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Critical Limb Ischemia and Limb Salvage

(Exerpted from Wound Care Practice, Best Publishing, Ed. Sheffield, Smith, and Fife)
Fernando Boccalandro MDRichard W. Smalling, MD, PhD
From the Division of Cardiology -The University of Texas Houston Medical School at Houston

DEFINITION OF CRITICAL LIMB ISCHEMIA

ENDOVASCULAR THERAPY

PATHOPHYSIOLOGY OF CRITICAL LIMB ISCHEMIA

AMPUTATION

CLINICAL MANIFESTATIONS

FUTURE TREATMENTS FOR LIMB SALVAGE

DIAGNOSTIC TESTS

IMAGES

THERAPEUTIC OPTIONS

REFERENCES

SURGICAL REVASCULARIZATION

Definition of Critical Limb Ischemia & Limb Salvage:
Peripheral vascular disease of the lower extremities comprise a clinical spectrum that goes from asymptomatic patients, to patients with chronic critical limb ischemia (CLI) that might result in amputation and limb loss. Critical limb ischemia is a persistent and relentless problem that severely impairs the patient functional status and quality of life, and is associated with an increased cardiovascular mortality and morbidity. It can present acutely (i.e. distal embolization, external compression, acute thrombosis, etc.) or, in the majority of cases, as chronic CLI which will be the main focus of this chapter.

Authors have proposed different definitions for chronic CLI taking into account a variety of hemodynamic measurements in combination with clinical findings, since the diagnosis based on the usual clinical manifestations of CLI (i.e. chronic non-healing wounds, resting pain, or gangrene) could also be caused by other non-vascular diseases. A practical and simple definition is the one proposed by the European Working Group on CLI. This group defined CLI as the presence of ischemic rest pain requiring analgesia for more than two weeks, or ulceration, or gangrene of the lower extremity with an ankle systolic blood pressure ≤ 50 mmHg and/or toe systolic pressure  ≤ 30 mmHg.

Limb salvage can be defined as any revascularization procedure, surgical or percutaneous aimed at improving the blood flow in the ischemic limb with the purpose of preventing limb loss, and ideally achieving wound healing and resolution of chronic ischemic pain or gangrene.
 
Pathophysiology Of Critical Limb Ischemia
Chronic CLI in the vast majority of cases are related to advanced atherosclerotic disease. Other diseases have to be kept in mind by the clinician, specially in young patients, those with ulcers in atypical locations, or those with few or no risk factors for CLI (Table 1). Chronic CLI secondary to atherosclerosis develops when arterial stenosis reaches a critical point in which the blood flow supplied to the distal extremity is insufficient to provide the basal tissue oxygen demand. This occurs despite two compensatory mechanisms: post-stenotic arteriolar vasodilatation and development of collateral circulation. When the basal tissue oxygen demand cannot be met by the peripheral vascular system, ischemic injury occurs in the tissues with the lowest blood supply and necrosis results leading to tissue destruction, the appearance of ulceration, gangrene, and rest-pain. Besides the tissue necrosis secondary to the poor oxygen demand/supply relationship seen in these patients, they are also threatened by severe microvascular dysfunction secondary to a local and systemic inflammatory response and a thrombotic milieu that worsens their poor capillary blood flow. Also reported in this group of patients are: impaired vasomotor response, vasospasm, increased platelet aggregation, impaired fibrinolysis, abnormal healing, micro-thrombus formation, increased leukocyte activation and adhesion, increased capillary permeability with interstitial edema, local activation of the immune system with increased levels of C-reactive protein and other systemic inflammatory mediators. These seem to be accentuated in diabetics, which present with a combination of macro and micro angiopathy due to accelerated atherosclerosis, increased blood viscosity, thrombosis and an enhanced inflammatory response, which leads to a more distal and diffuse disease that might significantly limit the possibility of an effective revascularization. The presence of neuropathy in this later group also plays an important role in the pathogenesis of CLI. Neuropathy increases the risk of severe toe and foot lesions due to the absence of pain during and after trauma and the lack of early recognition of wounds that require prompt attention. It also might alter the mechanics of normal gait, worsening the perfusion on certain points of repeated pressure on the foot and toes, and predisposing some of these areas for wound formation. The lack of blood flow predisposes the ischemic tissues in diabetics to have extensive wounds with poor healing potential even after minor trauma. Diabetes mellitus predisposes the formation of early wet gangrene with polymicrobial infections that are difficult to treat due to the limited blood supply, predisposing them to the formation of deep wound infections and osteomyelitis.
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Clinical Manifestations Of Critical Limb Ischemia
Evaluation of patients with suspected CLI is of great importance to confirm the suspected clinical diagnosis, to assess the severity of limb compromise, and to rule out the possibility of other diseases that might mimic vascular insufficiency.

The first assessment in patients with suspected CLI should always be to look for the presence of signs of acute limb ischemia that will require immediate attention and emergent revascularization. They can be remembered by the rule of the 5-“P’s”: Absence of Pulse, presence of resting Pain, Pallor, Paresthesia and Paralysis.

Chronic CLI is present usually in patients with previous history of intermittent claudication, smokers, diabetics, history of cerebrovascular or coronary artery disease, who now present with one or all the four hallmarks of CLI: resting pain, non healing ulcers, dry gangrene, and absence of palpable pulses.

Resting Pain: Patients with CLI usually describe their pain as a throbbing pain, dull ache, or numbness that classically worsens when the patient elevates the leg, and in the evenings or nights. It is relieved by lowering the leg to a dependent position and, interestingly, in contrast to patients with intermittent claudication, the resting pain of CLI can actually improve slightly with deambulation due to mild improvement in the arteriolar blood flow caused by the effects of gravity.

Non Healing Ulcers: Ulcers usually appear in the distal areas of the extremities such as the tips of the toes, or at bony prominences. They are associated with severe pain (except in diabetic patients with neuropathy). They are generally dry, have poor vascularity, and contain a base that can be pale, gray or black with gangrenous tissue (Figure 1).

Dry Gangrene: The presence of devitalized tissue is the end-stage clinical manifestation of CLI. It usually appears as very painful areas (except in diabetic patients with neuropathy) of necrotic and dry tissue (Figure 2). If it become infected it can present with a purulent and fetid drainage with signs of inflamation surrounding the necrotic area (wet gangrene).

Absence Of Palpable Pulses:   Palpation of distal pulses are of great importance in patients in whom CLI is suspected. Posterior tibial and dorsalis pedis pulses are almost always absent, except in selected patients with severe disease above the knee with an adequate collateral flow in whom distal pulses might be appreciated. Routinely, the physician should include examination of the popliteal and femoral pulses to localize, if possible, the area of vascular compromise. When distal pulses can not be palpated, the use of a hand-held Doppler is recommended to assess for distal blood flow.

At the bedside, measurement of an ankle systolic blood pressure using a hand-held Doppler and a regular blood pressure cuff is mandatory using the dorsalis pedis or posterior tibialis. An ankle systolic blood pressure ?50 mmHg with any of the above signs of CLI confirms the suspected diagnosis. Also a bedside ankle-brachialbrachial (ABI) index is recommended. The ABI is the ratio between the ankle systolic blood pressure and the brachial systolic blood pressure. In patients with CLI the ABI is almost universally below 0.5.

One important caveat of the ankle systolic pressure and ABI is the fact that diabetic patients with severe medial artery calcification might have falsely elevated distal pressures due to the presence of a markedly decrease in their vascular compliance. This might confuse the physician with limited experience with a discordance between the clinical presentation of the patient and the hemodynamic measurements obtained by Doppler.

In patients with palpable pulses and suspected CLI, the elevation/dependency test is a simple and accurate bedside test: the limb is elevated for 60 seconds and then lowered. In the ischemic limb the elevation and the dependency results in a purple, ruborous red color. The presence of faint pulses that disappear after a six minute walk test are also very suggestive of severe peripheral vascular disease in patients with suspected CLI and palpable pulses. The six minute walk test can be done with no equipment in the outpatient setting and its results have a good correlation with a formal treadmill test.

In an excellent review of the physical examination findings in patients with peripheral vascular disease, McGee et al. found that classic signs like abnormal resting coloration of the lower extremities, atrophic skin, lack of foot hair and abnormal capillary refill time were not associated with the presence or severity of peripheral vascular disease.

 

Diagnostic Test For Patients With Suspected CLI
Noninvasive vascular testing should be the next step after a thorough clinical history and physical examination. As mentioned above, an ankle systolic blood pressure and an ankle-brachial index (ABI) are two initial tests that can be easily performed at the bedside to confirm the clinical impression of CLI.
However, other tests are needed to assess the severity and anatomic localization of the sites of vascular compromise and to predict the likelihood of wound healing and need for revascularization in the case of ischemic ulcers.

Magnetic resonance arteriography (MRA): Magnetic resonance arteriography has recently become one of the preferred methods of evaluation of CLI (Figure 3). It is a non-invasive test that avoids the use of iodinated contrast and gives detailed anatomic information including graft patency and plantar archs. The use of MRA requires experienced technologists and radiologist if used as the sole pre-operative test in patients undergoing surgical revascularization. It is a technology that is evolving and continually improving.
MRA gives information not only of stenotic areas, but also provides valuable anatomic information regarding the patency of the renal arteries as well as the distal aorta, iliac and common femoral arteries that are difficult to evaluate with duplex ultrasound. Therefore the use of MRA is currently used to plan the best percutaneous or surgical strategy based not only in the stenotic segments, but moreover in the whole vascular tree of the lower extremities.

Transcutaneous Oxymetry: Tanscutaneous oxymetry measures the transcutaneous oxygen pressure at the skin surface produced by heat induced hyperemia. Different than the previous tests that give hemodynamic or anatomic information, transcutaneous oxymetry serves as a practical functional test that evaluates the oxygen delivery to the ischemic tissues. It is used not only to evaluate the need for revascularization in patients with CLI (transcutaneous oxymetry < 40 mmHg), but also predicts outcome of patients requiring amputation, survival of skin grafts, prognosis of wound healing with hyperbaric therapy and effective percutaneous or surgical revascularization.

Laser Doppler perfusion studies:  As transcutaneous oxygen measurements, the use of laser Doppler perfusion with blood flow images are being used to assess tissue perfusion in compromised limbs. Its clinical use is currently limited, but has a good potential in the future for patients with CLI to determine need for revascularization, healing potential, amputation level determination, and revascularization success after percutaneous interventions.

Conventional angiography:   Although it represents an invasive test, conventional contrast angiography with digital substraction is the “gold standard” for patients with CLI (Figure 4). It allows a detailed evaluation of all the different parts of the vascular tree and importantly of the distal circulation and plantar archs. It can be performed from the retrograde approach using a femoral access or antegrade through the common femoral artery or the brachial/transradial approach.

The use of digital substraction angiography that can eliminate the superimposing shadows of the underlying tissues, has enhanced the resolution of conventional angiography using modern digital technology. Emphasis must always be placed in having an adequate visualization of the distal run-offs and plantar circulation, which becomes critical in patient with CLI in which revascularization is considered. New digital angiographic systems with modern technology have improved its performance and now provide better resolution with less radiation, a better three-dimensional evaluation of the vasculature and new features that help in diagnostic and percutaneous interventions with less contrast use and radiation exposure (i.e. rotational angiography with or with out rapid computer three dimensional reconstructions, landmarking, view-trace and fluoro-trace modes, etc.).

Which diagnostic method to use? Clearly the most important is to gather a complete history and detailed physical examination with an ankle systolic blood pressure or ABI to confirm the diagnosis of CLI. Once the diagnosis of CLI is made, further tests depend largely on the experience of the center where the patient is evaluated and the clinical presentation. When resting pain or gangrene is present, a functional test is not needed and the patient should be evaluated with an MRA (or duplex ultrasound in centers with expertise in this technique) to assess the anatomic localization of the stenosis, the severity of the vascular compromise and the feasibility of revascularization. Based on this initial evaluation, a revascularization strategy is made using the preferred approach (surgical vs percutaneous) according to the patients individual situation to achieve the best short and long term results. If surgery or amputation is contemplated, MRA in experienced centers might suffice as the sole diagnostic tests. However, the information provided by the MRA is not definitive, a conventional contrast angiography with digital substraction will be needed to define the patient’s vasculature and establish the best surgical technique.

For wound healing purposes, the best approach is to start with a functional test to assess the possibility of wound healing (transcutaneous oxymetry or laser Doppler perfusion) or a simple toe systolic blood pressure. If these tests show a reasonable prognosis for wound healing, a trial of intensive wound care and medical therapy should be attempted first. If this fails to achieve wound healing, or if patients have limiting intermittent claudication, or if the functional tests are suggestive of a poor healing potential; a MRA or duplex ultrasound is recommended to establish the best method of revascularization (percutaneous versus surgical revascularization). This is followed by conventional angiography if the percutaneous approach is used or if the non-invasive evaluation is inconclusive or insufficient to get the needed information before surgical revascularization.

Therapeutic Options:
Patients with true CLI have end-stage peripheral vascular disease and their therapeutic options are narrowed to either revascularization for limb salvage or amputation with its consequent limb loss. Therefore the presence of CLI is a clear indication to pursue an aggressive arterial revascularization to prevent limb loss and its associated increased mortality and morbidity. However, although revascularization represents the cornerstone in the treatment of these patients, a comprehensive team approach is needed between the primary care physician, the wound care specialist, the radiologist, the interventional cardiologist and the vascular surgeons, to offer the best care to this difficult group of patients.

The primary care physician should identify the signs and symptoms of CLI as soon as they are present, and should refer the patient as early as possible to the wound care specialist or to the vascular specialist for further assessment and aggressive treatment. The wound care specialist plays a pivotal role in the care of this patient, not only in the wound care management before and after revascularization, but also assessing the potential for wound healing and making the decision with the vascular specialists on the best timing for revascularization. All the team involved in patient care should focus in improving the patient modifiable risk factors and optimize the patient medical therapy to attempt to arrest disease progression without forgetting the high incidence of concomitant heart and cerebrovascular diseases seen in this group of patients. The vascular specialist (interventional cardiologist/radiologist or vascular surgeon) must make the best decision regarding the preferred revascularization approach based upon the disease segment to treat, the inflow and outflow in the affected limb and the underlying operative risk to the patient. Three forms of revascularization therapy are available for patients for limb salvage: surgical revascularization, endovascular therapy and thrombolysis.

 

Surgical Revascularization:
Currently there are different surgical techniques that allow long-lasting lower extremity revascularization for patients suffering from CLI. The surgical treatment depends on the anatomical area to revascularize (aorto-iliac, femoral or below the knee), the type of conduit used (venous versus prosthetic) and quality of the graft inflow and outflow runoffs. In different surgical series with unselected patients, limb salvage has been reported to be between 65 to 80%. Better success is attained when the lesion is higher in the vascular tree, with best outcomes in aortoiliac disease and worst outcomes when disease is present below the knee.

The type of graft in CLI is also an important consideration, prosthetic grafts are successfully used for aorto iliac disease with patency at 5-years close to 90%. However, the use of venous grafts have significantly improved patency rate compared with prosthetic grafts when anastomosed at the knee level (68% versus 38% at 5 yr.) or below (50% versus 12% at 5 yr); and therefore should be the preferred conduit for these anatomic sites.

One of the most important aspects of graft patency depends on the distal run-off. Patients with severe distal disease, poor pedal arches, and slow or poor distal run-offs have a very low patency rate. Thus, it is generally recommended to have at least two vessel runoffs before surgical revascularization is considered. Besides the quality of the runoffs and the severity of the vascular disease, graft failure is not uncommon in patients undergoing limb salvage due to spontaneous thrombus formation, disease progression and graft or anastomotic neointimal hyperplasia. To limit disease progression, an aggressive medical therapy should be instituted to try to the control risk factors and improve lipids, glucose, smoking and blood pressure control. The use of pharmacologic therapy to prevent graft failure remains uncertain, except for the use of antiplatelet agents that are recommended (i.e. aspirin and clopidrogel) and, in some cases, of prosthetic grafts going to the femoropopliteal or below. The use of coumadin is also advocated.

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Endovascular Therapy:
In the past two decades, endovascular therapy has revolutionized the treatment of patients with vascular disease. In this group of patients with multiple medical problems, advanced age and high surgical risk, endovascular therapy is playing a leading role in providing effective revascularization and limb salvage, while limiting the operative risks as compared with vascular surgery.

Although advances have been made in innovative technologies with emphasis in lesion modification, atheroablation and other ingenious approaches, the mainstay of endovascular therapy still is balloon dilatation and stenting (Figure 4).

Outcomes of endovascular therapy as in surgical revascularization are dependent on the distal run-off. mproved outcomes are also seen in the iliac vessels as compared with femoro-popliteal or distal disease revascularization procedures. Higher success rates are seen in patients with focal and short stenosis, with mild diffuse distal disease, in non-diabetics, in patients with reconstituted pedal arches after the procedure, and in non smokers.

The 5-year patency rates for aortoiliac disease have been reported close to 85% with stent implantation and for femoropopliteal disease, between 38 to 70% in combined series of balloon angioplasty with and with-out stenting. Although the immediate angiographic and clinical success are usually good, the long-term patency of these procedures are jeopardized by restenosis, especially at the femoropopliteal level and below the knee, requiring in many cases a repeat revascularization procedure to reestablish and maintain vessel patency.

For infrapopliteal disease, the use of angioplasty with coronary techniques have demonstrated generally a poor durability, but nevertheless its recognized role in limb salvage is now accepted (up to 80% of limb salvage was produced by Bakal et al. in carefully selected patients), preventing limb amputation and improving wound healing even in patients that are not candidates for surgical revascularization.

There have been no randomized studies comparing the current endovascular therapies with surgical revascularization for CLI, but data from different comparative studies and from series of patients suggest that they might have a similar outcome regarding limb salvage. However, the patients undergoing endovascular therapy might require repeat revascularization procedures due to the presence of restenosis to maintain patency, with the advantage of avoiding an initial surgical procedure. In patients undergoing endovascular therapy for CLI, it is also very important to aggressively modify their risk factors and maintain an adequate antiplatelet regimen with aspirin and most likely also combined with clopidrogel for long term.

 

Amputation:
For patients who are not candidates for revascularization, amputation is an important treatment option. The level of amputation and the potential for effective rehabilitation are the two main factors to take into account. More distal amputation has a better rehabilitation potential, but also have a higher risk of incomplete healing with a sub-optimal treatment, resulting in further amputations. Therefore, before the level of amputation is chosen it is important to consider the following factors besides the overall cardiopulmonary condition of the patient: Non-invasive or invasive assessment of the arterial perfusion in the affected limb to guarantee effective healing (usually a calf pressure > 70 mmHg or an ankle pressure > 30 mmHg are considered adequate for healing after amputation), the presence or absence of infection (i.e. celullitis, osteomyelitis, etc), glucose control in diabetics, adequate nutrition, and attention to any mechanical feature that might compromise wound healing after the amputation.

With the current techniques must patients with CLI can benefit from revascularization. Initially, the percutaneous approach is preferred by many centers in order to avoid a surgical procedure in a group of patients that are at high operative risk. However, the best treatment to achieve the highest rates of limb salvage and long-lasting revascularization can not be generalized; and in the best interest of the patient, needs to be individualized based on their underlying risk factors, comorbidities, severity of peripheral vascular disease and particular anatomy.

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Future Treatment Options for Limb Salvage
Many efforts are devoted to try to improve the revascularization outcomes in patients suffering from CLI. Use of debulking techniques with rotational atherectomy has been disappointing. Effectiveness of laser angioplasty for limb salvage is still undetermined, although it also has been disappointing in other vascular applications. One area of intense research is the prevention of restenosis in the peripheral vasculature in which the use of drug eluting stents holds a bright future. Other emerging strategies to prevent or treat restenosis include the use of beta or gamma radiation, platelet derived growth factors (PDGF), angiopeptin, arterial gene therapy with nitric oxide donors, stent gene delivery, drug electroencapsulation, and crio or photoangioplasty.

With this endovascular armamentarium, also novel pharmacologial approaches are being studied to try to improve the restenosis rates (i.e: iloprost and prostaglandin derivates, cilostazol, low molecular weight heparins and direct thrombin inhibitors, etc) and improved vascular growth and collateral vessels formation (gene therapy and vascular growth factors). Also newer graft materials are being tested and some novel techniques in which gene delivery is combined with new prosthetic graft materials are being developed to prevent graft thrombosis and to improve graft patency.

Protocol For Limb Salvage
As a guide for the clinician, we provide this simple algorithm to help in the management of patients with CLI:
Protocol For Limb Salvage
 
Table 1: Differential diagnosis for chronic critical limb ischemia.
Atheroembolism.
Cardioembolism.

     Atrial fibrillation.
     Patent foramen ovale.
     Left ventricular thrombus.
     Endocarditis.
Drugs induced.
     Ergotamine abuse.
Hypercoagulable states.
     Homocystinemia
     Antithrombin III deficiency
     Protein C and S deficiency
Insect bites
     Brown recluse spider.
Parasitic diseases
     Filariasis.
Radiculopathies and spinal stenosis.
Systemic vasculitis.
     Polyarteritis nodosum
     Thromboangitis obliterans
     Wegner’s disease
     Essential cryoglobulinemia
     Takayasu’s disease
     Giant cell arteridities
Sympathetic dystrophy
Vasospastic disorders

     Raynaud’s phenomenon
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Images
Figure 1 Figure 4A
Figure 2 Figure 4B
Figure 3  

FIGURE 1:
Non-healing ulcer in a patient with chronic limb ischemia.

Figure 1


FIGURE 2:
Gangrenous foot due to severe advanced chronic limb ischemia in a diabetic patient.

FIGURE 2:  Gangrenous foot due to severe advanced chronic limb ischemia in a diabetic patient.


FIGURE 3:
Magnetic resonance angiography showing bilateral total superficial femoral occlusions in a patient with a non-healing ulcer of the right lower extremity. (CFA = Common femoral artery, PFA = Profunda femoral artery, SFA = Distal superficial femoral artery filling from collateral flow from the profunda femoral artery with no visible proximal run-off).

Figure 3:  Magnetic resonance angiography


FIGURE 4:
(a) Digital substraction angiography of the right leg of the patient in Figure 3 showing a stump in the take off of the superficial femoral artery.
Figure 4A:  Digital substraction angioraphy of the right leg.

FIGURE 4:
(b)
Regular angiography in the same patient following a percutaneous retrograde superficial femoral artery reconstruction using the popliteal approach. Note the nitinol stents placed in the superficial femoral artery with its reconstituted runoff and the differences in the quality between digital substracted and regular angiography.
Figure 4B:  Regualr angiography in the same patient.


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The University of Texas Medical School at Houston
     
The Memorial Hermann Center for Wound Healing
6411 Fannin
Houston, TX 77030-1501
Telephone: 713-704-5900 
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Last Updated May 22, 2007