Critical Limb IschemiaSarah Elsayed, MDa, Leonardo C. Clavijo, MD, PhDb,*

mated to reduce quality of life in about 2 millionsymptomatic Americans, and millions more Amer-icans without claudication are likely to sufferPAD-associated impairment.This impairment leads to significant morbidity

and health care expenditures. Perhaps, moreimportantly, PAD is a powerful independent pre-dictor of coronary artery disease (CAD) and cere-brovascular disease events and mortality (Fig. 1).1

The incidence of CLI in the United States is esti-mated at 1% of the population aged 50 yearsand at approximately double that rate in thoseolder than 70 years. Within 1 year of CLI diagnosis,40% to 50% of diabetics will experience an ampu-tation, and 20% to 25% will die. The estimated

attributable to objectively proven arterial occlu-sive disease. The term CLI implies chronicityand is to be distinguished from acute limbischemia. CLI is defined by most vascular clini-cians as those patients in whom the untreatednatural history would lead to major limb amputa-tion within 6 months.3

CAUSES OF CRITICAL LIMB ISCHEMIA

CLI is usually caused by atherosclerosis; however,it can also be caused by atheroembolic or throm-boembolic disease, vasculitis, in situ thrombosisrelated to hypercoagulable states, thromboangiitisobliterans, cystic adventitial disease, or trauma.

a Vascular Medicine Graduated Fellow, Division of Cardiovascular Medicine, University of Southern California,1510 San Pablo Street, Suite 322, Los Angeles, CA 90033, USA; b Interventional Cardiology Fellowship Program,

rsity of Southern

* Corresponding author.

KEYWORDS

Critical limb ischemia Diagnosis Management Endovascular Guidelines Review

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.comCardiol Clin 33 (2015) 3747E-mail address: lclavijo@usc.eduVascular Medicine and Peripheral Interventions, Division of Cardiovascular Medicine, UniveCalifornia, 1510 San Pablo Street, Suite 322, Los Angeles, CA 90033, USAof CLI, including different treatment options andcurrent review of the literature. PAD has been esti-

ity. The term CLI should be used for patients with

chronic ischemic rest pain, ulcers, or gangrenemortality. This article is a comprehensive review compromise of blood flow to the affected extrem-DEFINITION AND PREVALENCE OF CRITICALLIMB ISCHEMIA

Critical limb ischemia (CLI), the most advancedform of peripheral artery disease (PAD), carriesgrave implications with regard to morbidity and

KEY POINTS

Certain patient populations should be screened Critical limb ischemia is becoming increasinglyand early referral is recommended.

Meticulous history and physical examination ar Arterial profile is performed for patients suspecischemia.

Once critical limb ischemia is confirmed, lediagnosed.

In addition to guideline-directed medical therap Coronary artery disease is the major cause of dhttp://dx.doi.org/10.1016/j.ccl.2014.09.0080733-8651/15/$ see front matter 2015 Elsevier Inc. Allcost for treating CLI in the United States alone is$10 to $20 billion per year, but just a 25% reduc-tion in amputations could save $2.9 to $3.0 billionannually.2

CLI is defined as limb pain that occurs at rest orimpending limb loss that is caused by severe

r peripheral artery disease.

evalent. A high index of suspicion is warranted

ecessary.

d with peripheral artery disease or critical limb

n location and severity should be promptly

different revascularization options are weighed.

th in the critical limb ischemia population.rights reserved. car

Severe renal failure

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mortality in patients with CLI compared to thosewithout, this should prompt clinicians to recognizethe ideal care strategies to optimize risk factorsand be aware of the possibility of CAD, cerebro-vascular disease, and aortic aneurysmal disease.

NEW CLASSIFICATION OF CRITICAL LIMBISCHEMIA

CLI was first defined in 1982. The purpose of these2 prior classification systems was to classify risk ofamputation and benefit of revascularization. Overthe last 40 years, diabetes has become increas-ingly prevalent, and there has been significant

The SVS grade from each table is then catego-

Fig. 1. Prevalence overlap of different vascular terri-tories in peripheral arterial disease (PAD). (FromNorgren L, Hiatt WR, Dormandy JA, et al. Inter-SocietyConsensus for the Management of Peripheral Arterial

Elsayed & Clavijo38DISEASE AND CRITICAL LIMB ISCHEMIA

Fontaines Stages and Rutherfords Categoriesare used to classify the degree of ischemia and

sacoth

Fr(T Severe heart failure, shock Vasospastic diseases Smoking

Factors that increase demand for blood flowto the microvascular bed Infection (cellulitis, osteomyelitis) Skin breakdown Trauma

LASSIFICATION OF PERIPHERAL ARTERYFactors that increase the risk of limb loss in pa-tients with CLI include:

Factors that reduce blood supply Diabetes mellitus

Disease (TASC II). J Vasc Surg 2007;45(Suppl S):S12A;with permission.)lvageability of the limb (Table 1). CLI is amponent of the more advanced stages. Givene 3- to 5-fold increase in cardiovascular (CV)

Table 1Classification of peripheral arterial disease and critic

Fontaine

Stage Clinical Gra

I Asymptomatic 0

IIa Mild claudication I 1 Mild claudication

IIb Moderate-severe claudication II

III Rest pain II

IV Ulcers or gangrene IIIIV

omNorgren L, Hiatt WR, Dormandy JA, et al. Inter-Society CoASC II). J Vasc Surg 2007;45(Suppl S):S29A; with permission.2 Moderate claudication3 Severe claudication

4 Rest pain

5 Minor tissue loss6 Ulcers or gangrene

nsensus for theManagement of Peripheral Arterial Diseaserized into 5 clinical stages in ascending order:very low, low, moderate, high, and unsalvageablefoot. These categories provide risk stratificationof amputation risk at 1 year and estimated likeli-hood of benefit of revascularization (assuminginfection can be controlled first).

EVALUATION OF CRITICAL LIMB ISCHEMIAPATIENTSHistory

Patients with CLI present with ischemic restpain with or without skin changes, which isworse when supine and tends to lessenwhen the extremity is in the dependentposition.

al limb ischemia

Rutherford

de Category Clinical

0 Asymptomaticadvent of revascularization strategies, especiallyendovascular therapy. The Society of VascularSurgery Lower Extremity Guidelines Committeecreated a comprehensive new classificationtermed the Society of Vascular Surgery (SVS)Lower Extremity Threatened Limb ClassificationSystem (Table 2). This classification system in-cludes 3 factors: wound, ischemia, and foot infec-tion (SVS WIfI).4

tened l

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Critical Limb Ischemia 39Table 2Society of Vascular Surgery lower extremity threa

Wou

Grade Ulcer

0 No ulcer

1 Small shallow ulcer

2 Deeper ulcer with exposed bone, te

3 Extensive deep ulcer full thickness

Ische

Grade ABI A

0 0.80 >11 0.60.79 70

2 0.40.59 50

3 0.39

DBhepmliptefoec

Fier

Elsayed & Clavijo40 Motor and sensory assessment is alwaysnecessary.

Source of infection should be detected. Distinction should be made between ulcersischemic in origin (toes, foot) versus venous(oftenmalleolar) versus neuropathic (foot, sole).

Patients with a history of critical limb ischemiashould be assessed at least biannually forrecurrence by thorough physical examinationand inspection of the feet.

IAGNOSIS

aseline investigations should be done, includingmatologic and biochemical tests, such as com-lete blood count, fasting blood glucose level, he-oglobin A1c level, serum creatinine level, fastingid profile, and urinalysis (for glycosuria and pro-inuria). Resting electrocardiogram is importantr perioperative evaluation. Also, transthoracichocardiography and nuclear stress test are

g. 2. Physical examination findings. (A) Rutherford gradeford class 6.often done to provide risk stratification beforehigh-risk peripheral vascular surgery.A single academic center performed a retro-

spective review of CLI patients undergoing bypasssurgery using a contemporary preoperative evalu-ation. There was a low incidence of perioperativemortality and morbidity.5

Objectives for diagnostic evaluation of patientswith CLI should be directed at:

Confirmation of the diagnosis. Localization of the responsible lesion(s) withrange of severity (usually multilevel disease).

Assessment of the hemodynamic require-ments for successful revascularization.

Assessment of individual patients endovas-cular or operative risk.

Arterial profile provides useful information, suchas baseline ankle-brachial index (ABI), ankle or toepressure measurement, toe-brachial index, wave-form analysis, and localization of lesion (Fig. 3).

4, dependent rubor. (B) Rutherford grade 5. (C) Ruth-

Critical Limb Ischemia 41 ABI less than 1.0 is abnormal and greater than1.4 is considered noncompressible (Table 3).3

Generally, measurement of an absolute sys-tolic blood pressure 50 mm Hg at the ankleand 30 mm Hg at the toe will often implythat spontaneous healing will not occur inthe absence of successful revascularization.If there is major tissue loss, a toe pressure of30 to 40 mm Hg may still not be sufficient topromote healing.

ABI less than 0.90 is up to 95% sensitive andspecific for detecting angiographic arterialdisease, which was identified by the TransAtlantic Inter-Society Consensus (TASC)working group in 2000.

The predictors of nonhealing were found to beinsulin-dependent diabetes mellitus, end-stagerenal disease dependent on hemodialysis, andmajor tissue loss after endovascular therapy.6

Similar factors were found relevant after bypasssurgery.7 Some believe that angiosome-directedendovascular revascularization is more beneficial

to promote wound healing.8

Table 3Ankle-brachial index interpretation

Ankle-Brachial Index Interpretation

1.01.4 Normal

0.900.99 Borderline

0.7.089 Mild

0.400.69 Moderate

0.40 SevereFrom Rooke T, Hirsch A, Misra S, et al. 2011 ACCF/AHAfocused update of the guideline for the managementof patients with peripheral artery disease (updatingthe 2005 guideline). Circulation 2011;124:2025; withpermission.The next step is localization of the lesion(s) andidentification of severity, which can be done inva-sively or noninvasively before endovascular or sur-gical intervention. Imaging of the lower limbarteries can be done using duplex ultrasoundscan, digital subtraction angiography (DSA), mag-netic resonance angiography, or computed tomo-graphic angiography (Table 4).9 DSA providesdiagnostic and interventional opportunities and isthe commonly performed method to identify lowerextremity arterial anatomy.On the other hand, individuals who present with

clinical features to suggest atheroembolization,such as onset of signs and symptoms of CLI afterrecent catheter manipulation with associated sys-temic fatigue or muscle discomfort, symmetricbilateral limb symptoms, or increasing creatininelevel, should be evaluated for more proximal aneu-rysmal disease such as aortoiliac, commonfemoral, or popliteal aneurysms.

MANAGEMENT

Fig. 3. Ankle-brachial index (A)and toe-brachial index (B), bothwith normal triphasic waveforms.Management is optimally directed at:

Increasing blood flow to the affected extrem-ity to relieve rest pain.

Healing ischemic ulcerations and wound care. Avoiding limb loss.This management is achieved by guideline-

directed medical therapy and risk factor modi-fication. The mainstay of therapy remains to berevascularization by endovascular or surgicalmeans for potential candidates.

Medical Therapy

Medical therapy strategies include the use ofantiplatelet agents, anticoagulant medications,intravenous prostanoids, rheologic agents, andoptimization of risk factors for all CLI patients,

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Elsayed & Clavijo42especially for those who are poor revascularizationcandidates because of multiple comorbidities.However, few of these clinical interventions

have been evaluated adequately or have beenproven to offer predictable improvements in limboutcomes in prospective clinical trials. The201110 and 201311 American College of Cardiol-ogy Foundation/American Heart Association(AHA) Guidelines for the Management of PADaddress all therapies and emphasize the impor-tance of screening for PAD. Currently, asymptom-atic patients 65 years old should receive aresting ABI, as should patients 50 years oldwith a history of smoking or diabetes mellitus.This new recommendation stems from theGerman Epidemiologic Trial on ABI study groupthat included 6880 patients 65 years of age. Intotal, 21% of this cohort had asymptomatic orsymptomatic PAD.

Table 4Characteristics of imaging methods used to diagn

Characteristic Duplex UltrasoundDigital-SubtAngiograph

Advantages Noninvasive Can visualize &quantitateseverity.

Gold Stan High reso Can guideinterventi

Disadvantages Operatordependent

Limited by densecalcification

Invasive Radiation Contrast 2 dimensi

Adapted from White C. Intermittent claudication. N Engl J Antiplatelet therapy with aspirin is currentlyrecommended for symptomatic PAD patients(class 1).

The Critical Limb Ischemia Prevention Study(CLIPS) showed direct evidence, for the firsttime, that PAD patients treated with low-dose aspirin had a decrease in major vascularevents (P 5 .022) and CLI (P 5 .014).10

The combination of aspirin and clopidogrelmay be considered to reduce CV events in pa-tients with symptomatic lower extremity PAD,low risk of bleeding events, and high CV risk(class IIb).

In the Clopidogrel for High AtherothromboticRisk and Ischemic Stabilization, Manage-ment, and Avoidance (CHARSIMA) trial, sta-ble, high-CV-risk patients were randomlyassigned to receive aspirin plus clopidogrelversus aspirin only and were followed up fora mean of 2.3 years. The authors concludedthat dual antiplatelet therapy did not confer adifference in primary outcome of CV death,myocardial infarction, or stroke comparedwith aspirin monotherapy. Interestingly, thesymptomatic PAD cohort showed a benefitwith clopidogrel (6.9% vs 7.9%; relative risk,0.88; P 5 .046).

b-blockers are recommended to treat hyper-tension in patients with PAD (class I).

Angiotensin-converting enzyme inhibitors arerecommended in patients with PAD toreduced adverse CV events (class IIa).

Goal low-density lipoprotein is less than100 mg/dL with use of statin (class I).

Smoking cessation is also recommended(class I).

Warfarin in addition to antiplatelet therapy iscontraindicated in the absence of any other

e peripheral arterial disease

tionMagneticResonanceAngiography (MRA)

ComputedTomographicAngiography (CTA)

don

Noninvasive No radiation No contrast 3 D

Noninvasive Higher resolutionthan MRA

3 D

l

Lower resolutionthan CTA

Claustrophobia Image artifact ifstent present

Radiation (25% ofdose with DSA)

Contrast Limited bycalcification

d 2007;356:1246.proven indication for warfarin in patients withPAD (class III).

The Project or Ex-Vivo Vein Graft Engineeringvia Transfection (PREVENT) III trial, a prospective,randomized controlled trial using molecular ther-apy to prevent vein graft failure in CLI patientsundergoing infrainguinal bypass surgery, did apost-hoc analysis showing mortality benefit withstatin in the CLI population.12 Treatment of infec-tion may decrease the metabolic demands thatimpede wound healing. Investigation of angio-genic therapies, via administration of gene or pro-tein, to enhance collateral blood flow, has offeredpromise as a potential strategy to treat CLI, butfurther investigations are needed to prove theirsignificant utility and cost effectiveness.Parenteral administration of pentoxifylline is not

useful in the treatment of CLI. Parenteral adminis-tration of prostaglandin E-1or iloprost for 7 to

28 days may be considered to reduce ischemicpain and facilitate ulcer healing in patients withCLI, but its efficacy is likely to be limited to a smallpercentage of patients as specifically mentioned inthe 2006 American College of Cardiology (ACC)/AHA management of PAD guidelines. Oral iloprostis not an effective therapy to reduce the risk ofamputation or death in patients with CLI. Cilosta-zol remains first-line medical treatment whenapplicable for patients with claudication to in-crease walking distance.Mohler and Giri13 reviewed the significant differ-

ences between the ACC/AHA management ofPAD guidelines and the TASC II guidelines fortreatment and diagnosis of PAD, which are

The study investigators found that 83% of pa-tients were aware of their PAD diagnosis butonly 49% of physicians were aware.

Hypertension and hyperlipidemia weretreated less often in the PAD cohort (88%and 56%, respectively, P

Fig. 4. Angiograms of patientwith critical limb ischemia before(A) and after (B) revascularization.

Elsayed & Clavijo44from 39.9 to 54.2 mm Hg (P 5 .0001). Medianamputation-free survival (AFS) was 18 monthsand limb salvage at 3.5 years was 94%.18

Endovascular and Surgical Treatment

The goal of revascularization in patients with CLI isto establish inline flow to the foot. Examples areshown in Figs. 4 and 5. If it is unclear whether he-modynamically significant inflow disease exists,intra-arterial pressure measurements acrosssuprainguinal lesions should be measured with orwithout the administration of a vasodilator (givenpossible false low trans-stenotic pressure gradientin the setting of severe outflow disease). Catheter-

based thrombolysis is generally reserved for pa-tients with acute limb ischemia.The Bypass versus Angioplasty in Severe

Ischemia of the Leg (BASIL) trial evaluated patientswith severe lower limb ischemia caused by infrain-guinal diseasewho had a life expectancy of 2 yearsafter an intervention and were randomly assigned

Fig. 5. Critical limb ischemia patient with patent stent insound scan (left) and with color Doppler (right). (Not theto receive bypass surgery first versus balloon an-gioplasty (PTA) first as revascularization strate-gies.19 Of note, this trial was performed in thepredrug-eluting stent (DES) era.

Bradbury and colleagues19 determined thatthe primary endpoint of AFS, as well as thesecondary endpoint of overall survival (OS),was not different between the 2 strategies at1 and 3 years.

Considering the follow-up period as a whole,AFS and OS did not differ between treat-ments; however, for patients survivingbeyond 2 years from randomization, bypass

was associated with reduced hazard ratio(HR) for OS (HR, 0.61; 95% CI 0.500.75;P 5 .009) but not for AFS (HR, 0.85; 95% CI,0.501.07; P 5 .108) during the subsequentfollow-up period.

Vein bypasses and angioplasties performedbetter than prosthetic bypasses.

the anterior tibial artery on gray-scale duplex ultra-same patient shown in Fig. 4.)

These findings suggest that in patients withSLI caused by infrainguinal disease, the deci-sion whether to perform bypass surgery orballoon angioplasty first appears to dependon anticipated life expectancy.

Patients expected to live less than 2 yearsshould usually be offered balloon angioplastyfirst, as it is associated with less morbidity andlower costs.

Patients with longer expected longevity

includes the same parameters in addition to pres-ence of tissue loss, number of ankle pressure mea-surements detectable, maximum ankle pressuremeasured, a history of myocardial infarction orangina, and history of stroke or transient ischemicattack (but not diabetes). Furthermore, the Weibullmodel can be used to help predict outcomes forindividuals and subsequent optimal decision mak-ing for choice of procedure.20

The Preventing Leg Amputations in Critical Limb

Table 6Comparison of outcomes between major trials

TASC II24 PaRADISE25 BASIL26

Major amputation 30% at 1 y 6% at 3 y 11% at 1 y18% at 3 y

Symptom relief FAILURE 20% 1%

Patient population Benchmark All CLI Older Renal failure

Elsayed & Clavijo46that the volume of major amputations decreasedby 38% as a result of endovascular lower extrem-ity revascularization (LER) techniques, as its usedoubled during this time. The volume of openLER decreased by 67% from 1998 to 2007. It isworth noting that interventions declined by 20%for CLI but increased by nearly 50% for claudica-tion. Although patients today have more comor-bidities, regardless of whether treated forclaudication or CLI, the rates of amputation, theprocedural morbidity and mortality, and the lengthof hospital stay have all significantly decreased. In-frainguinal surgical bypass with at least 3 mm veinconduit at 1 year has a primary, assisted primary,and secondary patency of 68.4%, 93.3%, and95.2%, respectively.23

Primary Amputation

Patients who have significant necrosis of theweight-bearing portions of the foot (in ambulatorypatients), an uncorrectable flexion contracture,paresis of the extremity, refractory ischemic restpain, sepsis, or a limited life expectancy becauseof comorbid conditions should be evaluated forprimary amputation of the leg. Surgical or endo-vascular intervention is not indicated in patientswith severe decrements in limb perfusion (ie,ABI

13. Mohler E, Giri J. Management of peripheral arterial

disease patients: comparing the ACC/AHA and

TASC-II guidelines. Curr Med Res Opin 2008;24:

250922.

14. Stone N, Robinson J, Lichtenstein A, et al. 2013 ACC/

AHA guideline on the treatment of blood cholesterol

to reduce atherosclerotic cardiovascular risk in

adults. Circulation 2014;129(25 Suppl 2):S145.

15. Hirsch A, Criqui M, Treat-Jacobson D, et al. Periph-

eral arterial disease detection, awareness, and treat-

ment in primary care. JAMA 2001;286:131724.

16. Elsayed S, Shavelle D, Matthews R, et al. Aspirin

and clopidogrel high on treatment platelet reactivity

resistance in critical limb ischemia. J Am Coll Car-

diol 2012;59(13s1):E2114.

17. Spiliopoulos S, Pastromas G, Katsanos K, et al.

Platelet responsiveness to clopidogrel treatment after

peripheral endovascular procedures: the PRECLOP

study: clinical impact and optimal cutoff value of on-

treatment high platelet reactivity. J Am Coll Cardiol

2013;61:242834.

18. Sultan S, Hamada N, Soylu E, et al. Sequential

trial: a survival prediction model to facilitate clinical

decision making. J Vasc Surg 2010;51(5 Suppl):

52S68S.

21. Feiring A, Krahn M, Nelson L, et al. Preventing leg

amputations in critical limb ischemia with below-

the-knee drug-eluting stents. The PaRADISE (PRe-

venting Amputations using Drug eluting StEnts) Trial.

J Am Coll Cardiol 2010;55:15809.

22. Egorova N, Guillerme S, Gelijns A, et al. An analysis

of the outcomes of a decade of experience with

lower extremity revascularization including limb

salvage, lengths of stay, and safety. J Vasc Surg

2010;51:87885, 885.e1.

23. Slim H, Tiwari A, Ritter J, et al. Outcome of infra-

inguinal bypass grafts using vein conduit with less

than 3 millimeters diameter in critical leg ischemia.

J Vasc Surg 2011;53:4215.

24. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Soci-

ety Consensus for the Management of Peripheral

Arterial Disease (TASC II). J Vasc Surg 2007;

45(Suppl S):S567.

25. Feiring A, Krahn M, Nelson L, et al. Preventing leg

Critical Limb Ischemia 47compression biomechanical device in patients with

critical limb ischemia and nonreconstructible periph-

eral vascular disease. J Vasc Surg 2011;54:4406.

19. Bradbury A, Adam D, Bell J, et al. Bypass versus an-

gioplasty in severe ischaemia of the leg (BASIL) trial:

an intention-to-treat analysis of amputation-free and

overall survival in patients randomized to a bypass

surgery-first or a balloon angioplasty-first revascu-

larization strategy. J Vasc Surg 2010;51:5S17S.

20. Bradbury A, Adam D, Bell J, et al. Bypass versus

angioplasty in severe ischaemia of the leg (BASIL)amputations in critical limb ischemia with below

the-knee drug-eluting stents. The PaRADISE (PRe-

venting Amputations using Drug eluting StEnts) Trial.

J Am Coll Cardiol 2010;55:15809.

26. Bradbury A, Adam D, Bell J, et al. Bypass versus

Angioplasty in Severe Ischaemia of the Leg (BASIL)

trial: An intention-to-treat analysis of amputation-free

and overall survival in patients randomized to a

bypass surgery-first or a balloon angioplasty-first

revascularization strategy. J Vasc Surg 2010;51:

5S17S.

Critical Limb IschemiaKey pointsDefinition and prevalence of critical limb ischemiaCauses of critical limb ischemiaClassification of peripheral artery disease and critical limb ischemiaNew classification of critical limb ischemiaEvaluation of critical limb ischemia patientsHistoryPhysical Examination

DiagnosisManagementMedical TherapyEndovascular and Surgical TreatmentPrimary Amputation

SummaryReferences