Acute limb ischemia is a medical emergency with significant morbidity and mortality. Rapid diagnosis is required because it is a time-sensitive condition. Timely treatment is necessary to restore blood flow to the extremity and prevent complications. The differential diagnosis of acute limb ischemia is broad. Classification of severity of acute limb ischemia is based on clinical variables. A suspicion of acute ischemia based on history and physical examination warrants heparin administration and vascular surgery consultation. The decision for endovascular thrombolysis or standard surgery depends on etiology, duration, and location of vascular occlusion. This review evaluates the diagnostic approach and management for acute limb ischemia.
Key points
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Acute limb ischemia (ALI) occurs when there is sudden decrease in limb perfusion that threatens limb viability and requires urgent diagnosis and management to prevent loss of life and limb.
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If ALI is suspected based on history and physical examination, intravenous (IV) heparin should be initiated immediately and vascular surgery consulted.
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Assessment of pulses (by palpation and Doppler flow), sensation, and motor strength determines limb viability. Patients are then classified based on viability of the ischemic limb as follows: viable (stage I), marginally threatened (IIa), immediately threatened (IIb), and irreversibly damaged (III).
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Endovascular thrombolysis is most appropriate for patients with a viable or marginally threatened limb (I and IIa), acute occlusion (less than 2 weeks duration), and a history strongly suggestive of arterial or graft thrombosis.
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Surgical revascularization is preferred for patients with an immediately threatened limb (IIb), occlusion of more than 2 weeks’ duration, proximal occlusion (suprainguinal), and embolic occlusion.
Introduction
Acute limb ischemia is a medical emergency with significant morbidity and mortality. The incidence is estimated to be 1.5 cases per 10,000 persons per year. Rapid diagnosis is essential because timely treatment needs to be initiated to restore blood flow to the extremity. This is a time-sensitive condition, and the diagnosis is primarily clinical. An emergency physician must make the diagnosis and urgently involve the vascular surgeon for definitive management to prevent loss of life or limb.
Introduction
Acute limb ischemia is a medical emergency with significant morbidity and mortality. The incidence is estimated to be 1.5 cases per 10,000 persons per year. Rapid diagnosis is essential because timely treatment needs to be initiated to restore blood flow to the extremity. This is a time-sensitive condition, and the diagnosis is primarily clinical. An emergency physician must make the diagnosis and urgently involve the vascular surgeon for definitive management to prevent loss of life or limb.
Definitions
It is important for an emergency physician to distinguish between acute versus chronic limb ischemia. Chronic limb ischemia is most commonly caused by peripheral arterial disease (PAD) and gradually worsens over time, leading to progressive symptoms, known as claudication. PAD includes a broad variety of disorders that cause progressive stenosis or occlusion of arteries, most commonly atherosclerosis.
Claudication is defined as fatigue, discomfort, or pain occurring in a specific limb muscle group during effort. Symptoms of claudication are a result of exercise-induced ischemia. Patients with claudication have sufficient blood flow to the limb so that symptoms are absent at rest. During exertion when there is increased demand for oxygen, blood flow is inadequate to meet metabolic demands, and therefore the limb suffers from muscular fatigue or pain.
Chronic ischemia from PAD can progress to the degree of causing compromised limb viability, known as critical limb ischemia (CLI). CLI is defined as limb pain that occurs at rest or impending limb loss caused by severe compromise of blood flow to the extremity. CLI may be the result of acute or chronic ischemia and is usually caused by progressive obstructive PAD but can also be caused by embolic disease, vasculitis, and thrombosis in situ related to hypercoagulable states, popliteal entrapment, vasospasm, compartment syndrome, or trauma. Patients with CLI have resting perfusion that is inadequate to sustain metabolic demands of the distal tissue bed, causing pain at rest or loss of tissue, such as skin ulceration or gangrene.
ALI occurs when there is sudden decrease in limb perfusion that threatens limb viability, with “acute” defined as within 2 weeks of the onset of symptoms. ALI can be the result of thrombotic, embolic, inflammatory, traumatic, anatomic, or iatrogenic causes. Whereas claudication reoccurs with walking set distances and abates after 2 minutes to 5 minutes of rest, acute ischemia occurs abruptly and is not relieved by rest.
Chronic ischemia induces the development of collateral blood vessels and results in skin changes secondary to progressive ischemia. Patients with preexisting occlusive PAD and claudication can also present with ALI; however, because there has been time for collateral vessels to develop, they may have milder symptoms than patients with minimal or no preexisting PAD. Patients with normal underlying vasculature who develop acute ischemia have greater threat to limb viability because there has been insufficient time for new blood vessel growth to compensate for sudden loss of perfusion ( Table 1 ).
| Claudication | Acute Limb Ischemia | |
|---|---|---|
| Onset of symptoms | Occurs with physical activity, gradually worsens over time | Occurs suddenly |
| Pain relieved with rest | Yes | No |
| Pathophysiology | Progressive stenosis of peripheral arteries | Sudden occlusion of a peripheral artery |
| Most common causes | Atherosclerosis | Thrombosis or embolism |
| Skin findings | Changes associated with chronic vascular disease (hair loss, shiny skin) | May be normal (embolic occlusion) or show changes of vascular disease (thrombotic occlusion) |
Risk factors
The most common cause of PAD is atherosclerosis. Risk factors for atherosclerosis include cigarette smoking, diabetes, dyslipidemia, hypertension, family history, and hyperhomocysteinemia.
Disorders of collagen formation and vascular inflammation (vasculitis) may also lead to PAD by causing loss of structural integrity and dilation of the arteries. Disorders of collagen formation include Marfan and Ehlers-Danlos syndromes. Vasculitis can affect any arterial bed; for example, the aorta and its first-order and second-order branches may be involved in Takayasu disease, Behçet syndrome, and relapsing polychondritis ; medium-sized vessels are the target of polyarteritis nodosa, temporal arteritis, Wegener granulomatosis, Churg-Strauss syndrome, and Kawasaki disease ; and radiation-associated arteritis can affect any size of vessels. Thromboangiitis obliterans, or Buerger disease, is an arterial obliterative and thrombotic disease that is observed in young patients who smoke—it behaves like a vasculitis and can affect arteries of all sizes.
Prothrombotic diseases may predispose patients to limb ischemia and can be caused by abnormalities in the clotting system (eg, protein C, protein S, or antithrombin III deficiencies; factor V Leiden or prothrombin mutations; and hyperhomocysteinemia); the presence of a lupus anticoagulant or anticardiolipin antibody; and the prothrombotic state associated with malignancies, inflammatory bowel disease, and heparin-induced thrombocytopenia (HIT).
Vasospastic diseases (ie, those causing pathologic vasoconstriction) may also predispose a patient to limb ischemia and can affect any muscular vessel in the body. Migraine headache, Prinzmetal angina, Raynaud syndrome, and ergot toxicity are all examples of vasospastic syndromes. In the extremities, vasospasm may occur as a primary event (Raynaud syndrome) or secondary to an underlying disease process such as scleroderma or systemic lupus erythematosus, medications, or in the advent of trauma.
Pathophysiology
CLI results when there is insufficient oxygenated blood to meet the metabolic demand of the tissues. The longer the limb is without oxygen, the greater the likelihood of cell death and irreversible damage. The tissues most sensitive to ischemia are peripheral nerves, skin, and subcutaneous tissues, followed by skeletal muscle. Animal studies have shown that cell damage results approximately 3 hours after acute ischemia, and complete cell death results by 6 hours. In humans, however, the ability of a limb to tolerate ischemia varies because not all ischemic insults are complete due to the presence of preexisting collateral vessels.
Traditionally, it has been taught that a patient with acute arterial occlusion has approximately 6 hours before irreversible damage occurs; however, the time frame varies depending on the presence and degree of collateral vessels. Therefore, the old belief that salvage is possible if reperfusion occurs within 4 hours to 6 hours is not accurate. Patients without well-formed collateral circulation can suffer significant tissue loss at shorter time intervals.
Ischemia causes depletion of oxygen to tissues, leading to inability of cells to perform mitochondrial oxidative phosphorylation. The cell shifts energy metabolism from aerobic to anaerobic process, producing lactic acid. Progressive ischemia causes depletion of energy-rich ATP, leading to leakage of extracellular calcium into the muscle cells. This ultimately results in dysfunction and cell death. Reperfusion injury occurs on restoration of blood flow to the ischemic limb. Ischemic tissue in the limb produces oxygen free radicals. These free radicals trigger peroxidation of membrane lipids, leading to increased capillary permeability and filtration causing swelling, associated with compartment syndrome. Inflammation results and leukocyte-activated platelets cause platelet aggregation and activation of the complement system. This results in occlusion of the reperfused vessels, exhibiting the no-reflow phenomenon. Byproducts of cell death are released into the systemic circulation and include potassium, phosphate, myoglobin, creatine kinase, and thromboplastin. Resulting hyperkalemia, hyperphosphatemia, metabolic acidosis, and myoglobinemia can lead to rhabdomyolysis, cardiac dysrhythmia, multiorgan failure, disseminated intravascular coagulation, and death.
Etiologies of Acute Limb Ischemia
ALI arises when a rapid decrease in limb perfusion threatens tissue viability. Severity depends on location and extent of arterial obstruction and the presence of capacity of collateral arteries to perfuse the limb. Severity may also be influenced by variables of systemic perfusion, such as cardiac output and peripheral vascular resistance. Acute ischemia is most often due to thrombosis within a diseased artery with thromboemboli being the second most common cause of ALI.
Thrombotic limb ischemia occurs in patients with underlying PAD. Atherosclerotic plaques within the arteries cause progressive narrowing of the vessel associated with symptoms of claudication. Complete arterial obstruction can occur when a vulnerable plaque ruptures and a thrombus forms. Thrombotic occlusion is the most common cause of ALI (80%–85%). Arterial thrombosis superimposed on a stenotic atherosclerotic plaque commonly occurs in the superficial femoral artery, although occlusion can occur anywhere from the aorta to digital arteries. Thrombosis may also occur in arterial aneurysms (particularly in the popliteal artery) and in bypass grafts, previously normal limb artery in patients with thrombophilic conditions, and secondary to compression, as seen with popliteal artery compression syndrome, or secondary to trauma, as seen with knee dislocation. Once thrombosis occurs, the thrombus tends to propagate proximally in the artery, and the resultant low-flow state of blood distal to the thrombus encourages distal thrombus propagation, which supports the rationale for systemic anticoagulation.
Embolic limb ischemia is less common (14%–15%). Most emboli are generated in the heart, with atrial fibrillation associated with two-thirds of all peripheral emboli. The second most common source is a mural thrombus in the ventricle after recent myocardial infarction (MI) (20% of limb emboli). These emboli form due to poor cardiac wall motion leading to stagnant blood in the cardiac chambers and clot formation. Other sources of emboli include atrial myxoma, vegetation from valve leaflets, thrombi formation on prosthetic valves, thrombi formation in the walls of arterial aneurysms, and atherosclerotic plaques in the proximal vessels. Smaller atheroemboli are produced from plaque fragmentation, resulting in obstruction of the microcirculation and ischemia to the toes and hands peripherally (blue toe syndrome). Additionally, paradoxic emboli occur when a venous clot passes from the right to the left side of the heart through a shunt, such as a patent foramen ovale (PFO) or atrial septal defect (ASD).
If an embolism affects an artery, which has not been conditioned by collaterals, the resulting ischemia is severe. Arterial embolism, therefore, is more likely than arterial thrombosis to cause severe, limb-threatening ischemia. Arterial emboli typically lodge at the branch points in the arteries where the caliber decreases: 34% at the common femoral artery, 14.2% at the popliteal artery, 13.6% at the common iliac artery, and 9.1% at the aortic bifurcation. Embolism to the aortoiliac bifurcation may produce bilateral lower limb ischemia, which has a high mortality rate and can be associated with paraplegia.
Aortic dissection may lead to limb ischemia via propagation resulting in the false lumen extending across a branch point for an artery where the false lumen occludes blood flow to the involved artery. Traumatic vessel injury secondary to invasive catheters, intravascular balloons, surgery, and intra-arterial drug injection are other potential causes of ALI. Rare causes of arterial thrombosis include popliteal entrapment, cystic adventitial disease, and repetitive trauma.
Presentation
The clinical features of ALI are colloquially known as the Six Ps: pain, pallor, paralysis, pulselessness, paresthesias, and poikilothermia. The diagnosis cannot be excluded, however, if all of these features are absent. Additionally, patients with chronic peripheral vascular disease often have a well-developed collateral blood supply, resulting in more subtle symptoms. Differentiation of thrombotic versus embolic cause can be difficult and is clinically impossible in 10% to 15% of cases. In general, sudden-onset development of ischemic symptoms in a patient who was previously asymptomatic is most consistent with embolus, and sudden worsening symptoms in a patient with a history of chronic ischemia and claudication is more indicative of arterial thrombosis ( Table 2 ).
| Embolism | Thrombosis | |
|---|---|---|
| History | ||
| Onset of pain | Rapid onset of symptoms | Sudden worsening of claudication symptoms |
| Past medical history | No known PAD history ± atrial fibrillation, recent MI, valvular disease | Known history of PAD ± coronary artery disease, cerebrovascular disease |
| Prior vascular surgery | Usually none | Often yes |
| Physical examination | ||
| Appearance | Mottled, distinct demarcation | Bluish, no distinct demarcation |
| Temperature | Cold | Cool |
| Neurologic | Paralysis | Paresthesias |
| Contralateral limb | Normal | Abnormal pulse examination, hair loss, shiny skin, thickened nails |
| Most common cause | Cardiac thromboemboli | Plaque rupture |
| Most common ischemic class | Immediately threatened (IIb) | Marginally threatened (IIa) |
Pain is typically the first symptom of ALI, most often distal to the site of obstruction. The pain of lower extremity ischemia is often localized to the forefoot and gradually increases in severity, progressing proximally with increased duration of ischemia, eventually extending above the ankle. As ischemia progresses to the degree of neurologic damage, the pain may begin to subside.
Numbness or paresthesias are common complaints associated with persistent limb ischemia and reflect early nerve dysfunction. The anterior compartment of the lower leg is most sensitive to ischemia, and therefore patients often first complain of sensory loss over the dorsum of the foot as the earliest neurologic manifestation. As ischemia progresses, anesthesia and paralysis become more prominent and are signs of impending loss of limb viability.
It is important for an emergency physician to determine whether a patient has a history of claudication or arterial interventions or arterial or aortic aneurysm and whether there is an established diagnosis of heart disease with particular reference to prior or recent MI, atrial fibrillation, PFO or ASD, or ventricular dysfunction. The patient should also be evaluated for concurrent diseases and risk factors for PAD, such as hyperlipidemia, hypertension, and tobacco use.
Diagnosis
Differential Diagnosis
The differential diagnosis of ALI includes conditions that mimic arterial occlusion, nonatherosclerotic causes of arterial occlusion, and differentiation of ALI secondary to thrombosis versus embolism.
Conditions that mimic arterial occlusion include low cardiac output (especially when superimposed on chronic lower extremity PAD), acute deep vein thrombosis (DVT), (especially when associated with features of phlegmasia cerulea dolens), chronic peripheral neuropathy (diabetic neuropathy), or acute compressive peripheral neuropathy (compartment syndrome). Acute DVT and peripheral neuropathy should be distinguished from acute arterial occlusion by palpable pulses, unless chronic arterial occlusive disease or vasospasm exists. In chronic peripheral neuropathy, skin temperature is normal, which is unusual for ALI. DVT may present with cyanosis and coolness (phlegmasia cerulean dolens), and pulses may be difficult to palpate if significant edema exists. Edema does not occur, however, with acute arterial occlusion unless diagnosis is delayed and swelling begins to develop. Compartment syndrome may present with cool, pale, pulseless limb and tense muscle compartments, which are absent in acute ischemia. Potential causes of nonischemic limb pain include acute gout, spontaneous venous hemorrhage, or traumatic soft tissue injury.
Nonatherosclerotic causes of arterial occlusion include arterial trauma, vasospasm, vasculitis, hypercoagulable states, aortic dissection, and external arterial compression, such as with popliteal cyst. A history of recent arterial catheterization may suggest direct arterial trauma or arterial dissection as the cause of acute ischemia. Aortic dissection should be suspected in patients with tearing chest pain with radiation to the back and should be strongly considered in patients with unilateral or bilateral iliac occlusion. Popliteal cysts and popliteal entrapment syndrome should be considered in younger patients with absent atherosclerotic risk factors.
Physical examination may demonstrate skin pallor early after onset of ischemia, but over time, cyanosis develops. Coolness of the painful limb when the other extremity is warm is a typical finding. Patients with embolic occlusion are more likely to have a cold limb with mottled skin, whereas patients with thrombosis are more likely to have cool skin (owing to collateral blood vessels) and a bluish discoloration (indicative of chronic ischemia). There may be an abrupt line of transition in temperature or color, more commonly in embolic occlusion. Capillary refill is variable and dependent on environmental and interobserver factors, but in general, capillary refill is slower or absent in ALI.
Some patients with sensory loss describe numbness or paresthesias. Sensory deficits may be subtle in the early phase of ALI. Light touch 2-point discrimination, vibratory perception, and proprioception are usually lost before perception of deep pain and pressure. Motor deficits indicate advanced, limb-threatening ischemia. In acute ischemia, the more distal portion of the limb is affected first. More proximal muscles produce foot movement at the ankle, whereas the intrinsic muscles of the foot produce toe movement. Therefore, detection of early motor weakness requires testing toe movement (eg, extension of the great toe) in comparison with the contralateral foot. Persistent pain, sensory loss, and toe muscle weakness are among the most important findings that identify a patient with threatened limb loss. Muscle rigor, tenderness, paralysis, and pain on passive movement are signs of advanced ischemia ( Box 1 ).
History of present illness
Location, timing, and onset of symptoms
Increasing or decreasing severity
Associated neurologic symptoms (numbness, tingling, and weakness)
Recent symptoms of claudication
Recent traumatic injuries or other inciting events (injections)
Other associated symptoms (swelling, redness, fevers/chills, chest pain, and shortness of breath)
Medical history
Vascular disease (coronary artery disease, peripheral arterial disease, cerebrovascular disease, vasculitis, and aortic or arterial aneurysm)
Cardiac disease (atrial fibrillation or other dysrhythmias, recent MI, valvular heart disease, PFO, or ASD)
Tobacco use
Diabetes mellitus
Hypertension
Hyperlipidemia
Clotting disorder
Prior interventions, including vascular grafts to the aorta or extremities
Differential diagnosis
Ischemic causes
Thrombotic arterial occlusion secondary to atherosclerosis
Embolic arterial occlusion
Arterial trauma
Arterial vasospasm
Aortic dissection
Spontaneous thrombotic occlusion secondary to hypercoagulable state
Arterial compression secondary to compartment syndrome, phlegmasia cerulea dolens, popliteal cyst, knee dislocation
Nonischemic causes
Deep venous thrombosis
Neuropathy
Acute gout
Cellulitis
Musculoskeletal trauma
Spontaneous venous hemorrhage
Classification
Classification of ALI by severity is important because evaluation and treatment modality depend on the degree of ischemic tissue damage and the prognosis for limb salvage. The degree of severity is determined by physical examination, specifically evaluating for sensory and motor deficits and the presence of arterial or venous flow signals using a handheld Doppler device. Physical examination findings categorize patients as follows: stage I, viable; stage IIa, marginally threatened; stage IIb, immediately threatened; and stage III, irreversible ( Table 3 ).
| Category | Description/Prognosis | Sensory Loss | Muscle Weakness | Arterial Doppler | Venous Doppler |
|---|---|---|---|---|---|
| Viable (I) | Not immediately threatened | None | None | Audible | Audible |
| Marginally threatened (IIa) | Salvageable if promptly threatened | Minimal (toes) or none | None | Often inaudible | Audible |
| Immediately threatened (IIb) | Salvageable with immediate revascularization | Extends beyond toes; pain at rest | Mild to moderate | Usually inaudible | Audible |
| Irreversible damage (III) | Major tissue loss or permanent nerve damage inevitable | Profound, anesthetic | Profound, paralysis or rigor | Inaudible | Inaudible |
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