By 50 years of age the prevalence of PAD is 2% to 3%, and it rises to 20% in those older than 75 years.⁴ The clinical findings of PAD in patients older than 50 years is as follows: 10% to 35% have classic claudication, 20% to 50% are asymptomatic, 40% to 50% have atypical leg pain, and the remaining 1% to 2% have critical ischemia.^5,⁶ Women have a relative risk of 0.7 in comparison with men. African American subjects have the highest risk for PAD (2.5) relative to the white population, followed by Hispanic subjects (1.5).

Box 68.1 lists the risk factors for PAD.⁶ They are similar to the risk factors that promote the development of coronary atherosclerosis. The risk factor with the highest correlation to PAD is cigarette smoking. When compared with nonsmokers, smokers have a 1.7- to 5.6-fold increase in the development and progression of atherosclerosis in the peripheral vasculature.⁷ In patients with symptomatic PAD, smoking increases this risk 8 to 10 times.⁸ Risk increases in a powerful dose-dependent manner according to the number of cigarettes smoked per day and the number of years of smoking. Diabetes increases the risk for PAD, 3.5 times in men and 8.6 times in women.⁹ Diabetic patients are also 7 to 15 times more likely to require amputation. The Framingham Heart Study found that risk for the development of intermittent claudication was 2.5-fold and 4-fold higher in men and women, respectively, who had hypertension and that this risk was proportional to the severity of the hypertension.⁹ Genetic predisposition represents an important risk factor for atherosclerosis, and such predisposition accounts for as much as 50% of the risk in some studies.¹⁰ Patients who have PAD also have a high incidence of coronary heart disease (CHD), and in general, patients have a two to four times higher incidence of CHD and cerebrovascular disease if PAD is also present.⁷

Box 68.1 Risk Factors for Lower Extremity Peripheral Arterial Disease

Age 70 years and older

Age 50 to 69 years with a history of smoking or diabetes

Age younger than 50 years with diabetes and one other atherosclerotic risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)

Leg symptoms with exertion (suggestive of claudication) or ischemic rest pain

Abnormal lower extremity pulse findings

Known atherosclerotic coronary, carotid, or renal artery disease

Data from Hirsch AT, Haskal ZJ, Hertzer NR, et al. American Association for Vascular Surgery/Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on Practice Guidelines: ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Associations for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): summary of recommendations. J Am Coll Cardiol 2006;47:1239-312.

Pathophysiology

Atherosclerosis was originally thought to be primarily lipoprotein accumulation but is now better understood, fundamentally, as chronic inflammatory disease of the arterial system.¹¹ The inflammatory process leads to plaque disruption and thrombosis, and the plaques that are vulnerable are characterized by a large lipid core, a thin fibrous cap, and inflammatory cells at the thinnest portion of the cap surface (Fig. 68.1).¹² Plaque rupture has been shown to be critical in the development of acute coronary syndromes, but the importance of this event in patients with PAD is not known at this time.

Fig. 68.1 Cross section of a human artery with advanced atherosclerotic plaque.

The fibrous cap is a layer of smooth muscle cells and fibrous tissue that separates the necrotic core of the plaque from the lumen.

The vascular smooth muscle cell is important in the development of atherosclerosis. Once activated, the cell migrates into the intima and begins to proliferate and secrete matrix proteins and enzymes. This step has been shown to be important in the development of stenosis both in the atherosclerotic vessel and in vessels that have been stented.¹³ In addition, the vessel often constricts rather than dilates, thereby narrowing the lumen even more.¹⁴ Progression of PAD can result from worsening local atherosclerotic disease or a superimposed embolic, thrombotic, inflammatory, traumatic, or vasospastic event.

Thromboembolism

More than 80% of arterial emboli originate in the heart and travel to the extremities, the lower extremities being much more frequently affected than the upper ones. Emboli typically lodge in places with acute narrowing of the artery, such as an atherosclerotic plaque or a point where the vessel branches. The frequencies with which emboli lodge in various areas are as follows ¹⁵: femoral arteries, 28%; arm vessels, 20%; aortoiliac vessels, 18%; popliteal arteries, 17%; and visceral vessels, 9%.

Because of the size of most emboli, the femoral and popliteal arteries are involved more often than the larger aortic and iliac vessels. Atrial fibrillation can lead to thrombosis of the left atrium and is present in 60% to 75% of patients with embolic events. Valvular heart disease (aortic and mitral) accounts for approximately 5% to 10% of cases of thromboembolic disease. The amount of tissue destruction depends on the size of the vessel, the extent of obstruction, and the amount of collateral circulation available to compensate. Once the embolus has lodged in the vessel wall, further propagation can occur either distally or proximally via thrombosis, which can further exacerbate the ischemia.

Atheroembolism

Debris from atherosclerotic plaque can break off in proximal vessels and give rise to atheroemboli. Atheroemboli are less likely to produce symptoms of acute arterial occlusion. The atheroembolus is usually irregularly shaped and nondistensible, thus leading to incomplete occlusion with secondary ischemic atrophy. One exception is blue toe syndrome, in which atheroemboli cause complete occlusion of the digital arteries in the foot. In patients with simultaneous evidence of both venous and arterial embolism, a patent foramen ovale should be considered.

Inflammation

Irradiation, drugs, trauma, or bacterial or fungal invasion can result in an inflammatory arterial injury. Infectious causes lead to direct invasion of the vessel wall and are usually related to intravenous drug abuse, infective endocarditis, or generalized sepsis.

Trauma

Blunt injury to vessel walls can result in disruption of the intima, which can then cause obstruction and thrombosis. Usually, it takes hours to days for complete occlusion to become manifested. Arterial lacerations can be partial or complete, and either type can cause distal ischemia and infarction. Partial arterial lacerations continue to bleed because of the intact portion of the vessel, and such bleeding can result in hematoma formation outside the vessel and thrombosis within the vessel. The hematoma can cause progressive pain, deformity, nerve compression, and subsequent vascular compromise. Complete arterial lacerations actually bleed very little acutely because of spasm of the transected ends. Eventually, however, the spasm relaxes, which can lead to delayed bleeding, and the thrombus on the distal side may separate and move distally.

Vasospasm

Abnormal vasomotor responses in distal small arteries can cause ischemic symptoms without tissue loss.

Arteriovenous Fistulas

Sometimes there may be communication between the arterial and venous systems, which can cause vascular distention, tortuosity, aneurysm formation, and alterations in hemodynamics that are favorable for the development of thrombosis. The fistulas result in elevation of the local venous system, which can lead to skin breakdown in the form of dermatitis and ulceration.

Presenting Signs and Symptoms

The clinical signs and symptoms of PAD may be nonspecific and be manifested in a variable fashion according to degree and location of the atherosclerotic disease, as well as the presence of other previously described pathologic processes, such as thromboemboli, atheroemboli, inflammation, trauma, and vasospasm. The clinical spectrum ranges from a nonspecific systemic illness to a catastrophic event such as an ischemic leg. The gastrointestinal tract is an often-overlooked area of involvement that has been shown to be involved in about a fifth of cases. Patients may complain of nausea, vomiting, abdominal pain, melena, or hematochezia. Stools may be heme positive, and intestinal ischemia can progress to infarction in some cases. Skin manifestations are the most common finding in patients with PAD and appear in approximately a third of cases.¹⁶ Livedo reticularis is a red-blue netlike mottling of the skin and represents embolization to the skin. Such mottling is generally seen on the legs, buttocks, and thighs and rarely involves the arms.

Key components of the vascular review of symptoms and family history are listed in Box 68.2. Physical findings in patients with PAD are listed in Box 68.3. Despite general relationships between PAD and the site of pain, the history and physical examination are not reliable for the detection of lower extremity PAD. Relying solely on the presence of classic claudication will miss up to 90% of cases.^5,⁶ Physical examination can also be unreliable. For instance, an abnormal femoral pulse has high specificity and positive predictive value but low sensitivity for large-vessel disease. The best single discriminator is an abnormal posterior tibial pulse.¹⁷

Box 68.2 Key Findings in the Vascular Review of Systems

Any exertional limitation of the lower extremity muscles or any history of walking impairment (fatigue, aching, numbness, or pain). The primary site or sites of discomfort in the buttock, thigh, calf, or foot should be recorded along with the relationship of such discomfort to rest or exertion

Any poorly healing or nonhealing wounds on the legs or feet

Any pain at rest localized to the lower part of the leg or foot and its association with the upright or recumbent positions

Postprandial abdominal pain that is reproducibly provoked by eating and is associated with weight loss

Box 68.3 Key Components of the Vascular Physical Examination in a Patient with Possible Peripheral Arterial Disease

Measurement of blood pressure in both arms and notation of any interarm asymmetry

Palpation of the carotid pulses and notation of carotid upstroke and amplitude and the presence of bruits

Auscultation of the abdomen and flank for bruits

Palpation of the abdomen and notation of the presence of aortic pulsation and the maximum diameter of the aorta

Palpation of pulses at the brachial, radial, ulnar, femoral, popliteal, dorsalis pedis, and posterior tibial sites

Auscultation of both femoral arteries for the presence of bruits

Assessment of pulse intensity, which should be recorded numerically as follows: 0, absent; 1, diminished; 2, normal; 3, bounding

Inspection of the feet for evaluation of color, temperature, and integrity of the skin and intertriginous areas and recording of the presence of ulceration

Documentation of the presence of symmetry, edema, and venous distention of the lower extremities

Recording of additional findings suggestive of severe peripheral arterial disease, including distal hair loss, trophic skin changes, and hypertrophic nails

Acute Arterial Occlusion

Patients with acute arterial occlusion commonly complain of a sudden onset of pain and coldness distally, on the side of the occlusion (Fig. 68.2). As the ischemia progresses, the classic findings of acute arterial occlusion become evident, as described by the six “P’s”: pain, polar (cold) sensation, paresthesia, paralysis, pallor, and pulselessness. As the peripheral nerves become ischemic, paresthesias, numbness, and then paralysis develop sequentially. The sensory peripheral nerves are affected first, with decreases in proprioception and light touch, and then the larger pain and motor fibers become involved and give rise to a loss of sensation, weakness, and paralysis. Paralysis is usually a bad prognostic sign for reversibility of the ischemia. Signs of ischemia can be seen distal to the level of arterial occlusion. During the first 8 hours after the ischemic insult, the extremity looks pale because of the spastic nature of the arterial tree surrounding the region. Twelve to 24 hours after the injury, the extremity may become cyanotic and mottled. As arterial flow ceases, venous drainage also slows or stops, thereby leading to profound stasis, which further aggravates the damage. On careful examination, the cold part of the extremity can easily be demarcated from its warmer proximal portion. The ischemia is unlikely to be reversible if the affected limb is paralyzed.

Fig. 68.2 Large saddle clot at the bifurcation of the aorta at the iliac vessels.

This clot not only can cause symptoms by itself but can also embolize more distally.

Intermittent Claudication

The primary symptom of lower extremity atherosclerotic disease is intermittent claudication. Claudication, from the Latin word for “limp,” is defined as reproducible discomfort of a defined group of muscles that is induced by exercise and relieved with rest. It results from an imbalance in the blood flow needed to meet the metabolic demands of the tissue. Intermittent claudication has three major clinical features: it is consistent and reproducible from day to day, symptoms resolve within a couple of minutes after cessation of exercise, and discomfort occurs again at the same distance once the patient resumes the activity. The symptoms usually occur gradually and may be absent or minimal, even in those with significant disease. The pain may also be felt in the thigh, hip, and buttock as the level of obstruction moves proximally. If many of the vessels are involved, the most distal muscle group is affected first, followed by proximal migration as the patient continues to walk. The pain is primarily unilateral at onset but may be bilateral if distal aortic occlusion occurs. Progressive arterial insufficiency causes a collateral circulation to develop, which will allow the patient’s symptoms to not progress despite worsening of the culprit artery. As described, there is a relationship between the site of pain and the site of arterial disease, as follows: foot (tibial and peroneal artery), calf (superficial femoral artery or popliteal artery), thigh (common femoral artery or aorta and iliac artery), and buttocks and hips (aorta and iliac artery).

Rest Pain

Ischemic pain at rest can be a symptom of severe to critical limb ischemia. The pain typically occurs at night when the patient is supine, and the patient may awaken from sleep with pain in the toes or forefoot. The pain is generally worse in a single extremity and is relieved by dependency. The patient may either stand up or hang the legs over the edge of the bed for relief. In this scenario, physical examination may show marked pallor with elevation of the legs, marked rubor with dependency, and delayed venous filling times. Usually by the time that rest pain occurs, severe arterial insufficiency is present in multiple arterial segments.

After rest pain, progression of disease causes necrosis of tissue, generally between two toes. Eventually, the ulcers may coalesce or progress to dry gangrene over the tips of the toes or at pressure points. Peripheral gangrene arising from an arterial cause may be difficult to differentiate from that with a venous cause. A patient with arterial ischemia exhibits severe ischemic changes followed by edema because the limb is kept in a dependent position. With venous gangrene, however, the edema occurs first, before the onset of frank ischemic changes.

Differential Diagnosis and Medical Decision Making

The clinician will often need to determine whether the patient’s symptoms are related to peripheral neuropathy or ischemic disease. Patients with neurologic disease usually have bilateral leg pain that is not relieved by dependency, as well as neurologic signs such as decreased deep tendon reflexes and loss of touch and vibratory sensation. With ischemia, the sensory peripheral nerves are affected first and result in decreases in proprioception and light touch; the larger pain and motor fibers then become involved, which leads to loss of sensation, weakness, and subsequently paralysis.

Once the clinician is convinced that the patient’s symptoms are related to PAD, the first priority is to determine whether the symptoms represent PAD without occlusion (nonischemic) or whether ischemic PAD is present. The next step is to determine whether the extremity is viable, threatened, or nonviable (Box 68.4). When arterial blood flow is insufficient to meet the metabolic demands of resting muscle or tissue, limb-threatening ischemia results. This is the most common indication for emergency arterial reperfusion. The selected group of patients requires immediate assessment of their vascular system. Arteriography provides the most useful information in the setting of acute arterial occlusion because in addition to providing information on anatomy, it can distinguish between embolism and thrombosis. Embolism has a sharp cutoff of contrast agent with a reverse meniscus sign; thrombosis usually has a more tapered cutoff. Diffuse atheromatous disease is also usually found around a thrombotic occlusion.

Box 68.4 Categories of Acute Limb Ischemia

Viable: The extremity is not immediately threatened. The patient does not complain of ischemic rest pain, no neurologic deficit is present, and the capillary circulation in the skin appears to be adequate. Physical examination demonstrates pulses with either palpation or a Doppler flowmeter.

Threatened viability: Reversible ischemia has occurred, and the extremity is salvageable without major amputation if the arterial obstruction is relieved promptly. Affected patients have ischemic rest pain with mild transient or incomplete neurologic symptoms. The pulses are not detected with a Doppler flowmeter.

Nonviable (major, irreversible ischemic change): Major amputation of the affected limb is frequently required. Affected patients have profound sensory loss and muscle paralysis, absence of capillary flow, or evidence of more advanced ischemia (muscle rigor or marbled skin). No pulses can be palpated or detected with a Doppler flowmeter.

Acute Arterial Occlusion

Acute arterial occlusion (critical limb ischemia) is defined as a sudden decrease in limb perfusion that causes a potential threat to limb viability in patients seen within 2 weeks of the acute event.¹⁸ Acute arterial occlusion can be the result of emboli from a distant source, thrombosis of a previously patent artery, or direct trauma to an artery (Box 68.5).

Blue Toe Syndrome

Blue toe syndrome is a commonly seen condition characterized by the sudden appearance of a cool, painful, cyanotic toe or forefoot. It generally occurs in the presence of a palpable peripheral pedal pulse and warm forefoot. This syndrome is usually due to embolic occlusion of the digital arteries as a result of atheroemboli from proximal arterial sources. It is not typically due to local atherosclerotic disease. Identification of the embolic source and treatment of the diseased segment are required.

Anke-Brachial Index

Because blood flow is diminished, the most common sensor used is the Doppler flowmeter. Calculation of the ankle-brachial index (ABI) is an accurate way to diagnose PAD. The ABI is a simple and relatively inexpensive test to confirm the clinical suspicion of occlusive arterial disease, and it provides a measure of the severity of the peripheral vascular disease.¹⁹ The ABI is calculated by measuring systolic blood pressure with a Doppler probe in the brachial, posterior tibial, and dorsalis pedis arteries. The highest of the measurements in the ankle and foot is divided by the highest in the upper extremity. The ABI in normal individuals is 1.0 or greater; values higher than 1.3 usually indicate a calcified vessel that is noncompressible. An ABI of less than 0.9 has 95% sensitivity (100% specificity) for PAD and is associated with 50% or greater stenosis in one or more major vessels (Box 68.6).

Box 68.6 Ankle-Brachial Index Measurements

Measurements must be obtained properly for accuracy and reliability and be done in the following sequence:

1. Arm systolic pressure should always be measured with a Doppler flowmeter because measurement by auscultation can be inaccurate.

2. Pressure must be recorded in both arms and both tibial arteries at the ankle.

3. Systolic pressure is measured at the point at which flow is first detected, not at the point at which it is lost during inflation.

4. The absolute levels of blood pressure and the ankle-brachial index are then measured.

Imaging

Treatment

The spectrum of PAD ranges from asymptomatic to critical limb ischemia, and coronary artery disease and other atherosclerotic vascular disorders may coexist with PAD. Indications for urgent intervention are (1) incapacitating claudication that interferes with work or lifestyle and (2) limb salvage in persons with limb-threatening ischemia, as manifested by rest pain, nonhealing ulcers, or infection or gangrene.

Prompt initiation of therapy is the most important aspect of the treatment of acute limb ischemia. Patients should immediately receive a heparin bolus followed by an infusion to prevent clot propagation and inhibit thrombosis distal to the lesion, where low flow or stasis is present. Heparin should be administered before diagnostic testing is performed.^25,²⁶ Subsequent therapy depends on whether the extremity is viable, threatened, or nonviable.

Patients with Viable Extremities

Patients found to have an ischemic but viable extremity on clinical examination should undergo urgent arteriography. Once the anatomy has been defined, vascular surgeons can determine whether surgical or intraarterial thrombolytic therapy is needed. One study reported limb salvage rates of approximately 70% with both thrombolytic therapy and surgical intervention in this patient population.²⁷ The important thing for the emergency physician to remember is that thrombolytic therapy is limited by the length of time needed to dissolve the thrombus and the severity of the ischemia. Thrombolytics are given at the site of occlusion through the catheter used for angiography. This method has been shown to have a better outcome with fewer bleeding complications than is the case with intravenous administration. Both urokinase and tissue plasminogen activator have been studied and appear to be similar in outcome measures. Patients who have had ischemic symptoms for less than 14 days and are treated with thrombolytics have better amputation-free survival and shorter hospital stays than do those who undergo surgery; patients with ischemic symptoms for longer than 14 days have a better outcome with surgical intervention. In addition, in patients who have received thrombolytic therapy and eventually require surgical intervention, the magnitude of the surgical procedure is less than in patients who have not received thrombolytics.

The surgeon and interventional radiologist help determine the optimal therapy for a patient with limb ischemia and a viable extremity according to (1) the location and length of the lesion, (2) the cause (embolus versus thrombus), (3) the duration of symptoms, and (4) the suitability of the patient for surgery. In general, smaller, more distal emboli are best treated with thrombolytics, whereas a large embolus at a more proximal location is best treated by embolectomy ²⁷ (Figs. 68.3 and 68.4).

Fig. 68.3 Popliteal artery with a sharp cutoff of the contrast material in a patient with a painful, acutely ischemic leg.

See Figure 68.4.

Fig. 68.4 Leg of the same patient as in Figure 68.3 after administration of a thrombolytic agent.

Note the resumption of normal flow distal to the previous obstruction.

Patients with Threatened Extremities

Patients with threatened extremities should undergo immediate surgical revascularization.²⁵ The vast majority of such patients have had an embolic event. Irreversible changes, including necrosis, may occur within 4 to 6 hours of the initial insult, thus leaving a fairly small therapeutic window. The small amount of time available makes thrombolytic therapy of limited utility^27,²⁸ (Figs. 68.5 and 68.6).

Fig. 68.5 Angiogram of a patient with embolic disease at the proximal femoral artery as it bifurcates to the deep femoral system (arrow).

Note the abrupt cutoff of contrast material. See Figure 68.6.

Fig. 68.6 Angiogram of the same patient as in Figure 68.5 after thrombectomy.

Note the resolution of flow and absence of visible clot (arrow).

Surgery usually reveals an embolus that can be removed by embolectomy. After embolectomy, most surgeons perform intraoperative arteriography to assess distal blood flow. If small distal emboli are found after embolectomy, intraoperative thrombolytic therapy may be considered. If the ischemia has been prolonged, compartment syndrome may result once blood flow is restored. Therefore, oral anticoagulation should be instituted after the procedure to prevent subsequent embolization.²⁶

Patients with Nonviable Extremities

If clinical evaluation of a patient’s extremity reveals nonviability, amputation should proceed promptly.²⁵ Angiography is not normally required to make this diagnosis, and the clinical findings dictate the level of amputation. In general, surgeons try to preserve as many joints as possible to decrease the work of ambulating with a prosthesis. If amputation is not performed in an expedient manner, the patient may have complications such as sepsis, acute renal failure, rhabdomyolysis, hyperkalemia, and cardiovascular collapse.