Critical limb ischemia (CLI)

Overview

Some individuals with peripheral artery disease may develop critical limb ischemia, a condition with a significant morbidity and fatality rate. To avoid amputation and decrease death, early diagnosis, adequate medical management, and revascularization are recommended. 

For these patients, a multidisciplinary strategy involving endovascular interventionists, vascular surgeons, podiatrists, infectious disease specialists, and wound care specialists is ideal.

Definition of critical limb ischemia (CLI)

Critical limb ischemia (CLI) is a clinical illness characterized by ischemic discomfort at rest or tissue loss caused by peripheral arterial dysfunction, such as nonhealing ulcers or gangrene. CLI carries a substantial risk of limb loss and cardiovascular complications in the near term. Angiography, whether noninvasive or invasive, aids in determining the feasibility and method of arterial revascularization.

CLI is traditionally described as rest discomfort or tissue loss (ulcers or gangrene) accompanied with ischemia as characterized by hemodynamic parameters such as low ankle or toe pressures or low transcutaneous oxygen (TcO2) readings. Ankle pressure requirements vary from 40 to 70 mm Hg, toe pressures from 30 to 50 mm Hg, and TcO2 levels from 20 to 40 mm Hg. Higher cut offs for tissue loss are frequently utilized under the idea that higher perfusion is necessary for wound healing, however expert consensus on these hemodynamic criteria varies between standards.

The initial standards were intended to standardize entry requirements for clinical trials of CLI in patients without diabetic mellitus, allowing for cross-study comparisons or assessing the likelihood of wound healing. 8 However, their use as CLI diagnostic tests in clinical practice is questionable.

Because of the significant overlap in readings among patients with CLI who progress or do not proceed to severe amputation or cardiovascular events, defining particular cut points for toe pressure or TcO2 for the clinical diagnosis of CLI is problematic. According to one study, they had no effect on the choice to undergo revascularization. 12 In addition to ischemia, other definitions of CLI include wound infection and osteomyelitis. 

Risk factors of critical limb ischemia

The risk factors for chronic limb ischemia are the same as those for atherosclerosis, which is the hardening and constriction of the arteries caused by the accumulation of fatty deposits known as plaque. This syndrome is exacerbated by the following factors:

• Age
• Smoking
• Diabetes
• Overweight or obesity
• Sedentary lifestyle
• High cholesterol
• High blood pressure
• Family history of atherosclerosis or claudication

Pathophysiology

CLI is most commonly caused by multi-segmental PAD with decreased blood flow in peripheral tissues. In rare situations, the presence of reduced cardiac output at the same time may worsen peripheral perfusion in CLI patients.

Even though this common symptom of PAD is diminished or absent in diabetic individuals with neuropathy, decreased oxygenation and nourishment of peripheral tissues might produce claudication or rest discomfort. Furthermore, diabetic CLI patients typically have distal arterial lesions characterized by involvement of the artery below the knee (BTK), and ulceration, necrosis, or gangrene are frequently the initial indications of PAD.

Critical limb ischemia symptoms

The most noticeable symptoms of critical limb ischemia are ischemic rest pain, which is acute pain in the legs and feet while a person is not moving, or non-healing sores on the feet or legs. Other signs and symptoms include:

• Pain or numbness in the feet
• Shiny, smooth, dry skin of the legs or feet
• Thickening of the toenails
• Absent or diminished pulse in the legs or feet
• Open sores, skin infections or ulcers that will not heal
• Dry gangrene (dry, black skin) of the legs or feet

Diagnosis

The clinical manifestation of CLI is determined by the degree of ischemia, the presence of infection, and the existence of coexisting neuropathy. Ischemic pain is typically worse when the patient is supine and frequently necessitates the use of drugs for analgesia. It has the potential to rouse people from their slumber and prevent them from wandering. Even in the absence of significant ischemia, infection can exacerbate discomfort. Neuropathy can cause tissue damage or disguise the discomfort of an ulcer.

Current recommendations call for measuring ankle pressure or the ankle brachial index. Despite the fact that medial calcinosis may provide falsely high results, toe pressures may suggest arterial blockage. TcO2 levels or skin perfusion pressures may be used to predict the likelihood of wound healing.

The primary objective is to keep limb function intact. Revascularization is a critical technique for limb preservation, however it does not enhance limb function and mobility in all patients. Cognitive impairment, nonambulatory state before to CLI, and significant comorbidities, for example, all predict a poor outcome even with revascularization. When considering revascularization, arterial imaging determines the targets and manner of revascularization.

Noninvasive angiography utilizing computed tomographic angiography (CTA) or magnetic resonance angiography, as well as duplex ultrasonography, can detect artery blockage. Duplex ultrasonography does not require contrast, although it does necessitate specialized skill and may struggle to scan the tibial arteries. Vein mapping is essential in infrainguinal illness to establish the feasibility of surgical bypass with autogenous vein.

CTA necessitates the administration of iodinated contrast, which can result in contrast nephropathy in individuals with reduced renal function. Artifacts caused by heavily calcified arteries can restrict CTA, especially in distal disease. Noncontrast time-of-flight magnetic resonance angiography is prone to artifact with nonlaminar flow typical of atherosclerotic plaque, and gadolinium contrast issues restrict its utility in advanced renal disease.

CTA and magnetic resonance angiography are occasionally insufficient for assessing the smaller tibial arteries. Nonetheless, CTA and magnetic resonance angiography can aid in the localization of disease targets as well as the planning of the technique and strategy of revascularization.

Because noninvasive imaging of distal arteries is limited, invasive angiography is frequently done to determine the possibility for revascularization and should be evaluated before severe amputation. Iodinated contrast is used in invasive angiography, which has the highest spatial resolution. With conventional and digital subtraction angiography, diagnostic cases can need as little as 30 mL of contrast for both legs.

Controlling pain, which may include drugs, relieving pressure on ulcers, wearing sheepskin boots to promote superficial collateral supply, and tilting the bed downward to increase limb reliance and perfusion are among first therapies. 2 Pain treatment has the potential to reverse sympathetic-mediated vasoconstriction. Although some of these methods only slightly improve perfusion, they may alleviate the pain associated with CLI while final therapy is planned.

Management

The objective of CLI therapy is to alleviate pain, promote wound healing, enhance patient function, avoid limb amputation, and minimize death. Lower limb revascularization is the first-line therapy for CLI patients who are able to tolerate it. CLI patients with many comorbidities or a limited possibility of effective revascularization may necessitate a primary amputation in a few circumstances. Pain management, cardiovascular risk factor control, and glycemic control all require simultaneous medical intervention. 

Medical treatment

Pain

Pain treatment is critical for enhancing quality of life and function. In most situations, sufficient peripheral revascularization alleviates peripheral discomfort. Medical therapy is required in no-option-CLI patients, who have been recognized as those who are not curable by revascularization.

Even though opioids are frequently necessary, paracetamol and nonsteroidal anti-inflammatory medications are typically the first-line treatments. Analgesic therapy administered on a regular basis is usually more effective than analgesic therapy administered on demand. In some circumstances, pain may be neuropathic due to the existence of peripheral neuropathy. Because neuropathic pain may necessitate a distinct treatment strategy, a comprehensive differential diagnosis should be undertaken.

Smoking

To lessen the progression of PAD and the risk of major amputation and cardiovascular events, smokers must quit smoking. Furthermore, smoking raises the likelihood of revascularization failure. In addition, smoking cessation lowers mortality and increases amputation-free survival in patients when compared to those who continue to smoke.

Dyslipidemia

Total cholesterol, LDL-C, triglycerides, and lipoprotein(s) are all risk factors for the development and progression of PAD. The use of statins in PAD patients is suggested. Low LDL-C levels have been shown to minimize cardiovascular events (myocardial infarction, cerebrovascular events), and the objective for all patients with PAD is LDL-C 70 mg/dL.

Hypertension

Blood pressure should be kept under control at 140/90 mmHg in all patients and 130/80 mmHg in diabetics or individuals with proteinuria, according to guidelines. Thiazide diuretics, angiotensin-converting enzymes (ACEs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and beta-adrenergic blockers are all useful blood pressure medications. ACE and ARB are considered first-line treatments in diabetic individuals.

Diabetes

Diabetes has been identified as a significant risk factor for PAD. Even though PAD is frequently associated with numerous cardiovascular risk factors, strict glycemic management should be considered to slow the onset of micro- and macrovascular problems.

Diabetes raises the risk of PAD by three to four times and the risk of claudication by two times. The majority of diabetic patients have other cardiovascular risk factors (smoking, hypertension, and dyslipidemia) that contribute to the development of PAD. Diabetes is also linked to peripheral neuropathy and lowered resistance to infection, which increases the risk of foot ulcers and infections.

Furthermore, there is a widespread belief that poor glycemic control increases the risk of diabetic foot ulcer nonhealing, despite the fact that no studies have been conducted to assess the influence of HbA1c on the outcomes of diabetic foot ulcers. HbA1c, on the other hand, is thought to be a predictor of major amputation, and hyperglycemia is an independent risk factor for death in hospitalized diabetic foot patients. The target HbA1c level is 7.0 percent to lower the risk of macrovascular complications and the development of PAD.

Antiplatelet therapy

Secondary prophylaxis with aspirin/acetylsalicylic acid (ASA) or clopidogrel is recommended in individuals with PAD and/or other cardiovascular disorders. During associated issues such as gastrointestinal bleeding, a low dosage of aspirin/ASA (75–160 mg) is beneficial and safe. Dual antiplatelet medication (ASA+clopidogrel) is advised for at least 1 month following endovascular operation in diabetic patients; beyond 1 month, ASA or clopidogrel should be maintained for life.

Surgical management of CLI

Endovascular Revascularization

Endovascular revascularization is the preferred treatment to CLI in many locations because to reduced morbidity and mortality than open surgery. The best treatment technique (endovascular versus open surgery) will be determined by anatomic considerations, comorbidities, patient desire, and operator experience and ability. 

Although inflow revascularization (aorto-iliac and femoral) can cure claudication, CLI is frequently accompanied with multilevel disease and typically necessitates outflow (tibial) revascularization in addition to treating inflow disease. The majority of the data for endovascular therapy of inflow illness comes from trials of individuals who had claudication or a combination of claudication and CLI.

Open Surgical Revascularization

The aims of surgical revascularization are to provide straight-line flow into the foot, facilitate wound healing, and restrict amputation level. Endovascular revascularization is associated with a lower risk of perioperative myocardial infarction, mortality, and stroke than open surgery. However, in the case of CLI, the potential loss of limb and function may favor surgery if endovascular treatment is not viable or effective and patients have a respectable 2-year survival.

Endovascular treatments for inflow disease (e.g., iliac stenting) and surgical revascularization for femoral or infrainguinal illness are frequently used to treat multilevel disease (eg, common femoral endarterectomy and femoral popliteal bypass). Distal aortic occlusion and iliac disease may need aorto-bifemoral bypass, contralateral femoral to femoral bypass, or axillary-femoral bypass.

The proximal SFA or profunda artery may be reached during a common femoral endarterectomy. To decrease restenosis, closure is normally performed using a bovine or synthetic patch, however primary closure without a patch is also used. Complications include wound infection (especially in obese people), hematoma, and lymph leak. This procedure offers a high long-term patency rate (>90 percent ) and considered superior to endovascular treatment particularly for heavily calcified disease involving the SFA and profunda origins.

Infrainguinal bypass, like endovascular therapy, is dependent on adequate input and outflow. The three kinds of saphenous vein bypass include reversed (translocated) vein, nonreversed vein, and in situ bypass, which involves ligating vein branches and mobilizing and anastomosing the distal ends to the artery. The latter two configurations necessitate valvulotomy excision of the valves, which can occasionally harm the venous conduit. Observational studies indicate that all three layouts have similar results.

Comparisons of Open Surgical Versus Endovascular Revascularization

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) research is the first randomized trial comparing endovascular versus open surgical therapy of patients with CLI. This experiment, which was published a decade ago, found no difference in major amputation or mortality after 5 years. The surgical group had a greater rate of myocardial infarction, wound infection, and pulmonary problems, whereas the endovascular arm had a higher rate of repeat revascularization.

However, perioperative mortality from open surgery has decreased in the last 10 to 15 years, and there are more alternatives for graft salvage with endovascular procedures. Endovascular solutions developed during the BASIL study include bare-metal stents, drug-coated balloons and stents, and a variety of wires and devices to aid in traversing lengthy occlusions.

Recently, various ideas for key CLI end objectives have focused on limb salvage (avoiding severe amputation) and the requirement for extensive reintervention (a new bypass graft, or thrombolysis of graft or treated segment). As a result of these findings, the National Institutes of Health funded the Best Endovascular Vs Best Surgical Therapy in Patients With Critical Limb Ischemia (BEST-CLI) research, a new randomized evaluation comparing open surgery versus endovascular revascularization in CLI.

Amputation

Minor amputations, such as toe, ray (toe and metatarsal), or transmetatarsal amputations, require a sufficient blood supply into the foot to promote recovery and are typically part of the treatment plan for gangrene or tissue loss following successful revascularization. In general, small amputation does not impede functional independence or need the use of a prosthesis.

Major amputations (below or above the knee) reduce functional independence and need the use of a prosthesis to walk. Although avoiding significant amputation is a priority, amputation may be necessary in the following situations: unsuccessful revascularization, patients with substantial tissue loss or infection, patients unsuitable for surgical revascularization with no endovascular choices, and potentially nonambulating patients. Up to one-third of all below-knee amputations may necessitate further surgery or an above-knee amputation due to poor recovery.

A patent popliteal pulse decreases the healing failure rate to 10%. Above-knee amputations recover at a rate of more than 90%, but only 20% of amputees achieve complete mobility with a prosthetic, compared to 60% with a below-knee prosthesis. Age, bilateral or above-knee amputations, dementia, and poor function before to amputation are all associated with poor prosthesis usage and function following major amputation.

Wound Care

Improving perfusion into the limb, addressing infection, minimizing pressure on a wound, debridement, and proper nourishment are all wound care concepts. Wound healing is aided by the removal of devitalized or diseased tissue with a scalpel, collagenases, or even maggots. To avoid osteomyelitis, antibiotics may be necessary to treat infection. Avoiding pressure on the wound (for example, off-loading the foot) also aids in wound healing.

Using sheepskin (Rooke) boots, the local temperature of the limb may be raised, which may promote superficial collateral flow and assist perfuse a limb. Negative pressure dressings (for example, vacuum-assisted) improve capillary flow and aid in wound drainage. Although there are no benefits to hyperbaric oxygen treatment for amputation prevention, it may enhance the more subjective end point of wound healing in diabetes mellitus.

Intermittent pneumatic compression may aid wound healing and prevent catastrophic amputation in individuals who do not have revascularization alternatives. Cell-based treatments, such as the injection of bone marrow-derived mononuclear cells, have not yet avoided significant amputation in patients who have no revascularization alternatives.

Medical Therapy and Surveillance After Revascularization

Failure of endovascular and surgical therapy of CLI caused by thrombosis, neointimal proliferation, or development of atherosclerosis necessitates continuous monitoring of patients by vascular specialists. Surveillance also entails aggressively addressing atherosclerotic risk factors in order to lower the high risk of cardiovascular events.

Recurrent ischemia discomfort in the leg, a lack of wound healing progression, or a drop in ankle brachial indices are all signs of restenosis or occlusion. The use of duplex ultrasonography on bypass grafts is frequent in order to discover graft stenoses for repair and to maintain long-term patency. However, in one randomized experiment, this procedure was not related with decreased amputation or greater patency, and there are no randomized investigations of its efficacy following endovascular treatment.

Following endovascular therapy, we provide a history and physical, as well as employ duplex ultrasonography in the femoral artery, especially after treating long segment disease or when symptoms or poor wound healing raise concerns about patency.

Evidence for therapy to prevent thrombosis or restenosis following endovascular procedures is limited and frequently extrapolated from coronary artery interventions. Low-dose aspirin is often taken for the rest of one's life to avoid not just thrombosis of a treated segment but also other cardiovascular problems. Clopidogrel's duration of action to prevent occlusion of endovascularly treated segments is unknown.

Most bare-metal stenting clinical trials utilize dual antiplatelet medication for 1 to 3 months, however findings from medical studies of patients with PAD may warrant extended treatment. Clinical trials in Japan show that cilostazol may minimize instent restenosis, however this has not yet been integrated into latest CLI revascularization recommendations.

The usefulness of anticoagulation for lower extremity bypass is contradictory, with some trials demonstrating a benefit over aspirin for autogenous vein against prosthetic conduit and vice versa. Most surgeons reserve anticoagulation for graft thrombosis or hypercoagulable conditions due to the higher risk of bleeding. There is no advantage to combining clopidogrel and aspirin for graft patency.

Conclusion 

For the aging population, critical limb ischemia (CLI) remains a prominent morbid disease process. Rigid recommendations for the care of patients with CLI are ineffective due to the difficulties involved in treating these individuals appropriately.

The vascular examination, the ankle-brachial index (ABI), and a number of imaging modalities make CLI diagnosis simple, but how to best treat for individuals with CLI, whether surgically or medically, is less apparent. This review will investigate these concerns and give insight into the best clinical care of patients with CLI.

Revascularization, including bypass surgery with or without thromboendarterectomy, as well as endovascular treatments, gives the highest chance of limb salvage for patients who can withstand surgical operations.