Chronic ischemia of the lower extremities is extremely prevalent in Western societies and accounts for a significant amount of morbidity and mortality. Atherosclerosis, although not the only cause of chronic lower extremity ischemia, is, by far, the most common. Together with critical ischemia of the heart, brain, and abdominal organs, atherosclerotic peripheral vascular disease constitutes the leading cause of death in the United States.¹ As the mean age of the population increases, the number of individuals with atherosclerotic lesions of the lower extremities also rises. Patients with peripheral arterial disease (PAD) are at significantly higher risk of death compared to healthy controls from cardiovascular morbidity and mortality, as well as at increased risk of impaired functional status.² A basic understanding of the pathogenesis, presentation, diagnosis, and treatment of chronic peripheral vascular disease is an integral part of medical and surgical practice in the United States.

In order to gauge the prevalence of PAD in asymptomatic subjects, several epidemiological studies have been done using ankle–brachial index (ABI) as a measure of arterial stenosis. ABI is obtained using a standard blood pressure cuff placed just above the ankle. A Doppler is used to measure the systolic pressure of posterior tibial and dorsalis pedis arteries of each leg. The higher of the systolic pressures in each leg (DP vs. PT) is divided by the higher systolic pressure of either arm. An ABI of ≤0.90 indicates hemodynamically significant stenosis. The National Health and Nutritional Examination Survey included 2174 asymptomatic subjects aged ≥40 years. The prevalence of PAD, defined by an ABI of ≤0.90, ranged from 2.5% in people aged 50 to 59 years to 14.5% in people aged >70 years.³ All told, PAD affects a total of around 10 million people. This translates to around 3% to 10% of the general population, with this percentage increasing to 15% to 20% in people older than 70 years (Figure 35-1).^4,5,6

Despite aggressive screening policies with ABI, studies show that the number of people in the general population with PAD is grossly underestimated. This is, in part, because of the limitations of ABI alone in diagnosing PAD in some patients.⁷ This underestimation could indicate that the prevalence of this already widespread disease is actually much higher. Exercise testing in a noninvasive vascular laboratory setting should be considered in patients for whom the clinical suspicion of PAD is high, yet they have a normal or indeterminate ABI.⁸

Atherosclerosis is a chronic inflammatory condition that affects the intima of elastic and muscular arteries of the body in a segmental fashion. Atherosclerosis is evident from early childhood in susceptible populations, and lesions progress through a series of stages before manifesting with clinically significant symptomatology later in life.

Risk factors for PAD are similar to those for heart disease. Most factors have been proven only to have an association with disease, not a true causal relationship.

Increasing age has been found to be associated with increased risk of PAD. Because atherosclerosis is a process related to aging, there is a stepwise increase in the incidence of PAD with each decade of age. This is demonstrated clearly in epidemiological studies.⁶

Male gender is a risk that slightly increases the incidence of PAD, with a ratio of 2:1 when compared to females, especially in younger age brackets. However, some studies conflict these data, illustrating a 1:1 ratio, or even a slightly higher percentage of women with chronic critical limb ischemia in postmenopausal populations.⁶

The GENOA study (Genetic Epidemiology Network of Arteriopathy) showed that PAD was more common in non-Hispanic blacks than in whites, with percentages of 7.8% and 4.4%, respectively. This increased prevalence is not explained by a difference in classical risk factors for atherosclerosis and is, therefore, considered an independent risk factor.⁹

Perhaps the most widely recognized risk factor for PAD is its relationship to cigarette smoke. In fact, it has been suggested that the association between smoking and PAD is even greater than that between smoking and coronary artery disease. A diagnosis of PAD is often made earlier in smokers than in nonsmokers, up to a decade earlier. Cigarette smoking increases the severity of PAD in both men and women proportionally to the number of cigarettes smoked, with heavy smokers having a fourfold increased risk of developing intermittent claudication than nonsmokers.¹⁰

Diabetes has also been shown to have a significant relationship with the development of PAD. Intermittent claudication is approximately twice as common among diabetic patients as nondiabetic patients.⁶ For every 1% increase in hemoglobin A1C, there is a 26% increased risk of PAD.¹¹ Even in nondiabetic patients, insulin resistance is shown to carry an increased risk for the development of limb ischemia.¹² PAD in diabetic patients is also more aggressive than that found in nondiabetic patients, with early large vessel disease combined with peripheral neuropathy.⁶ This translates to a 5 to 10 times higher risk for amputation. Currently, the American Diabetes Association recommends that diabetic patients have ABI screening every 5 years.¹³

Hypertension, shown to be associated with all forms of cardiovascular disease, increases the risk of symptom development as much as 2.5-fold in men and 3.9-fold in women in some studies. However, the relative risk of PAD is less for hypertension than diabetes or smoking.^6,14,15

Dyslipidemia has also been implicated in the development of PAD. In the Framingham study, a fasting total cholesterol level of greater than 270 mg/dL was shown to correlate with a doubling of the incidence of intermittent claudication.⁶ Patients with PAD have significantly higher levels of serum triglycerides, very low-density lipoproteins, intermediate-density lipoproteins, and lower levels of high-density lipoproteins than controls.¹⁶ Cigarette smoking and dyslipidemia may actually have a synergistic effect in the development of PAD.

Other risk factors such as hyperfibrinogenemia, elevated C-reactive protein, hypercoagulable states, and hyperhomocysteinemia have also been implicated in the development of PAD.^2,6,17 The recognition and modification of these risk factors are essential in the diagnosis and treatment of chronic lower extremity ischemia. Guidelines for risk factor modification are published and updated by the American Heart Association.

Atherosclerosis accounts for most cases of peripheral arterial occlusive disease; however, there are other conditions that cause chronic limb ischemia. These include popliteal artery entrapment, mucinous cystic degeneration, Burger disease (thomboangiitis obliterans), abdominal aortic coarctation, fibrodysplasia, and primary arterial tumors.¹⁸

Atherosclerosis is a chronic, progressive disease of the intima. Many factors are involved in the development of atheromatous plaques, the common denominator between them all being endothelial injury. The most likely model for atherosclerosis points to intimal injury and the subsequent repair process leading to the formation of fibrous plaques. Factors contributing to this model of intimal injury are multifactorial and can include shear stress, hyperlipidemia, and cigarette smoking.¹⁹

The earliest manifestation of atherosclerosis is the fatty streak, which is identifiable in children as young as 10 years of age. The fatty streak consists of lipid-laden macrophages superimposed over lipid-laden smooth muscle cells of the arterial intima. These occur at the same places where subsequent fibrous plaques are most often found, namely, at bifurcations or bends where decreased shear stress, turbulence, and stasis are known to occur. Increased surface involvement of fatty streaks has been shown to precede the development of fibrous plaques, supporting the idea that the fatty streak is the precursor to fully developed fibrous plaques.²⁰

The “response to injury” model of atherosclerosis demonstrates the clustering of monocytes on arterial endothelium. Activated monocytes, induced by IL-1 released in response to endothelial injury, adhere to the intimal lining and migrate to a subendothelial position and become activated macrophages.²¹ The receptors for low-density lipoproteins found on the surface of monocytes allow them to absorb lipids and transform into the so-called foam cells. These activated macrophages release chemoattractants (IL-1, TNF-α, and transforming growth factor-β), which serve to recruit more macrophage and smooth muscle cells, as well as lymphocytes and other inflammatory cells, to the developing plaque. The recruited smooth muscle cells will also migrate to the subendothelial position and convert into foam cells. The accumulation of these foam cells distorts the endothelial lining, leading to platelet deposition and the formation of a fibrous cap. Platelets also contribute to the recruitment of more precursors to plaque development by the release of platelet-derived growth factor. Platelet-derived growth factor is a potent stimulus for the migration and proliferation of smooth muscle cells. This process repeats itself, leading to a progressively larger plaque with progressive inflammation and luminal narrowing.²⁰

The inflammatory response initiated by the release of cytokines from recruited macrophages and lymphocytes is the driving force behind thrombosis and subsequent arterial occlusive disease. Inflammation leads to increased levels of C-reactive protein, matrix metalloproteinases, and other enzymes that, once released by the recruited macrophages and smooth muscle cells, weaken the connective tissue matrix of the fibrous cap. This leads to plaque instability and rupture. Rupture of the plaque leads to plaque hemorrhage and thrombus formation.²⁰

Because chronic lower extremity ischemia develops slowly over time, a good portion of patients will have had time to adapt to a compromised arterial system and will present with minimal symptoms in the face of hemodynamically significant stenoses or occlusions. Collaterals will often form and vasodilation will be maximized, bypassing areas of atherosclerosis and minimizing symptoms. In addition, the patient’s activity level will sometimes be severely limited by coronary disease or other processes, allowing symptoms to remain undetected for some time.²²

The patient with lower extremity pain, classically described as a reproducible cramping pain, which is elicited by exercise and relieved only by rest, is said to have intermittent claudication. The pain usually occurs in the muscle group immediately below the level of arterial disease. For example, patients with calf claudication usually have superficial femoral arterial disease, while patients with buttock claudication will have iliac disease. Intermittent claudication is the most common presentation of short segmental disease.¹⁸ For patients with multiple sequential segments of disease affecting the aortoiliac level and the superficial femoral and popliteal levels, or one of these segments combined with severe infrapopliteal disease will more frequently present with disabling intermittent claudication, or rest pain, defined as constant, severe pain in the foot, often at the metatarsophalangeal joint, which is relieved only by dependency, or tissue necrosis. It is important to note that there is no evidence to support that patients with symptoms of PAD progress more frequently or rapidly to critical limb ischemia than those without symptoms; in fact, the presence or absence of symptoms has more to do with the activity level of a patient rather than the severity of disease. Several studies demonstrate only a 1% to 7% amputation rate among claudicants at 5 to 10 years, and only one out of four patients will complain of escalating symptoms for more than 5 years.^23,24

Critical limb ischemia is defined as inadequate arterial blood flow to accommodate the metabolic needs of resting tissue.¹⁸ With critical limb ischemia, tissue necrosis and ulceration will often be present. The determination of the cause of ulcerating lesions on the ankle and foot becomes an important part of the presentation of PAD. Typical arterial or ischemic ulcers are exquisitely painful and are associated with other physical features of ischemia, including cool, dusky lower extremities, skin and nail changes, and hair loss. Usually they are located at an area of chronic pressure, such as over the malleoli, and their bases usually have a more necrotic appearance. Venous ulcers occur with the stigmata of associated chronic venous disease, including venous stasis dermatitis and edema, and usually improve with compression and elevation. Venous ulcers are also usually less painful than arterial ulcers.

One of the difficulties in evaluating the patient who presents with complaints of lower extremity pain is elucidating whether that pain comes from true limb ischemia or other etiologies. The incidence of PAD increases with every decade of age, as does the incidence of other conditions leading to lower extremity pain, such as osteoarthritis, degenerative joint disease of the spine, and other spine or nerve disorders. Careful history and physical examination, combined with selective diagnostic strategies, help to determine whether PAD is responsible for the patient’s symptoms or not.

Chronic lower extremity ischemia exists on a clinical spectrum. The Fontaine classification system for lower extremity arterial occlusive disease organizes patients by symptoms.

1. 
   

   Asymptomatic

   
   
2. 
   

   Claudication present after walking <1 block; no physical changes

   
   
3. 
   

   Ischemic rest pain, atrophy, cyanosis, and dependent rubor

   
   
4. 
   

   Ischemic ulceration/necrosis

Despite the existence of this classification system, many patients do not fit into these groupings. For every one patient who meets the criteria for intermittent claudication, there are an estimated three to four patients with PAD who do not meet these criteria.^25,26,27 For example, many patients who are considered “asymptomatic” will have some element of exertional lower extremity pain, but not the classic symptoms of claudication. Also, patients with ischemic ulceration and pedal necrosis are extremely variable with respect to the extent of pedal involvement, severity of the necrosis, and underlying etiology (i.e., trauma or pressure necrosis in the face of preexisting ischemia).

To accurately stage limb ischemia objectively and develop a reasonable treatment strategy, diagnostic testing combined with functional assessment remains the most effective way of stratifying the disease (Table 35-1). Results of ABI and selected noninvasive studies have been shown to correlate with risk of limb loss and cardiovascular mortality.^28,29,30 Walking distance in patients with symptoms of claudication will provide an indication of their functional status. This can be assessed by exercise testing in the noninvasive vascular laboratory. Exercise testing involves recording an ABI at rest, followed by having the patient walk on a treadmill at 3.5 km/h at a 12% incline until claudication symptoms begin. An ABI is then repeated. If there is a significant decrease, this indicates a vascular etiology. If there is not a significant decrease, a nonvascular etiology is likely.⁸ These parameters are commonly used to evaluate patients for treatment options.

As a general rule, patients with stage III and IV disease are those whose limbs are imminently threatened and who have disease at multiple levels. Invasive diagnostic procedures and aggressive revascularization interventions are easily justified in these patients.⁶ For patients with stage I and most patients with stage II disease, analgesia, risk factor modification, graded exercise programs, and reassurance with observation are more reasonable options. Without treatment, 10% to 15% of stage I patients will improve during 5 years and 60% to 70% do not progress further. The remaining 10% to 15% who do progress are best treated with therapeutic interventions after their disease progresses rather than before.

General Considerations

Treatment for PAD is aimed at limb preservation when possible (Table 35-2). A majority of patients with critical limb ischemia will receive some form of active treatment, whether that is revascularization or amputation, although medical management is still recommended as the first approach for non-limb-threatening ischemia. Approximately 25% of patients with chronic limb ischemia will receive medical treatment only, 50% eventually receive a revascularization procedure, and the remaining 25% will have a primary amputation. Figure 35-2 illustrates the 1-year outcomes of these patients after their respective treatments.⁶

Medical Therapy

Before surgical intervention should be pursued, medical treatment of lower extremity ischemia must first be attempted. No truly effective therapy is available; however, the principles of risk factor modification, graded exercise programs, smoking cessation, and prevention of local tissue trauma and infection in the foot can prolong and sometimes even prevent the need for surgical revascularization.

Risk Factor Modification

The first step in medical therapy of the patient with chronic lower extremity peripheral vascular disease should be risk factor modification. The risk factors associated with the development and progression of PAD, discussed earlier, are largely ones that can be reduced or eliminated by proper patient education, treatment of associated disease processes, and patient compliance. The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TransAtlantic Intersociety Consensus [TASC] II) provides specific recommendations for risk factor modification.

Smoking. One of the more important steps in nonoperative therapy of PAD is complete cessation of cigarette smoking. Studies show that less than half of patients understand the relationship between peripheral vascular disease and smoking.³¹ Physicians should encourage the cessation of smoking regularly, as studies have also demonstrated a higher incidence of abstinence in patient populations encouraged by their physician to quit, as opposed to those who received no counseling from a health care provider.³² Physicians should also provide nicotine replacement therapies as well as medications such as bupropion, fluoxetine, or varenicline, which can help decrease craving and physiological symptoms of withdrawal. The best success rates are achieved when these modalities are used together in conjunction with group counseling sessions.⁶

Diabetes. Diabetes is a strong risk factor for the development of peripheral vascular disease. Although strict control of blood glucose has been shown to have beneficial effects on other related complications like coronary artery disease, it has not been shown to slow the progression of PAD.³³ Preventive foot care in diabetic patients is of paramount importance in the nonoperative treatment of PAD in diabetic patients. Current recommendations advise aggressive control of blood sugars with a hemoglobin A1c goal of <7%.⁶

Hyperlipidemia. Studies have demonstrated that lipid-reducing strategies designed to increase HDL levels and decrease low-density lipoprotein and triglyceride levels have led to stabilization and sometimes regression of peripheral atherosclerosis. The Heart Protection Study also found that maintaining patients on lipid-lowering agents can reduce the need for surgical revascularization.³⁴ Physicians should obtain a fasting lipid profile on patients with PAD and initiate therapy when warranted. Dietary modification should be the initial intervention, with lipid-lowering agents started if this is ineffective. Target low-density lipoprotein levels are <100 mg/dL, target HDL levels are >35 mg/dL in men and >45 mg/dL in women, and target triglyceride levels are <150 mg/dL. If patients with PAD have a history of vascular disease in other locations, it is advisable to lower low-density lipoprotein levels to <70 mg/dL.⁶

Hypertension. Although hypertension is a major risk factor in the development of PAD, no data currently exist to prove that blood pressure control would alter the outcome of the disease.³⁵ β-Blockers are frequently given to patients with PAD in the preoperative period to reduce the incidence of myocardial infarction. Currently, it is recommended that patients with PAD should have blood pressure controlled to <140/90 mm Hg, or <130/80 mm Hg if in conjunction with diabetes and/or renal insufficiency, as per the JNC VII guidelines.⁶

Homocysteine. Elevated homocysteine levels, which are damaging to the vascular endothelium, have been shown to increase the risk of PAD by speeding the development of atherosclerosis.³⁶ No studies have shown that reduction of homocysteine levels affects outcomes. Although supplementation with B-vitamins and/or folate has been shown to decrease homocysteine levels, no data have demonstrated a benefit in patients with PAD or other cardiovascular disease and therefore is not recommended.⁶

Exercise Conditioning

If collateral pathways exist around a focal segment of atherosclerotic disease, often the symptoms of ischemia leading to the need for surgical revascularization are minimized. Although several pharmacologic treatments for claudication exist, the best stimulus to increase exercise conditioning seems to be a regular program of physical activity. The most effective exercise programs include supervised walking at least three times a week, for 60 minutes or more.³⁷ This has been shown to improve claudication symptoms and increase in exercise tolerance by 200 meters. Unless exercise is continued indefinitely, the benefits fade and symptoms return.

Pharmacologic Agents

Several agents exist for the treatment of claudication symptoms, although these have not been proven to change the eventual need for surgical revascularization in patients with advanced symptoms. Pentoxifylline (Trental) and cilostazol (Pletal) are two drugs currently available in the United States. Both have been shown to increase exercise tolerance, with cilostazol having a statistically significant advantage over pentoxifylline in some studies. A 3- to 6-month trial of cilostazol is currently recommended in patients with PAD and claudication symptoms.^6,38

In addition to the above medications, the use of antiplatelet therapy is also recommended in patients with PAD. A large amount of data exists to support the routine use of antiplatelet agents to decrease the risk of cardiovascular morbidity and mortality.³⁹ Aspirin/ASA should be routinely given to patients with PAD in conjunction with either coronary or cerebral artery disease.⁴⁰ Clopidogrel has also been shown to reduce cardiovascular events in patients with PAD.⁴¹

Prevention of Local Tissue Damage

Because of the impact of ischemia and reduced blood flow on wound healing, local foot care and the prevention of tissue trauma and infection are extremely important to the nonoperative management of PAD. A comprehensive wound management strategy emphasizing the principles of pressure relief, debridement, infection control, and moist wound healing increases wound closure rates without the need for revascularization.⁴² Trauma and infection are often the inciting events leading to gangrene and tissue necrosis, and the ultimate need for revascularization or amputation.

Surgical Consideration

Surgical correction of arterial occlusive disease should be considered in patients who have exhausted medical therapy and lifestyle limiting symptomatic ischemic disease, as well as in patients with limb-threatening ischemia. Unless the ischemia has progressed to gangrene with involvement of deeper tissues of the foot and leg, or the patient is unable to ambulate, communicate, and provide self-care or is otherwise severely disabled and bedridden, limb salvage should be attempted. Patients who are not candidates for surgical revascularization secondary to severe gangrene/necrosis or whose quality of life will remain unaffected by limb salvage should undergo primary above- or below-knee amputation. Medical optimization of comorbidities, such as cardiac, renal, and diabetic disease, should be undertaken prior to proceeding with arteriography and surgical intervention.

General Principles

The most common sites for chronic arterial occlusive disease are the infrarenal abdominal aorta and the iliac arteries.⁴³ Because atherosclerosis is a generalized disease process, aortoiliac disease often coexists with atherosclerotic disease in other locations, including the infrainguinal vessels. Segments of disease are usually short and focal, and, therefore, surgical strategies for revascularization are easily implemented, even in patients with multilevel disease. Diagnostic evaluation, including noninvasive studies and arteriography, should be implemented prior to proceeding with surgical revascularization in order to localize and determine the extent of the diseased segments, plan a surgical approach, and determine whether or not the patient is a candidate for surgical intervention at all. In addition, these studies will also help determine which patients are suitable for endovascular-based interventions.

The TASC has developed a classification system to stratify vascular lesions and guide decision making as to the most appropriate therapeutic intervention (Figure 35-3). TASC A lesions represent those that have excellent results with endovascular therapy. TASC B lesions still have good results with endovascular therapy and should be treated with such an approach unless an open revascularization is required for other lesions in the same anatomic area. TASC C lesions have superior results with open revascularization and should be treated in this manner except in patients with high operative risk. TASC D lesions do not achieve good results with endovascular therapy. With TASC B and C lesions, the patient’s comorbidities and the long-term success rates of the surgeon of record are taken into consideration when deciding what therapeutic strategy to use (Table 35-3).⁶

Graft Material

The choice of graft material for the management of infrainguinal occlusive disease is one which has resulted in much debate for the past three decades. Prior to the introduction of tubular expanded polytetrafluoroethylene (ePTFE), reversed autogenous saphenous vein grafts (ASV) were the material of choice. Once ePTFE grafts were introduced in the 1970s, practitioners were quick to side with one material type over the other. The first major comparison study of ASV and ePTFE grafts was published by Veith et al. in 1986. In this study, ASV and ePTFE grafts were compared in 845 infrainguinal bypass procedures: 485 to the popliteal and 360 to the infrapopliteal vessels. At 4 years, the primary patency rates between the two groups became significantly different, 68% for ASV vs. 47% for ePTFE.⁴⁴ Although this difference was not apparent in the above-knee group, the difference was striking in the infrapopliteal procedures, with 76% primary patency for ASV vs. 45% for ePTFE. This study failed to support the routine use of ePTFE for infrainguinal procedures. However, the authors did conclude that ePTFE was a viable bypass conduit in high-risk patients, especially in those patients without an autogenous vein source or in those patients with above-knee lesions. In 1992, Mcfarland et al. described using a composite bypass graft of ePTFE with a vein cuff in those patients without an adequate autogenous source. At 5 years, the primary patency rate of composite bypass grafts is slightly better than ePTFE alone.⁴⁵ Numerous alternatives to ePTFE have been proposed, including the human umbilical vein graft (HUV). Although randomized comparisons between HUV and ePTFE showed promising results, HUV seems to have a high rate of aneurysmal degeneration and should be used with caution.¹⁸ Recently HUV has gained attention as a possible material in composite grafts with autogenous veins. The primary patency rate at 4 years in patients with an HUV composite bypass was 53%, similar to composite ePTFE grafts. While autogenous vein should be used as the bypass conduit of choice whenever possible, up to 40% of patients will have a small (<3 mm), fibrotic, or insufficient saphenous vein. In these cases, it is much better to proceed with an ePTFE graft rather than compromising the procedure with an inadequate autogenous graft.¹⁸

Aortoiliac Disease

General Considerations