treated with a balloon angioplasty and stenting. The runoff to the ankle was the PT and peroneal arteries as the AT artery. The dorsalis pedis (DP) artery, which filled via collaterals, is the only flow to the forefoot. He underwent a toe amputation with the podiatry service. He presented back a month later with new third toe gangrene and dehiscence of the amputation site. He JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 2 n Fall/Winter 2017 125

CRITICAL LIMB ISCHEMIA: DIAGNOSIS AND CURRENT MANAGEMENT FIGURE 2 Supera stent in the mid popliteal artery. underwent an SFA to DP bypass using cephalic vein, as he had no usable leg veins. Postoperatively, his TBI increased to 0.52. He underwent debridement with primary closure of the right foot. At his follow-up appointment, the bypass was patent and the foot was completely healed. FIGURE 3 Completion angiogram. Not the significant improvement in flow through the PT, the AT fills via collaterals, but in a more delayed fashion. Diagnosis Clinical history and physical exam will often provide insight into the diagnosis. Pain at rest without exertion, which worsens with elevation of the foot and improves with dependency, is consistent with ischemic rest pain, although a number of other conditions may also cause leg pain. Physical examination often reveals an absence of pedal pulses. Doppler examination usually reveals monophasic or no signals. The foot is often cool and red, which blanches with pressure or elevation, termed dependent rubor. Additionally, the location and character of wounds on the legs and feet should be carefully considered. Noninvasive arterial studies are the primary diagnostic modality for peripheral arterial disease and critical limb ischemia. Ankle blood pressures divided by the brachial blood pressure yields the ankle brachial indices (ABIs). This and toe pressures are a relatively inexpensive, noninvasive means to measure arterial circulation. ABIs may be falsely elevated due to noncompressibility, which limits the diagnostic efficacy, particularly in diabetic patients. Arterial duplex ultrasonography, pulse volume recordings, or segmental pressures may assist with localizing the areas of disease. Computed tomographic angiography and magnetic resonance angiography are often useful, although have increased cost and risk. Digital subtraction angiography is the gold standard for diagnosis, and also offers the potential for intervention at the time of procedure. 126 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 2 n Fall/Winter 2017

KARAM AND STEPHENSON challenge. This scenario is typically encountered in patients with severe diabetic arteriopathy and end-stage renal disease. In a review of 169 patients with CLI and uncomplicated ulcers treated with wound care, antibiotics and optimization of medical management, the amputation rate was 23% at 12 months. Among patients with ABI,0.5, however, the amputation rate increased to 35% at 12 months. 5 Statins, antiplatelet agents, and antihypertensive medications have been shown to decrease cardiovascular adverse event rates in patients with PAD. For the subset of patients with CLI, Schanzer et al. 6 showed that only statins conferred a survival advantage for CLI patients at 1 year following revascularization. Emerging evidence reveal that cilostazol may prevent in-stent stenosis. FIGURE 4 Stenosis in right popliteal artery. Clips from prior vein harvest for coronary bypass and prosthetic knee also noted. Management The goals of treating CLI are to relieve ischemic pain, heal ulcers, and prevent further tissue loss. More importantly, the patient s functional outcome, quality of life, and survival should be considered when assessing therapeutic modalities. When taking these factors into account, revascularization may not always represent the best option for management. Certain clinical presentations might dictate greater benefit to patients with medical therapy or primary amputation. Medical Therapy Medical therapy alone should be considered in patients who are poor surgical candidates with stable, uncomplicated tissue loss or rest pain that is adequately controlled with pain medications. Despite advances in endovascular technology, patients with severe tibial disease and poor outflow vessels continue to represent a Primary Amputation Primary amputation remains a commonly performed procedure for CLI, but has a rate of postoperative morbidity and mortality as high as 12%. 1,7 Up to 25% of patients presenting with symptomatic CLI receive a primary amputation. 8 Deciding whether a patient should receive a primary amputation must take into consideration both anatomic as well as clinical factors. In addition to arterial disease not amenable, other clinical reasons to consider primary amputation are lifethreatening infections, nonambulatory preoperative status, dementia, and terminal illness with limited life expectancy. While primary amputation may seem less complicated when compared to revascularization, it has been shown to be a poor prognostic factor. Fifteen percent of patients undergoing amputation subsequently require a contralateral amputation. Another 15% require revision to an above the knee amputation following initial below the knee amputation. Overall, about 30% of patients will be dead at 2 years following a below the knee amputation. 1 Modality of Revascularization The decision-making process on the choice of modality requires consideration of the patient s overall health status, comorbid conditions, life expectancy, and ambulatory status. The ability to tolerate general anesthesia and surgical bypass needs to be assessed. Although it may seem that perioperative mortality following endovascular revascularization using sedation is lower than that for bypass surgery, recent reports contradict this with rates of 2% to 8% for both. 9,10 Choosing a modality for intervention requires consideration of the following: A careful evaluation of the patient s affected limb with emphasis on identifying infection and soft tissue compromise. JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 2 n Fall/Winter 2017 127

CRITICAL LIMB ISCHEMIA: DIAGNOSIS AND CURRENT MANAGEMENT Obtaining a complete history of any previous vascular intervention(s). Evaluating the patient s vascular anatomy. Assessing the availability and usable autogenous conduit with vein mapping for a possible bypass. Surgical revascularization Bypass surgery using autogenous vein graft is the gold standard for the treatment of CLI. This procedure has been shown to be durable with up to 70% patency and limb salvage rates exceeding 80% at 5 years. 1,11 The quality of the conduit used is one of the most important predictors of outcomes. The status of the runoff is an equally important factor in predicting long-term outcome of a bypass. A single-segment great saphenous vein (GSV) with at least 3.5 mm in diameter is the optimal conduit. 12 Upper extremity veins and splicing veins harvested from different locations are other conduits to be considered if there is no usable GSV. Prosthetic conduits and homografts are usually a last resort. Composite veins and arm veins were shown to have a 1.6-fold increase in primary graft failure as compared to single segment GSV. Prosthetic grafts are known to have poor outcomes in femorotibial bypasses with patency of 30% at the most at 2 years, 13 compared to 60% patency at 5 years when used for above knee bypasses. 14 Prosthetic grafts are also plagued with the risk of infection that could eventually lead to limb loss. Despite having relatively similar rates of perioperative mortality as compared to endovascular procedures, surgical revascularization carries a higher risk of postoperative morbidity. Wound complications are common in this patient population, which may then lead to prolonged hospitalizations, higher rate of readmissions, and significant discomfort to the patient. Systemic complications such as cardiac, pulmonary, and renal issues are also common. Endovascular Revascularization There are multiple techniques and devices available for endovascular interventions. The key to a successful intervention is crossing the lesion with both a wire and the revascularization device. The mainstays for endovascular revascularization are balloon angioplasty and stenting. Stents are useful for treatment of stenoses that do not respond well to angioplasty. This may occur due to recoil or heavily calcified lesions. Stents may also be used to treat dissections that can occur with angioplasty. Among the benefits of endovascular intervention is its less invasive nature compared to open surgery. Interventions can be performed with local anesthesia and moderate sedation in most cases. Recovery is often accelerated, and hospitalizations can sometimes be avoided. Additionally, these procedures can be done as outpatients, decreasing cost. The primary risk is from the arterial access site, manifesting most frequently as hematoma or pseudoaneurysm, although arterial injury with dissection or occlusion can also occur. Open Versus Endovascular Intervention Currently, the only randomized trial comparing endovascular and open revascularization is the Bypass versus Angioplasty in Severe Ischemia of the Leg trial (BASIL trial). This was a trial from the 27 centers in the United Kingdom, which enrolled 452 patients with severe limb ischemia that were randomized to a bypass first or balloon angioplasty first strategy. Authors reported no significant difference between amputation free survival and overall survival between the 2 groups. However, the subgroup of patients who survived more than 2 years had a significant increase in overall survival and trend toward increase in amputation-free survival. 15 A number of issues limit the generalizability of the study. First, only balloon angioplasty was used for endovascular treatment. Second, there was a relatively high rate of crossover between the 2 groups and high percentage of patients in both arms required a second intervention. Patients who failed 1 revascularization option and subsequently were treated with the other available option, remained in the former analysis group as a result of the intention to treat design of the study. The fact that significant numbers from each strategy crossed over and received the alternative therapy makes conclusions difficult to interpret. Finally, the finding that patients who survived more than 2 years benefited from a surgery first approach is not easily generalizable as practitioners are notoriously poor at predicting patient longevity. 16 The ongoing Best Endovascular versus best Surgical Therapy for patients with Critical Limb Ischemia (BEST-CLI) is designed to address a number of the limitations of the BASIL trial. The definition of CLI included corroborating hemodynamic criteria. Additionally, the study of infrainguinal disease was clarified by the inclusion of adequate aortoiliac flow and defined the parameters to clarify that inflow was adequate. This is a multicenter trial including multiple specialties (vascular surgery, interventional radiology and cardiology). Treatment includes the best endovascular option versus best surgical option with the details and techniques left to practitioners. The surgical arm includes both optimal conduit (single segment of good great saphenous vein) vs disadvantaged conduit (spliced, arm vein prosthetic, etc.). The trial is currently enrolling. 17 Conclusion Currently, no good level 1 evidence exists to support an endovascular first or surgery first intervention. The BEST-CLI trial may help address this question, 128 JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 2 n Fall/Winter 2017

KARAM AND STEPHENSON although with the disparate processes likely certain patients would be better suited with an endovascular first strategy and certain patients may benefit from a surgical first strategy. Better classification schemes and future trials will hopefully offer evidence on which patients may benefit from one strategy over the other. Even with better evidence, there will likely be a continued need for both open surgical and endovascular techniques to best treat this challenging patient population. n REFERENCES 1. Norgren L, Hiatt WR, Dormandy JA, et al. TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease (TASC II). Int Angiol. 2007;26:81 157. 2. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). Circulation. 2006;113:e463 e465. 3. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381 386. 4. Nehler MR, Peyton BD. Is revascularization and limb salvage always the treatment for critical limb ischemia? J Cardiovasc Surg (Torino). 2004;45:177 184. 5. Marston WA, Davies SW, Armstrong B, et al. Natural history of limbs with arterial insufficiency and chronic ulceration treated without revascularization. JVascSurg. 2006;44:108 114. 6. Schanzer A, Hevelone N, Owens CD, Beckman JA, Belkin M, Conte MS. Statins are independently associated with reduced mortality in patients undergoing infrainguinal bypass graft surgery for critical limb ischemia. J Vasc Surg. 2008;47:774 781. 7. Karam J, Shepard A, Rubinfeld I. Predictors of operative mortality following major lower extremity amputations using the National Surgical Quality Improvement Program public use data. J Vasc Surg. 2013;58:1276 1282. 8. Conte MS. Critical appraisal of surgical revascularization for critical limb ischemia. J Vasc Surg. 2013;57:8S 13S. 9. Vogel TR, Dombrovskiy VY, Carson JL, Graham AM. Inhospital and 30-day outcomes after tibioperoneal interventions in the US Medicare population with critical limb ischemia. J Vasc Surg. 2011;54:109 115. 10. Conrad MF, Crawford RS, Hackney LA, et al. Endovascular management of patients with critical limb ischemia. J Vasc Surg. 2011;53:1020 1025. 11. Taylor SM, Cull DL, Kalbaugh CA, et al. Critical analysis of clinical success after surgical bypass for lower-extremity ischemic tissue loss using a standardized definition combining multiple parameters: a new paradigm of outcomes assessment. J Am Coll Surg. 2007;204:831 838. 12. Schanzer A, Hevelone N, Owens CD, et al. Technical factors affecting autogenous vein graft failure: Observations from a large multicenter trial. JVascSurg. 2007;46:1180 1190. 13. Kapfer X, Meichelboeck W, Groegler FM. Comparison of carbon-impregnated and standard eptfe prostheses in extraanatomical anterior tibial artery bypass: a prospective randomized multicenter study. Eur J Vasc Endovasc Surg. 2006;32:155 168. 14. Devine C, McCollum C. North West Femoro-Popliteal Trial Participants. Heparin-bonded Dacron or polytetrafluorethylene for femoropopliteal bypass: five-year results of a prospective randomized multicenter clinical trial. JVascSurg. 2004;40:924 931. 15. Bradbury AW, Adam DJ, Beard JD, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005;366:1925 1934. 16. Conte MS. Bypass versus angioplasty in severe ischaemia of the leg (BASIL) and the (hoped for) dawn of evidence-based treatment for advanced limb ischemia. J Vasc Surg. 2010; 51(suppl 5):69s 75s. 17. Menard MT, Farber A, Assmann SF, et al. Design and rationale of the best endovascular versus best surgical therapy for patients with critical limb ischemia (BEST-CLI) trial. J Am Heart Assoc. 2016;5:e003219. JOURNAL OF THE MINNEAPOLIS HEART INSTITUTE FOUNDATION n Volume 1 n Issue 2 n Fall/Winter 2017 129