Acute Limb Ischemia Management and Complications: From Catheter-Directed Thrombolysis to Long-Term Follow-Up, Including Considerations For COVID-19

Acute limb ischemia (ALI) is a vascular emergency that requires prompt diagnosis and treatment to prevent permanent tissue damage and amputation. Catheter-directed thrombolysis is a viable treatment option for mild to moderate ALI, with improved results from endovascular procedures and thrombolytic drugs. However, patients receiving thrombolysis may experience higher rates of distal embolization, serious bleeding events, and stroke than those undergoing surgery. The review article emphasizes the need for postoperative and long-term management of ALI patients, including monitoring for compartment syndrome, managing reperfusion damage, and reducing modifiable cardiovascular risk factors such as smoking cessation, diabetes management, and statin therapy. Complications that can arise from thrombolytic therapy are also discussed, including hemorrhagic complications, minor bleeding, and reperfusion damage, with recommendations to monitor patients closely during treatment and discontinue therapy immediately if any abnormalities are detected. Follow-up evaluations for patients, including vascular ultrasound, arterial brachial indices, pulse volume recordings, and laboratory tests, are recommended to ensure the best possible outcome for patients with ALI.

Acute limb ischemia (ALI) is a vascular emergency characterized by an abrupt reduction or deterioration in limb perfusion that jeopardizes limb viability and mobility. The condition is classified as acute if clinical symptoms manifest within 14 days of the onset of symptoms [1]. ALI presents with a constellation of symptoms referred to as the five Ps, including pain, pallor, pulselessness, paresthesia, and paralysis, along with a decrease in temperature in the affected limb [1].

Arterial embolism, arterial thrombosis, popliteal aneurysm thrombosis, trauma, and graft thrombosis are the primary etiologies of ALI, with arterial thrombosis accounting for the majority of cases [2]. Specifically, arterial thrombosis may arise due to the evolution and complications of a pre-existing atherosclerotic plaque, which may cause occlusion in regions where there are large, complex atherosclerotic plaques. Trauma, graft thrombosis, and popliteal aneurysm thrombosis are less common but significant causes of ALI, whereas arterial embolism accounts for 30% of cases [3].

Notably, in individuals with hypercoagulable disorders, previously healthy arteries may develop in situ thrombosis, leading to acute limb ischemia. Clinicians must be vigilant in identifying and promptly treating ALI, given the potentially devastating consequences for limb viability and mobility. Pain, the most common symptom of rapid circulation impairment in the lower extremities, should prompt an urgent evaluation for ALI, especially in individuals with risk factors for the condition [4].

Diagnosis

The management of ALI involves a comprehensive physical examination and a thorough history collection to determine the underlying etiology. Distinguishing between in situ thrombosis and embolic occlusions can be challenging, given the range of acute and long-term treatment options available for both [5]. Patients with native arterial thrombosis may have a history of intermittent claudication or previous limb revascularization and are commonly burdened with comorbidities, such as chronic renal failure, diabetes, coronary artery disease, and stroke history. These patients are usually frail, elderly, and susceptible to bleeding [5].

In contrast, patients with embolic occlusions typically present with sudden and severe symptoms that can often be pinpointed to a specific event. The absence of intermittent claudication, a history of previous embolic events, atrial fibrillation, or aneurysm, and known embolic sources can suggest an embolic occlusion [1]. Acute arterial occlusion results in severe vascular spasms and a "marble" white appearance in the affected limb. As the arteries relax, the skin of the limb becomes mottled and blanches under pressure in the following hours as the blood in the limb loses oxygen. Clinicians must be alert to these clinical signs and symptoms to accurately diagnose and promptly treat ALI to avoid potentially severe consequences for limb viability and mobility [6].

The severity of the ALI determined using the Rutherford classification (Table 1), is a crucial factor in decision-making [7]. Urgent imaging is necessary to evaluate the extent of the injury, especially in cases where the limb can be salvaged [8]. Co-existing conditions must also be carefully evaluated.

Table 1: Rutherford Classification Scheme for Prognostic Assessment of Limb Ischemia Using Doppler Signal and Clinical Findings.

The Rutherford classification helps to determine the prognosis of the affected limb based on physical examination findings, such as skin color, venous filling, motor and sensory function, and Doppler flow signals in the popliteal veins and pedal arteries [7]. A methodical vascular examination can identify the various causes of ALI, such as the location of the blockage and rhythm disturbances like atrial fibrillation. Bilateral palpation of the pulses in the groin, knee, and ankle can help to diagnose an embolism, which is suspected when there is a unilateral pulse deficit and a normal contralateral pulse test. A bilateral pulse deficit, on the other hand, suggests an atherosclerotic problem. Palpation of the brachial, radial, and ulnar arteries should also be performed to look for potential access sites and multi-site embolism. When the pulse state is questionable, the Doppler probe should be used to examine arterial signals.

During the patient's initial medical assessment, sensory abilities, and motor deficits should be examined, and periodically reevaluated, to help identify any changes in limb function. A methodical and thorough vascular examination is essential for the prompt diagnosis and management of the ALI [7].

When considering imaging options for ALI, duplex ultrasound is not typically mentioned. Rather, angiography is widely recognized as an important tool for localizing obstructions and visualizing the distal arterial tree [7]. Computed tomographic angiography and magnetic resonance angiography may also be employed to diagnose and assess the extent of the disease. In contrast, duplex ultrasonography (DUS) is a noninvasive imaging technique that utilizes 2D ultrasound with 7-10 MHz probes for limbs and 3-5 MHz probes for abdominal arteries, as well as color and pulsed wave Doppler [9]. Although the quality of DUS images can depend on the operator, this modality provides valuable data at the femoral and popliteal levels. However, it can be more challenging to assess the aorta and iliac arteries in obese patients or those with gas interference [6]. It should be noted that duplex ultrasonography is a useful noninvasive imaging technique that frequently enables a prompt choice between endovascular and surgical revascularization. When compared to traditional diagnostic angiography, it takes a lot shorter time and is crucial in showing aneurysms as the underlying pathology. Furthermore, in a minority of ALI patients who develop myonecrosis and consequent impairment of renal function, contrast injection may help the condition worsen even further [9].

Differential Diagnosis

ALI can be difficult to diagnose, as it can resemble other conditions such as cardiac failure, chronic occlusive illness, and severe deep venous thrombosis. It is important to distinguish between ALI and chronic limb ischemia (CLI), as CLI symptoms typically last for considerably longer than two weeks [1]. Other conditions that may resemble ALI or induce secondary ischemia include thromboangiitis obliterans, vasculitides, disorders of the connective tissue, aortic dissection involving the iliac arteries, phlegmasia coerulea dolens, compartment syndrome, trauma, systemic shock, and the use of vasopressor medications [1]. Non-ischemic causes of limb discomfort include acute gout, neuropathy, spontaneous venous bleeding, and severe soft-tissue damage [10,11].

To provide comprehensive diagnostic tools and facilities for quick retrieval, structured imaging databases may be constructed, including different imaging techniques such as cardiac and vascular ultrasonography, computed tomography, and digital subtraction angiography [12]. However, it should be noted that the use of contrast injection in diagnostic angiography may worsen the condition in a minority of ALI patients who develop myonecrosis and consequent impairment of renal function. Therefore, the choice of imaging technique should be made judiciously, with careful consideration of the patient's specific circumstances and medical history [7,12].

Patient Selection and Timing of Intervention

The Rutherford classification is a crucial factor in determining the optimal timing and course of therapy for acute limb ischemia. To identify any underlying chronic vascular disease and assess the need for elective vascular intervention, patients presenting with a viable limb have sufficient time to undergo noninvasive diagnostic imaging and laboratory testing [13]. Immediate revascularization is required for patients with Rutherford grade IIa and IIb limb ischemia. Endovascular therapy is typically used for grade IIa patients, while open surgery, such as intraoperative thrombolysis, is typically used for grade IIb patients, though this is not always necessary. A study that is currently being reviewed showed that endovascular revascularization produced comparable revascularization rates to open surgery, as well as 30-day morbidity and death rates [13,14].

Patients with irreversible limb ischemia (Rutherford class III) may need to have their limbs amputated without first attempting revascularization due to the abrupt release of toxic by-products of ischemic tissue (potassium, myoglobin, and reactive oxygen species) into the systemic circulation during reperfusion [13,15]. For patients with Rutherford classifications, I and II acute limb ischemia, endovascular revascularization is a viable alternative to open surgery since the criteria for the two procedures overlap significantly. Class I ALI patients require urgent revascularization within 12 hours of presentation, while class II ALI patients require emergent revascularization within 2–6 hours of presentation, according to available data [16].

Pharmacology

The optimal thrombolytic drug should have selective action for fibrin-bound plasminogen within the target thrombus, minimizing the risk of hemorrhagic complications. Thrombolytic drugs have undergone several generations of development, each with an improved specificity for fibrin-bound plasminogen and a reduced action on freely circulating plasminogen [13,14].

First-generation thrombolytics such as streptokinase and urokinase are no longer used in the treatment of ALI due to their higher risk of hemorrhagic complications and slower clot clearance periods as a result of their lack of specificity for fibrin [17]. Recombinant tissue plasminogen activator (alteplase), the most widely used second-generation thrombolytic, primarily targets fibrin-bound plasminogen and is less active on free circulating plasminogen [13,18].

Third-generation thrombolytics, which are small variations of the second generation (reteplase), have greater thrombus penetration, resistance to endogenous inactivating factors in the plasma (tenecteplase), and decreased affinity for free circulating plasminogen [13]. These drugs theoretically have fewer bleeding complications than second-generation drugs, but it is unclear if these in vivo pharmacologic changes have any therapeutic significance [17,19].

In addition to thrombolytics, adjunctive anticoagulation, and antiplatelet medications may aid in revascularization. Most interventionalists use continuous unfractionated heparin infusion during thrombolysis to enhance the effectiveness of lysis by preventing thrombosis [13,17].

Platelet glycoprotein IIb/IIIa antagonists have been suggested to accelerate natural thrombolysis, but definitive research for ALI is lacking. Positive data in lysis for acute ischemic stroke can be extrapolated. Recent survey findings suggest that interventionalists monitor serial plasma fibrinogen levels during catheter-directed thrombolysis and stop or lower lysis infusion when less than 100 to 150 mg/dL [18]. However, the largest prospective study, the PURPOSE trial, including 241 participants, showed no statistically significant difference [20]. Current Society of Interventional Radiology ALI practice recommendations do not endorse or discourage fibrinogen monitoring due to the lack of prospective randomized trials [21].

Catheter-directed Thrombolysis Versus Surgery

The use of urokinase-catheter-directed thrombolysis has been compared with open thrombectomy in five prospective randomized controlled studies conducted during the 1990s, which demonstrated that the former is at least as effective as the latter [22]. According to a Cochrane meta-analysis of these trials, no differences in limb salvage or death were observed at 1, 6, or 12 months [22]. However, patients receiving thrombolysis had higher rates of distal embolization (12.4%), serious bleeding events (8.8%), and stroke (1.3%) than those undergoing surgery (0%, 3.3%, and 0%, respectively) [13].

Since these trials, catheter-directed thrombolysis has been supported as a viable treatment option for mild to moderate ALI (classes I-II) due to improved results from endovascular procedures and thrombolytic drugs (Table 2) [13]. Newer techniques such as suction thrombectomy devices are also being employed for ALI without or with supplementary catheter-directed thrombolysis [13]. For instance, a recent study by Bose, et al. has demonstrated excellent safety and technical outcomes when using the Penumbra system [23].

Table 2: Absolute and Relative Contraindications for Catheter-Directed Thrombolysis (CDT).

Endovascular Revascularization

In endovascular therapy, prompt revascularization of the ischemic lower extremities and management of the underlying thrombogenic lesion are the primary goals. The first step is to perform arteriography to assess the run-off and inflow [24]. Distal aortography and aortoiliac arteriography can help identify embolic sources, such as aortic aneurysms with concomitant mural thrombus, dissection, traumatic damage, and other proximal thrombogenic lesions. Once the area of occlusion has been identified, attempts can be made to cross the lesion. Anticoagulation needs to be titrated to at least a 250-second active clotting time. The severity of the thrombosis can be estimated by observing the ease with which a guidewire can pass through the obstruction, with chronic lesions requiring more advanced wires and procedures, and new thrombus being easier to cross [24].

The primary objectives of endovascular therapy are to revascularize the ischemic lower extremities promptly and treat the underlying thrombogenic lesion. In the first step of the procedure, run-off and inflow should be evaluated through arteriography. Distal aortography and aortoiliac arteriography can help identify embolic sources such as aortic aneurysms with concomitant mural thrombus, dissection, traumatic damage, and other proximal thrombogenic lesions. Once the area of occlusion has been located, crossing the lesion may be attempted, and anticoagulation should be titrated to at least a 250-second active clotting time [25].

After crossing the lesion, a thrombolytic drug, such as Alteplase, Retavase, or Tenecteplase, may be infused through an infusion catheter across the thrombus. The dose and duration of thrombolytic infusions vary depending on the agent. However, low-dose, long-duration thrombolytic infusions may carry a higher risk of hemorrhagic sequelae, while high-dose, short-duration thrombolytic infusions may carry a higher risk of distal embolization. The method of administering the thrombolytic drug also varies, including continuous infusion, pulse-spray administration, and initial pulse-spray followed by continuous infusion. Pulse-spray infusion theoretically has the advantage of faster penetration and thrombus fragmentation, but there is insufficient evidence to support this claim [25].

In addition to catheter-directed thrombolysis, endovascular thrombectomy may be used as a supplemental or stand-alone percutaneous revascularization procedure that expedites revascularization and reduces the need for thrombolysis. Over the past several decades, endovascular thrombectomy has experienced fast innovation and a rise in the number of devices available [26]. These devices are frequently divided into four types: mechanical aspiration, hemolytic, ultrasonic, and combination devices. Percutaneous thrombo aspiration is one of the modern techniques that are highly efficacious in combination with thrombolysis.

In patients with a high risk of bleeding, Percutaneous Mechanical Thrombectomy (PMT) is highly useful to debulk the thrombosed mass, which shortens the lysis period [27]. After successfully removing the thrombotic material, balloon angioplasty or stent placement is often required. PMT has a greater 12-month amputation-free survival rate than CDT or surgical thrombectomy. However, some of these devices have drawbacks, such as an elevated risk of distal embolization. To reduce the risk of embolization, the use of protective devices is advised in high-risk patients with a single vascular run-off. It is essential to remember that endovascular thrombolysis or thrombo embolectomy restores the vasculature to its baseline condition at best [13]. Therefore, to achieve a durable result, the remaining thrombogenic lesion must be treated using an endovascular (angioplasty or stent placement), open surgical, or hybrid technique.

Open Surgery

For patients with an urgently endangered or nonviable limb, a suspected infection in their bypass graft, or who are contraindicated to thrombolysis, open revascularization is recommended. Moreover, surgery is preferred when ischemic symptoms have persisted for more than two weeks [1]. Surgical methods employed in ALI include thrombectomy using a balloon catheter (Fogarty), bypass surgery, and adjuncts such as endarterectomy, patch angioplasty, and intra-operative thrombolysis, often necessitating a combination of these techniques. Exposure to the common femoral artery bifurcation and balloon-catheter thrombectomy is the most effective surgical treatment for ischemic lower limbs.

Meta-analyses have demonstrated no significant difference in treatment outcomes between endovascular methods and open surgery, although, for Rutherford class IIb, open surgery is still recommended, while endovascular revascularization modality is recommended for Rutherford class I and IIa [1]. ALI caused by popliteal aneurysm thrombosis deserves special attention as significant amputation frequently occurs in these patients. In diffuse thromboembolic blockage affecting all main runoff arteries below the knee, intra-arterial thrombolysis or thrombectomy may be necessary to reopen a runoff artery before aneurysm exclusion and surgical bypass [1].

Amputations

When necrosis and tissue death are present, amputation may be necessary to prevent infection and sepsis-related death. Vasodilators like nitroglycerin and papaverine may be useful in cases of vasospasm [1]. In situations of atherosclerotic in situ thrombosis, it is essential to address the underlying vascular irregularity for long-term patency, but once the tissue is necrotic, amputation is necessary. The location and extent of necrosis are determined, and a safety margin of normal tissue is also removed. Sometimes, a larger area is excised to allow for better prosthetic fitting and improved functionality [28].

Post-Op and Follow-up Care

In the aftermath of revascularization surgery, it is crucial to monitor the patient for signs of successful therapy, such as the return of a palpable pulse, audible arterial Doppler signals, and an apparent increase in perfusion. However, medical professionals must also evaluate the sensory function and foot dorsiflexion to detect compartment syndrome [29].

For patients with a history of thromboembolism or thrombophilia, vitamin K antagonists are necessary to prevent further occurrences. For patients who have non-valvular atrial fibrillation and ALI with a cardioembolic etiology, novel oral anticoagulants (dabigatran, apixaban, rivaroxaban, edoxaban) should be considered [29,30].

Patients with thrombosis complicating atherosclerotic lesions can improve long-term vascular patency and survival by receiving long-term statin and antiplatelet therapy. Dual antiplatelet treatment with aspirin and clopidogrel is recommended for at least one month following stent placement. These interventions are vital for maintaining the long-term health of patients with ALI [1].

Complications

Thrombolytic therapy is a widely accepted treatment for ALI. However, during the administration of thrombolytics, patients are at high risk of developing hemorrhagic complications. Therefore, close neurological monitoring is essential to detect any abnormalities that may arise during the procedure [31]. If any new neurological or neurovascular abnormalities are identified, thrombolytic therapy should be discontinued immediately, and a non-contrast head computed tomography should be performed to rule out cerebral bleeding. In addition, sudden onset of flank discomfort, tachycardia, hypotension, or significant decrease in hemoglobin concentration (>1 g/dL) may indicate spontaneous or catheter-induced retroperitoneal hemorrhage, in which case aortography or computed tomography angiography should be considered, along with discontinuation of thrombolytic infusion [31,32].

Distal embolization is another potential complication of thrombolysis. While sustained thrombolytic drug infusion may lead to emboli resolution, surgical embolectomy or suction may be necessary if resolution does not occur. Moreover, thrombolytic therapy can result in minor bleeding from the arterial access site(s), which can usually be treated with manual compression. However, hematoma or pseudoaneurysm may develop, requiring ultrasound-guided thrombin injection or even open surgery [33,34].

Reperfusion damage is a common complication of thrombolytic therapy that occurs due to the release of high amounts of potassium, myoglobin, and reactive oxygen species into the systemic circulation. Hyperkalemia in cardiomyocytes can cause arrhythmias, and high levels of myoglobin can crystallize in renal tubules, potentially leading to renal failure and obstruction. Overloaded local intracellular antioxidant mechanisms can cause cell death and release of inflammatory cytokines and cell adhesion molecules, leading to tissue swelling, increased compartment pressures, and ultimately compartment syndrome. Management of reperfusion syndrome involves intensive hydration, potassium temporization, diuresis, and dialysis. Prophylactic fasciotomy may also be considered if new-onset pain and paresthesia suggest compartment syndrome [1].

Reperfusion Injury

Following successful revascularization, patients with severe ischemia may be at risk of developing reperfusion damage, which is characterized by limb swelling and a rapid increase in compartmental pressures [35]. The onset of severe pain and limb hyperesthesia is also reported by patients. Compartment syndrome is more common in the anterior compartment of the leg, where the peroneal nerve may be compromised. A compartment pressure greater than 30 mmHg is typically required to diagnose compartment syndrome, which is based on clinical symptoms. In such cases, thrombolysis is contraindicated, and other revascularization methods should be considered [1]. Surgical fasciotomy is the recommended treatment for compartment syndrome to prevent irreversible damage to soft tissue and the brain. It involves cutting the fascia surrounding the affected compartment to relieve pressure and prevent further injury. Close monitoring of patients after fasciotomy is crucial, as they may be at risk of infection and wound healing complications. Early detection and prompt intervention are essential to ensure the best possible outcome for patients with compartment syndrome [36].

Long-term Management

Following successful endovascular revascularization for acute limb ischemia, long-term treatment should prioritize the maintenance of native vessel or conduit patency and reduce modifiable cardiovascular risk factors. Smoking cessation, diabetes management, statin therapy, counseling on diet, and exercise should all be addressed to achieve this goal. Patients should attend follow-up evaluations in a clinic weekly, monthly, and every three months thereafter, with a reassessment of symptoms, vascular ultrasound, arterial brachial indices, pulse volume recordings, and laboratory tests such as complete blood count, electrolyte panel, serum blood urea nitrogen, serum creatinine, and coagulation studies if necessary [37]. Patients with the underlying thromboembolic disease are commonly anticoagulated with warfarin or a new oral anticoagulant, while those who had angioplasty or stenting are started on dual antiplatelet therapy with aspirin (81 or 325 mg) and clopidogrel (75 mg). However, some patients may require antiplatelet monotherapy and short-term anticoagulation. Currently, there is limited data to precisely guide antiplatelet and anticoagulation management [38] Recent research suggests that low-dose rivaroxaban is more effective than aspirin alone in preventing significant adverse cardiovascular and limb events [39].

COVID-19 and Arterial Thrombosis

Individuals previously infected with COVID-19 have been shown to have an increased risk of arterial thrombotic events and subsequent mortality due to a hypercoagulable state during the pandemic. The etiology of thrombosis in these patients is still uncertain; however, inflammation-induced endothelial damage or invasion of endothelial cells by a free-floating aortic thrombus via ACE2 receptors may cause arterial thrombosis. The decision to proceed with surgical intervention in these patients depends on the severity of the patient's clinical condition with COVID-19 and the morbidity of that illness [40].

Numerous studies have been conducted to investigate the medical and surgical management of these patients. Anticoagulation is commonly used as a palliative intervention for patients, while thrombectomy (both endovascular and open) is employed for others. Despite anticoagulation, there is a significant risk of thrombosis due to the ongoing damage to endothelial cells caused by the virus. Moreover, individuals previously infected with COVID-19 are at increased risk of postoperative mortality [41].

In conclusion, ALI is a medical emergency that requires prompt identification and treatment to prevent irreversible damage to limb viability and mobility. The use of catheter-directed thrombolysis and open surgery has been established as effective treatment options, with newer techniques such as suction thrombectomy devices showing promising results. Thrombolytic drugs, particularly third-generation agents, have been developed to enhance the effectiveness of lysis while minimizing the risk of hemorrhagic complications. The use of adjunctive anticoagulation and antiplatelet medications may aid in revascularization, and the Society of Interventional Radiology's practice recommendations regarding fibrinogen monitoring remain inconclusive. Despite these advancements, future research is necessary to determine the optimal treatment approach for acute limb ischemia.

It is worth noting that the COVID-19 pandemic has resulted in a reduction in hospital visits for non-COVID-19-related medical emergencies, including acute limb ischemia. Delayed presentation of ALI can result in irreversible limb damage and amputation, and prompt identification and treatment are essential. Clinicians must remain vigilant in identifying and promptly treating acute limb ischemia, particularly in individuals with risk factors for the condition, during the COVID-19 pandemic and beyond. Moreover, measures such as telemedicine and home-based management may be explored to ensure that patients receive timely and appropriate care, even in the face of healthcare system disruptions caused by the pandemic.

Competing Interests

The authors declare that they have no competing interests.

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Ethics

Given the nature of the manuscript, an IRB ethical Approval is exempted.

Acknowledgment

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Conflict of Interest

The authors declare that they have no conflict of interest.

Funding

This research received no external funding.