A Practical Approach to Endovascular Therapy fr Infrapopliteal Disease and the Treatment of Critical Leg

Interventional cardiologists have increasingly translated their coronary skills to the field of peripheral interventions. Patients with cardiovascular disease frequently have associated PVD. This places cardiologists at the vanguard of carotid, subclavian, renal and lower extremity interventions. Many interventional cardiologists are already aggressively treating suprainguinal and infrainguinal disease, and are participants in the expanding field of aortic aneurysm stent grafting. However, by and large, below-knee angioplasty is avoided, either out of the misguided belief that percutaneous interventions are fruitless, or for fear of enduring the consequences of a limb-threatening complication. The literature is replete with warnings that the tibial arteries are too small or prone to develop spasm or clot. Additionally, infrapopliteal endovascular interventions are viewed as high risk and prone to failure with little surgical recourse should disaster strike. In reality, the consequences of failed angioplasty in this area are unclear, however, known complications include amputations, renal failure, embolization and perforations. Tibial disease generally presents as critical limb ischemia (CLI), a condition which cardiologists have little working knowledge of. In roughly 25 to 30% of cases, however, infrapopliteal disease presents as claudication, particularly in concert with superficial femoral artery (SFA) and popliteal lesions, and yet we still relegate its treatment to the vascular surgeons. One can count on one hand the number of clinical reports of below-the-knee endovascular interventions reported in the cardiology literature over the last decade. We choose to ignore what we already know: that endovascular therapy can be performed without the need for general anesthesia or long surgical incisions and incurs lesser costs with decreased morbidity. Furthermore, recurrences can be simply retreated and surgery utilized only as a fallback position, allowing preservation of precious veins for subsequent procedures. The history of below-knee interventions in fact dates back to the earliest days of percutaneous angioplasty, being first described with mixed results by Dotter and Judkins back in 1964. Gruentzig's introduction in 1976 of dual lumen balloon catheters held the promise for more effective treatment of distal disease. The skills we have gained in treating coronary vessels, along with advancements in imaging and equipment, all mean that cardiologists with experienced peripheral training are prepared to assume the care of this difficult set of patients. The infrapopliteal vascular bed should not be approached by the novice endovascular interventionalist. The accepted indication for below-knee endovascular interventions remains primarily the treatment of critical or limb-threatening ischemia. Most patients with PVD maintain lower extremity perfusion adequate for tissue viability, but insufficient to prevent ischemic pain during exertion (claudication). Acute or chronic CLI is defined as the lack of sufficient perfusion to maintain the metabolic needs of the skin and other tissues, even under resting conditions. Only 1.4% of patients with PVD develop ischemic rest pain or tissue loss, though it is more frequent in diabetics and smokers. Acute ischemia is caused either by embolus or thrombosis. When pain, pallor, polar (cold) are accompanied by parathesias and paralysis, urgent revascularization, usually surgical embolectomy, is required. Percutaneous techniques assume a greater relevance when encountering the more frequent subacute or chronic manifestations of ischemic rest pain, trophic skin changes, tissue loss or simple claudication. Indeed, as techniques have evolved and success becomes more assured, only patients with severe claudication are now being treated. An additional important indication for below-knee angioplasty is to improve run-off and subsequent long-term patency after femoropopliteal angioplasty/stenting or bypass grafting. Before embarking for the first time in the treatment of these patients, the cardiologist must appreciate the five As of below-knee interventions: 1) Anatomy; 2) Additional considerations; 3) Angiography; 4) Access; and 5) Angioplasty. Anatomy Figure 1 describes the relatively simple anatomy of the infrainguinal vessels. The external iliac artery becomes the common femoral artery (CFA) just distal to the lateral circumflex and inferior epigastric arteries at the level of the inguinal ligament (Figure 2). The CFA subsequently divides into the deep profunda femoral artery (PFA) and superficial femoral artery (SFA). The laterally situated PFA is an important source of collateral flow to the distal vessels. Significant occlusive disease of the PFA, in conjunction with severe SFA disease, can lead to critical leg ischemia. This fact must be recognized and patency of the PFA preserved when working on the SFA. The tibial or infrapopliteal arteries provide blood flow to the gastrocnemius and soleus muscles of the calf, as well as to the arterial arcade of the foot. While these vessels are a common site of arterial disease, single or multiple stenosis of one crural vessel rarely provokes claudication. Rather, significant disease of all three infrapopliteal arteries (anterior tibial, peroneal, and posterior tibial) is usually required to provoke symptoms in the absence of proximal flow-limiting lesions of the ileofemoral system. In the setting of limb salvage, the majority of patients will present with multi-level and multi-lesion disease. Only 20-30% of patients have focal lesions, with only one to two vessels being favorable for PTA . A concomitant procedure, usually SFA and/or popliteal PTA, is necessary in most patients undergoing a below-knee PTA because of the predominance of multi-level occlusive disease. Thus, the results of femoropopliteal and tibial PTA are closely associated. Additional Considerations Before embarking on treatment, interventionists must appreciate that these patients represent a high-risk subset with vascular disease, which often negatively impacts on their treatment and expectations for success. They are older than average, with associated advanced cardiac and cerebrovascular disease. The natural history of patients with rest pain alone carries a five-year mortality rate of 50%. Patients undergoing a major amputation have an associated five-year mortality rate of 50-70%, which isn™t much surpassed by long-term survival rates after long leg surgical grafting. CLI is a particular concern in diabetics who represent 63-91% of patients undergoing PTA for limb salvage. These patients generally have relative sparing of iliac and femoropopliteal segments, but present with more extensive tibial disease and reconstitution of at least one pedal artery. Diabetic neuropathy frequently coexists with vascular disease, resulting in diminished protective sensation, limited joint mobility, subsequent pressure sores and development of infection. The presence of end-stage renal disease has a negative prognostic effect on the durability of endovascular techniques due to diffuse calcification with pedal involvement. In general, a successful treatment strategy will need to restore straight-line flow into the pedal arch (Figure 3). Dilatation of a proximal lesion, no matter how inviting or how much it may improve inflow to collaterals, will not yield lasting clinical benefit in limb salvage patients. Prior to angiographic studies, most of these patients will have had non-invasive studies such as ankle-brachial indices (ABI). Values below 0.3 to 0.4 are associated with severe claudication. Non-healing ulcerations or gangrene occur in the presence of ankle pressures of less than 50 mmHg. Toe systolic pressures are particularly useful in diabetic patients where the ABI may be falsely elevated due to arterial calcification. Values less than 30 mmHg suggest CLI and portend poor tissue viability. Similarly, transcutaneous oxygen levels of less than 40 mmHg predict limb loss or poor wound healing. No discussion of this topic would be complete without mention of compartment syndrome. This syndrome refers to the situation in which the pressure in a closed space, usually one of the enclosed myofascial compartments of an extremity, becomes high enough to restrict tissue perfusion and oxygen delivery. It usually follows prolonged ischemia and often results from both the original ischemic insult, as well as reperfusion. Although beyond the scope of this article, it would be wise for all cardiologists contemplating below-knee interventions to familiarize themselves with both the recognition and treatment of this feared complication. Angiography As in coronary interventions, precise imaging of the lesions prior to intervention is paramount to success. If you can't see it, you can't fix it! Most cardiologists have access to digital cardiac imaging, however many cath labs embarking on a peripheral program have not yet added digital subtraction angiography (DSA) to the cardiac imaging environment. Consequently, many diagnostic and interventional peripheral procedures in the cath lab environment still rely on cine angiography. Figure 4 demonstrates how interventionists and institutions substantially lower their odds for success. DSA, particularly the ability to perform arterial road-mapping, are crucial to the success of any interventional procedure. Due to the frequent presence of flow-limiting proximal disease, it can be very difficult to deliver sufficient contrast to opacify the distal vasculature. When severe multi-level disease is present, it is necessary to place a catheter in the common femoral artery (Figure 5), or even at the level of the knee, administer a vasodilator, and inject a dilute mixture of contrast with delayed DSA imaging. Cardiologists must further become familiar with the application and integration of alternative imaging modalities such as magnetic resonance angiography (MRA). Debate exists as to whether MRA can supplant angiography as the sole diagnostic tool prior to any contemplated intervention. Certainly, it is extremely effective in detailing the distal run-off vessels due to the ability of two-dimensional time of flight MRA to depict flow in distal vessels that may not opacify during contrast angiography because of proximal flow-limiting disease. Several reports have shown the potential for revascularization based on the results of MRA in the absence of DSA. However, limitations still exist in the widespread adoption of this technology such as in patients with prosthetic joints or vascular clips, or the inability to use it in individuals with devices such as pacemakers. In many instances, both techniques are required in the same patient because either alone failed to provide important diagnostic information. Generally speaking, most patients undergoing optimal digital subtraction angiography for chronic CLI will not benefit from the addition of MRA. However, MRA should be considered when DSA is suboptimal and when it is necessary to conserve contrast material. Indeed, vascular patients have associated renal insufficiency, which requires pre-treatment and the co-administration of various pharmacological agents to prevent further deterioration in renal function subsequent to iodinated contrast administration. Familiarity with new protocols utilizing N-acetylcysteine and fenolodopam is essential. Both carbon dioxide imaging and gadolinium have been advocated as alternative contrast agents for patients with renal insufficiency undergoing interventions. Their use, however, is limited by the impracticality of administration or dosage restrictions during these often complex procedures. Image quality is usually not sufficiently optimal with either carbon dioxide or gadolinium alone, which is then supplemented with iodinated contrast. Furthermore, to successfully image the most distal vessels, the legs must be elevated to take advantage of the lower density of CO2 relative to blood. This is impractical and time-consuming. Time is better spent relying on non-invasive imaging prior to the intervention, and then reducing the contrast load during the intervention through close surveillance of volume utilized, use of 5 cc injection syringes, dilute contrast and DSA, and the use of road-mapping. Access Often an afterthought in coronary interventions, the anatomy of the femoral triangle and pelvis (Figure 2) the proposed approach to the target vessels and the arterial stick are crucial to the ultimate success of the intervention. The CFA courses over the medial one-third of the femoral head, bifurcating into the PFA and SFA, usually just caudal to the femoral head. The mid-zone of the CFA overlies the femoral head and is the ideal entry point for all sticks because the vessel can be compressed against the underlying bone. Arterial punctures above the inguinal ligament can result in life-threatening retroperitoneal hemorrhage. Arterial puncture below the inguinal crease into the PFA or SFA may result in large hematomas, pseudo-aneurysms or A-V fistulas. A contralateral retrograde approach would be favored when there is concomitant iliac and significant proximal SFA disease. This would be particularly prudent in situations where management of the arterial access site after the line pull may be problematic, such as prolonged administration of thrombolytic agents or in very obese individuals. In such situations, a misplaced (ie. high) antegrade stick exposes the patient to significant bleeding risk. A simple approach would be to advance a braided 6 Fr x 40 cm sheath from the contralateral CFA around the aortic bifurcation, ultimately positioning it in the ipsilateral CFA for delivery of dye and equipment. The disadvantage of the loss of wire control when very distal lesions are approached from this remote location can be overcome by placing a 6 Fr guide in the distal SFA akin to coronary angioplasty. The working length of wires will have to be 300 cm and the balloon working length of at least 120 cm will be required when tackling the infrapopliteal vessels from this approach. An antegrade stick into the ipsilateral CFA is often the logistically easiest approach for working below the knee. This particular maneuver is often one of the last techniques interventional cardiologists master as they develop their peripheral skills. In order to perform most interventions through an antegrade puncture, the entry angle into the CFA should be as shallow as possible. Vertical punctures result in a greater likelihood of buckling and makes the introduction of introducer sheaths and catheters more difficult. In virtually all patients, but particularly in the obese, the skin entry site has to be several centimeters above the inguinal ligament. If necessary, a pillow can be placed under the buttocks to elevate the CFA and the abdomen taped cephalad to decrease redundant tissue. Prior to the puncture, it is prudent to review the anatomy of the femoral bifurcation from the initial diagnostic angiogram, particularly noting the origin of the PFA (Figure 6). One should attempt to enter the CFA at the lower half of the femoral head which lies below the inguinal ligament and above its bifurcation. A dye injection through the puncture needle with associated road mapping is very useful to determine the course of guidewire placement. Various maneuvers are possible if the wire is persistently directed into the PFA. After documenting that the entry point was into the CFA, the needle can be redirected to the contralateral wall, and the wire readvanced into the SFA (Figure 7). Alternatively, the floppy tip of a moveable core wire can be advanced into the PFA with the wire pushed to herniate into the SFA. A third method is to leave the wire in the PFA, exchange the entry needle for a small 4 or 5 Fr angled catheter, remove the wire, and withdraw the angled catheter while dye is injected to redirect it into the SFA. A variation on this maneuver would be to similarly exchange the needle for a 4 Fr dilator, place a 0.018 inch wire in the PFA through the dilator and attached Tuohy-Borst adapter, and then with dye injections and/or road-mapping, advance a second 0.018 inch wire through the dilator into the SFA. Finally, through special order from Cook, a Saddekni-Cope dilator catheter with dual lumen side and end holes allows for wire catheterization of the SFA after the PFA is inadvertently entered. For procedures which involve simple balloon angioplasty or even the placement of small vessel stents in the tibial vessels, a 4 Fr sheath (equivalent of the inner diameter of a 6 Fr guide) is sufficient and makes subsequent hemostasis simpler and safer. Sheaths should be removed when the ACT falls below 200 seconds. Protamine may be administered if necessary (except in diabetics). In antegrade punctures, the skin entry and the arterial entry points are further apart than in a retrograde stick, particularly in obese patients and in shallow angle punctures. Accordingly, compression must be applied over the presumed entry point, which is well below the skin entry site. Hemostasis after sheath removal is accomplished with a closure device or hand pressure with intermittent release to allow distal perfusion. Prolonged compression with clamps predisposes patients to downstream vessel thrombosis. Fanatical attention to post-sheath hemostasis will prevent much misery later. Angioplasty Many of the drugs used in below-knee interventions will be familiar to interventional cardiologists. Tibial vessels have a significant propensity for spasm. As in coronary disease, intra-arterial NTG and calcium antagonists are effective. Papaverine (30-60 mg) and tolazoline (12.5 mg) are also effective arterial vasodilators. All patients will need to be anticoagulated (heparin 5,000 mcg, ACT > 250-300 seconds) because of the very real risk of vessel thrombosis. An alternative anticoagulant, which is gaining popularity during coronary interventions, is bivalirudin (Angiomax, The Medicines Company). This compound is an intravenous direct thrombin inhibitor which is approved for coronary use. It is now being utilized more frequently off-label during peripheral interventions.^21,22 In fact, the Carotid Revascularization Endarterectomy versus Stent Trial (CREST) study investigators have incorporated bivalirudin into their study protocol for carotid stenting. The dose used is most often a 0.75 mg/kg bolus followed by a 1.75 mg/kg/hr infusion. A familiarity with various thrombolytic protocols, as well as infusion wires and catheters, is compulsory because of the associated thrombus burden particularly seen in the acutely ischemic limb.²³ Care needs to be taken when concomitant heparin or GP IIb/IIIa inhibitors are infused in conjunction with thrombolytics, particularly when an antegrade puncture is used. Choice of thrombolytic therapy is variable from institution to institution. Urokinase is once again commercially available in the U.S. Urokinase lacks fibrin specificity but is still used often in situations involving arterial thrombosis. The dose is variable but usually in the range of 60,00 to 240,000 international units infused per hour until antegrade flow is achieved. Other commonly used agents include rt-PA²⁴ (0.5-2.0 mg/hr) or r-PA²⁵ (0.25 U/hr). Patients may experience increased pain during lysis often due to embolization of small clots, which generally resolve with continued infusion. If pain or ischemia persists, repeat angiography is warranted with the catheter or guidewire being advanced distally, thus chasing the embolus down the leg, with lacing of the clot and or continued infusion until dissolution is evident. It is very helpful to have at least one mechanical thrombectomy device in the lab. We find the AngioJet (Possis Medical, Minneapolis, Minnesota) the most conducive to treating small vessel thrombosis and use it in conjunction with thrombolysis to reduce infusion times (ie. lacing the clot followed by mechanical thrombectomy). The techniques learned from coronary interventions are directly translatable to below-knee interventions and range from simple angioplasty to kissing balloons, to total occlusions (Figure 8). Lesions extending from the tibial-peroneal trunk through to occlusions of dorsalis pedis and plantar arteries can all be attempted.²⁶ Coronary 0.014 inch wires are utilized for distal lesions, along with hydrophilic 0.018 inch wires for total occlusions. Balloon diameters range from 1.5-4.0 mm, but lengths up to 10 cm need to be available in inventory. Initial enthusiasm for laser angioplasty has been tempered by disappointing long-term patency rates. A similar pendulum effect has been described for the use of the Rotablator device. A single center experience²⁷ enthusiastically reported an 81% four-month patency rate in lesions less than 7 cm. The multi-center Collaborative Rotablator Atherectomy Group²⁸ reported less compelling 47% six-month, 31% one-year, and 18.6% two-year patency rates. The most recent prospective evidence would indicate that although the Rotablator produces a high initial success rate (94%), it has an unacceptable 91% restenosis rate.²⁹ There has been resurgence in atherectomy in the lower extremity due to the Silverhawk atherectomy device (Foxhollow Technologies, Redwood City, California). This device allows the removal of large portions of plaque through continuous shaving. The catheter is opposed to the plaque without the use of a balloon, and the cutter consists of a carbide cutter, which is 3.5 times stronger than stainless steel and 23 times stronger than calcium. Further clinical results from registry data should soon be available. A technique generally unfamiliar to coronary interventionists, and in fact diametrically opposite to our training to assiduously avoid vessel dissection with guidewires, is subintimal angioplasty (Figure 9). This technique, pioneered in the United Kingdom, permits the treatment of longer lesions or hard long-term occlusions. The principle behind subintimal angioplasty³⁰ is to deliberately create a dissection with a hydrophilic guidewire in the same plane as a surgical endarterectomy. The dissection is extended until the wire re-enters the patent distal artery. The angioplasty balloon is inflated in the subintimal space. An occlusion is considered suitable for attempted subintimal recanalization if there is a patent distal arterial segment. Utilizing this technique, lesions as long as 30 cm can successfully be recanalized. The technical success rate for total occlusions > 5 cm is in excess of 80%. Twelve-month patency rates, including technical failures, are in the order of 50% with a one-year limb salvage rate of 85%.³¹ Complications such as distal embolization or perforation occur in approximately 5% of cases.³² A lack of run-off is viewed as a contraindication for attempting this form of revascularization because failure can precipitate ischemia without any surgical alternative.³³ Ultimately, the results of all of these techniques have to be compared to the gold standard of surgical distal bypass grafting. One can expect primary and secondary one-year patency rates of saphenous vein grafts of 70-75%, declining to around 50% at three years, with substantially inferior results when using PTFE-constructed grafts. The limb salvage rate exceeds the primary patency rates by > 10% in almost all series. These operations are technically demanding and are associated with a peri-operative mortality rate of 1.8-6.0%.^34,35 In comparison, endovascular interventions with modern equipment can yield angiographic success rates and limb salvage rates of 80-90%.^36,37 In the immediate post-procedural period, one typically observes a near doubling of the ankle pressures from the ischemic range, or in diabetic patients, a rise in toe systolic pressures and concomitant increases in transcutaneous oxygen levels above the ischemic range. These successes are coupled with a low complication rate and given the less invasive nature of endovascular interventions, compare favorably with surgical techniques. Table 1 illustrates the comparative success rates of various trials over the last decade. Diabetic patients constitute an inordinate percentage of the cases presenting with critical limb ischemia. Endovascular therapy can be successfully applied to this group with successful salvage of the majority of limbs otherwise doomed to amputation.³⁸ Over the years, the development of diabetic gangrene was believed to be a combination of PVD and peripheral neuropathy, with an emphasis on abnormalities associated with the microcirculation.³⁹ This led to a certain therapeutic nihilism and an increased incidence of lower extremity amputations in these patients. We now recognize the pathophysiological importance of large-vessel disease, the correction of which by either surgery or endovascular techniques, can lead to dramatic healing (Figure 10). These patients in particular often require the coordinated efforts of the diabetic foot team (interventionist, infectious disease, endocrinology and plastic surgery) to effect such changes. Several points can be gleaned from the cumulative experience of these trials. Generally, only seasoned interventionists with access to high-quality imaging equipment should attempt these salvage procedures. No randomized data exist comparing endovascular techniques to surgery, nor is there likely to ever be, but a large cumulative reported experience now exists that substantiates offering this to selected patients. When tibial angioplasty is used as part of a team approach to patients with CLI, amputation rates have been reported to decrease from 49% to 14%.⁴⁰ Although infrapopliteal intervention is a minimally invasive technique, surgery may still be indicated and perhaps preferred in certain instances. Although restenosis rates of 30-50% exist for these patients, limb salvage can be achieved in 60-80% primarily dependent on restoration of straight-line flow to the foot. Furthermore, as in surgical practice,^41,42 post-intervention surveillance and subsequent early re-intervention can prolong long-term patency.⁴³ Repeat PTA performed to enhance secondary patency is probably underutilized, yet relatively inexpensive and non-invasive compared to surgical options. The goal of intervention in patients with CLI is in fact not long-term patency, but rather the avoidance of a major amputation. Recurrent CLI is unlikely to redevelop in vessels that restenose. If a clinical failure results, endovascular techniques almost never preclude surgery, and if successful, spare precious veins for later surgical use if necessary. Complications occur in 2-6 % of cases, and most commonly occur at the access site. Spasm and thrombosis are the most likely complication related to the actual dilatation. Distal embolization is a rare event and is treatable with lysis or suction embolectomy, occurring most commonly in conjunction with lysing occluded bypass grafts. Compartment syndrome, an entity to be respected to be sure, is rarely encountered. As in all interventions, success is predicated on appropriate patient selection. Many patients who are poor surgical candidates (ie. lack of conduit, risk of infection, poor general medical condition) are often relatively ideal for endovascular therapies. However, many poor surgical candidates can equally be poor PTA candidates when they have diffuse or advanced occlusive disease and/or no identifiable distal anastamotic sites or restorable run-off. These patients should probably be avoided no matter how desperate the situation or the entreaties to treat, particularly by interventionists just beginning to embark on below-knee work. Endovascular techniques and surgery are indeed complementary procedures, and patients will benefit most by the cooperation and expertise of various specialists including surgeons, interventionists, diabetologists, infectious disease physicians and plastic surgeons. This article was reprinted with permission from the Journal of Invasive Cardiology, vol. 17, no. 1, pages 45-51. The authors can be contacted at: ngoswami@prairieheart.com

1. Wagner HJ, Starck EE, McDermott JC. Infrapopliteal percutaneous transluminal revascularization: Results of a prospective study on 148 patients. J Intervent Radiol 1993;8:81-90.

2. Dotter CT, Judkins MP. Transluminal treatment of arteriosclerotic obstruction: description of anew technique and a preliminary report of its application. Circulation 1964;30:654-670.

3. Gruentzig A. Die perkutane rekanalization chronisher arterieller verschlusse (dotter-prinzip) mit einem neuen dilatations katheter. ROFO 1976;1214: 80-86.

4. Jonason T, Ringqvist I. Factors of prognostic importance for subsequent rest pain in patients with intermittent claudication. Acta Med Scand 1985;218:27-33.

5. Bull PG, et al. Distal popliteal and tibioperoneal transluminal angioplasty: long-term follow-up. J Vasc Intervent Radiol 1992;3:45-53.

6. Horvath W, Oertl M, Haidinger D. Percutaneous transluminal angioplasty of cural arteries. Radiology 1990;177:565-569.

7. Schwarten DE, Cutcliff WB. Arterial occlusive disease below the knee: treatment with percutaneous transluminal angioplasty performed with low-profile catheters and steerable guide wires. Radiology 1988;169:71-74.

8. Veith FJ, et al. Changing arteriosclerotic disease patterns and management strategies in lower-limb-threatening ischemia. Ann Surg 1990;212:402-414.

9. London NJM, et al. Changing arteriosclerotic disease patterns and management strategies in lower limb threatening ischemia. Eur J Vasc Surg 1994;8:148-155.

10. Fraser SCA, et al. Percutaneous transluminal angioplasty of the infrapopliteal vessels: The evidence. Radiology 1996;200:33-36.

11. Bakal CW, Cnyamon J, Sprayregen S. Infrapopliteal percutaneous transluminal angioplasty: What we know. Radiology 1996;200:36-43.

12. Brown KT, et al. Infrapopliteal angioplasty: Long-term follow up. J Vasc Intervent Radiol 1997;4:139-144.

13. Lyden SP, Shortnell CK, Illig KA. Reperfusion and compartment syndromes: Strategies for prevention and treatment. Acute limb ischemia: Management strategies. Seminars Vasc Surg 2001;14:107-113

14. Owens RS, et al. Magnetic resonance imaging of angiographically occult runoff vessels in peripheral arterial occlusive disease. N Engl J Med 1992;362:1577-1581.

15. Leyendecker JR, et al. The role of infrapopliteal MR angiography in patients undergoing optimal contrast angiography for chronic limb-threatening ischemia. J Vasc Intervent Radiol 1998;9:545-551.

16. Tepel M, et al. Prevention of radiographic contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180-184.

17. Hunter DW, et al. Preventing Contrast-induced nephropathy with fenoldopam. Tech Vasc Intervent Radiology 2001;4:53-56.

18. Caridi JG, et al. Carbon Dioxide digital subtraction angiography: The practical approach. Tech Vasc Intervent Radiol 2001;4:57-65.

19. Spinosa D, et al. Gadolinium-based contrast agents in angiography and interventional radiology. Am J Radiol 1999;173:1403-1409.

20. Frankhous JH, et al. Carbon dioxide/digital subtraction arteriography-assisted transluminal angioplasty. Ann Vasc Surg 1995;9: 448-452.

21. Allie DE, et al. Bivalirudin as a foundation anticoagulant in peripheral vascular disease: a safe and feasible alternative for renal and iliac interventions. J Invas Cardiol 2003;15;334-342.

22. Shammas NW, et al. Bivalirudin in peripheral vascular interventions: A single center experience. J Invas Cardiol 2003;15:401-404.

23. Kandarpa K. Techniques of Thrombolysis. SCIVR Annual meeting 2001;87-90.

24. Semba CP, et al. Alteplase as an alternative to urokinase. J Vasc Interv Radiol 2000;11:-161.

25. Ouriel K, et al. Reteplase in the treatment of peripheral arterial and venous occlusions: A pilot study. J Vasc Intervent Radiol 2000;11:849-854.

26. Motarjeme A. PTA and thrombolysis in leg salvage. J Endovasc Surg 1994;1:81-87.

27. Henry M, et al. Percutaneous peripheral atherectomy using the rotablator: a single-center experience. J Endovasc Surg 1995;2:51-66.

28. Zacca NM, et al. Treatment of symptomatic peripheral atherosclerotic disease with a rotational atherectomy device. Am J Cardiol 1989;63:77-80.

29. Jahnke T, et al. Treatment of infrapopliteal occlusive disease by high-speed rotational atherectomy: Initial and mid-term results. J Vasc Intervent Radiol 2001;12:221-226.

30. Bolia A, et al. Subintimal and intraluminal recanalization of occluded crural arteries by percutaneous balloon angioplasty. Eur J Vasc Surg 1994;8:214-219.

31. Nydahl S, et al. Subinitimal angioplasty of infrapopliteal occlusions in critically ischemic limbs. Eur J Vasc Endovasc Surg 1997;14:212-216.

32. Vraux H, et al. Subintimal angioplasty of tibial vessel occlusions in the treatment of critical limb ischemia: Mid-term results. Eur J Vasc Endovasc Surg 2000;20: 441-446.

33. Bell PRF. The clinical impact of PIER technique. Eur J Radiol 1998;28:189-191.

34. Pomposelli FB, et al. Dorsalis pedis arterial bypass: durable limb salvage for foot ischemia in patients with diabetes mellitus. J Vasc Surg 1995;21:375-384.

35. Nehler MR, et al. Surgery for chronic lower extremity ischemia in patients eighty or more years of age: operative results and assessment of post-operative independence. J Vasc Surg 1993;18:18-26.

36. Soder HK, et al. Prospective trial of infrapopliteal artery balloon angioplasty for critical limb ischemia: Angiographic and clinical results. J Vasc Intervent Radiol 2000;11:1021-1031.

37. Boyer L , et al. Infrapopliteal percutaneous transluminal angioplasty for limb salvage. Acta Radiologica 2000;41:73-77.

38. Hanna GP, et al. Infrapopliteal transcatheter interventions for limb salvage in diabetic patients: Importance of Aggressive interventional approach and role of transcutaneous oximetry. J Am Coll Cardiol 1997;30:664-669.

39. Boulton AJM, Scarpello JHB, Ward JD. Venous oxygenation in the diabetic neuropathic foot: evidence of arteriovenous shunting? Diabetologia 1982;22:6-8.

40. Veith FJ, et al. Progress in limb salvage by reconstructive arterial surgery combined with new or improved adjunctive procedures. Ann Surg 1981;194:386-401.

41. Berkowitz HD, Greenstein SM. Improved patency in reversed femoral-intrapopliteal autogenous vein grafts by early detection and treatment of the failing graft. J Vasc Surg 1987;5:755-761.

42. Taylor PR, et al. Graft stenosis: Justification for 1-year surveillance. Br J Surg 1990;77:1125-1128.

43. Varty K, et al. Infrapopliteal percutaneous transluminal angioplasty: A safe and successful procedure. Eur J Vasc Endovasc Surg 1995;9:341-345.