Department Editor: Tania J. Phillips, MD, FRCPC

Overall Learning Objective: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds.

Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, eklumpp@hmpcommunications.com

Completion Time: The estimated time to completion for this
activity is 1 hour.

Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds.

At the conclusion of this activity, the participant should be able to:
1. Discuss the general risk factors of peripheral vascular disease
2. Explain the urgency of critical leg ischemia
3. Describe FDA-approved medications for peripheral vascular
disease
4. Describe the nonpharmacologic treatment role of peripheral
vascular disease
5. Discuss the current pathophysiology of peripheral vascular
disease
6. Describe the clinical signs of peripheral arterial disease.

Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications, LLC, are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Chakrabarty and Phillips disclose that they have no conflicts of interest relevant to the content of this article.

Accreditation: HMP Communications, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications, LLC, is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine.

Designation: HMP Communications, LLC designates this continuing medical education activity for a maximum of 1 credit hour in category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. HMP Communications designates this continuing medical activity for .1 CEUs available to participating podiatrists.

Method of Participation: Read the article, take, submit, and pass post-test by March 10, 2004.

This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.

Release date: 5/10/03

Expiration date: 5/10/04

Presentation

A 72-year-old Caucasian woman gave a one-year history of redness, itching, and increasing pain of the left foot. She was treated by her previous dermatologist with antibiotics and topical corticosteroid ointments without any signs of improvement. She presented to the authors’ clinic for further evaluation. The pain in her left leg had progressed to the point where she was having difficulty sleeping at night and walking more than a city block. The pain diminished with rest and with dependency. Prolonged standing exacerbated the pain. There was no history of deep venous thrombosis, cellulitis, or trauma to the lower extremities.

Her past medical history was significant for status-post myocardial infarction 12 years previously, dilated cardiomyopathy, atrial fibrillation, hypercholesterolemia, chronic obstructive pulmonary disease, and depression. She had a stroke eight years previously with no residual neurologic deficits. Her past surgical history involved a femoral arterial bypass of the right leg about 20 years ago. The patient’s medications included enalapril, isosorbide dinitrate, digoxin, coumadin, pravastatin, albuterol inhaler, triamcinolone steroid inhaler, sertraline, and oxycodone with acetaminophen for her left leg pain. She was allergic to aspirin. She has continued to smoke a pack of cigarettes per day for the last 40 years. There was no report of alcohol or drug abuse.

Physical Examination

Physical examination revealed an elderly, frail woman with diffuse xerosis. Her head, neck, chest, back, and abdomen were normal. There was marked purpura and erythema of the left foot, which was exquisitely tender to palpation. There was remarkable pallor on elevation of the left foot (Figure 1) followed by reactive hyperemia on dependency (Figure 2). The left lower extremity revealed cracked, fissured skin with absence of hair. The capillary refill time of the left lower extremity was delayed. The left dorsalis pedis pulse was not palpable. The left foot was cold to touch in comparison with the right foot. Bilateral onychodystrophy and mild pitting edema were evident. The right lower extremity was warm and had palpable peripheral pulses. A scar on the medial aspect of the right thigh from previous bypass surgery was evident.

Investigation

The dorsalis pedis pulse of the left leg was inaudible using the hand-held Doppler device. An ankle-brachial index could not be measured given the patient’s severe discomfort of the left leg. An arteriogram revealed a high-grade stenosis in her left common femoral artery.

Diagnosis

The clinical history of heavy smoking, severe rest pain, and previous right femoral artery bypass surgery along with the physical examination of the lower extremities provided the diagnosis of peripheral vascular disease leading to critical leg ischemia.

Discussion

Peripheral vascular or arterial disease, an important manifestation of systemic atherosclerotic disease, has an age-adjusted prevalence of 20 percent for the general population above age 70.[1] Less than 10 percent of patients with peripheral arterial disease develop critical leg ischemia, the most severe form of peripheral vascular disease (PVD).[2] The lower the ankle-brachial index, the greater the risk for cardiovascular complications. Patients with critical leg ischemia who have the lowest ankle-brachial index have an annual mortality of 25 percent.[2]

The risk factors for peripheral arterial or vascular disease are age greater than 40, diabetes mellitus, history of smoking, hypercholesterolemia, and hypertension.[3] In essence, all the risk factors essential to the development of coronary artery disease are the same for peripheral vascular disease. The severity of peripheral vascular disease is highly correlated with the risk of myocardial infarction and ischemic stroke. Patients with peripheral vascular disease have the same mortality-relative risk as patients with a prior history of cardiovascular or cerebrovascular disease.[4,5]

Pathogenesis. Numerous pathophysiologic observations have lead to peripheral vascular or arterial disease being attributed to endothelial dysfunction.[6] The injury to the endothelium creates a procoagulant environment. The inflammatory response to the endothelial injury alters the homeostatic characteristics of the endothelium. Elevated levels of low-density lipoprotein (LDL) can be oxidized and scavenged by macrophages leading to the formation of foam cells within the arteries. Mediators of inflammation, such as tumor necrosis factor, interleukin-1, and macrophage colony stimulating factor, are induced by the presence of LDL in the foam cells.[7] Hypertensive patients have elevated concentrations of angiotensin II, which is a potent vasoconstrictor of smooth muscle eventually leading to hypertrophy. Some studies of hypertension have reported an increase in free radicals, such as superoxide anions, which curtail the formation of nitric oxide in the endothelium.[6,8,9] High plasma homocysteine levels, free radicals created by smoking, and infectious microorganisms, such as herpes viruses and Chlamydia pneumonia, have shown a correlation with atherosclerosis.[6,10,11] Despite recent advances in the pathophysiology of atherosclerotic vascular disease, much still remains to be explained.

Clinical. Nearly 15 to 40 percent of patients with peripheral vascular disease suffer from intermittent claudication, defined as pain with exertional activity relieved by rest.[1,12] Leg pain is also exacerbated by lower-extremity elevation. In patients with claudication, about five percent eventually require amputation within five years.[13] Critical leg ischemia, a late manifestation of peripheral atherosclerotic disease, is also characterized by an increased risk of amputation due to ischemic ulceration or gangrene. Many patients with intermittent claudication have a diminished quality of life with limitations to activities of daily living. The physical exam commonly reveals absent or diminished peripheral pulses, prolonged capillary refill time, rubor with dependency, pallor on elevation, loss of hair, atrophic xerotic skin, and thickened nails.[14]

Diagnosis is mainly based on history and physical examination. The presence of atherosclerotic risk factors (e.g., diabetes, hypercholesterolemia) assists in the diagnosis of peripheral vascular disease.[12] Auscultation of bruits over the vessels and palpation of peripheral vessels are further cues to aid physicians in the diagnosis of peripheral vascular disease. Noninvasive modalities, such as the ankle-brachial index, provide additional information along with invasive methods, such as arteriography. Other modalities, such as x-ray digital subtraction angiography, have shown positive results in the diagnosis of peripheral arterial disease.[15]

Treatment

The primary goals of treatment in patients with peripheral vascular disease are to relieve their exertional pain or rest pain, maintain their activities of daily living, prevent ischemic ulceration and limb loss, and improve quality of life. Due to the systemic nature of atherosclerosis with peripheral vascular disease, patients require various management strategies involving lifestyle changes, intensive risk factor surveillance and treatment, pharmacologic therapy, and invasive procedures, such as angioplasty or bypass surgery, for severe cases.

Lifestyle modifications are the initial strategy for the management of mild to moderate peripheral vascular disease. Exercise training has demonstrated improvement in patients with claudication. Two separate studies have demonstrated a formal, rigorous exercise program to be equivalent to bypass surgery or angioplasty.[16,17] Smoking cessation has been shown to retard the progression of peripheral arterial disease to critical leg ischemia. Smoking cessation programs involving nicotine replacement therapy and the antidepressant drug, bupropion, are highly recommended.[18]

Medical management of underlying risk factors, such as diabetes, hypertension, and hypercholesterolemia, may slow the progression of peripheral vascular disease, a manifestation of systemic atherosclerosis. There is not sufficient data from clinical trials focused on the benefit of patients with peripheral vascular disease with regards to the treatment of diabetes, hyperlipidemia, and other underlying risk factors.[19] Nevertheless, patients with peripheral arterial disease should be adequately treated for risk factors of peripheral vascular disease given the substantial risk of mortality similar to patients with coronary artery disease.[19]

The two Food and Drug Administration (FDA)-approved medications for patients with peripheral vascular disease are pentoxifylline and cilostazol. There is significant controversy about the benefit of pentoxifylline. Some studies did not reveal a significant benefit of pentoxifylline compared to placebo-treated patients.[20,21] A meta-analysis of randomized, controlled trials suggested a possible benefit but further large-scale, multicenter trials are warranted to provide clear evidence of improvement in walking performance.[22] Several trials showed clinically significant improvement in walking distance for cilostazol-treated patients versus placebo on standardized treadmill testing.[23–25] One prospective trial comparing cilostazol versus pentoxifylline demonstrated statistically greater efficacy for cilostazol-treated patients in terms of pain-free and maximal walking distance at one month and thereafter.[26] Patients’ perception of physical health and quality of life correlated with the increase in ambulation. The primary mechanism of action for cilostazol, a phosphodiesterase type III inhibitor, involves inhibition of platelet aggregation and potent vasodilatory activity. Reports have demonstrated that cilostazol is 10 to 30 times more potent than aspirin in inhibiting platelet aggregation and potentiates the effects of endothelium-derived prostacyclin in addition to creating a favorable lipid profile.[27–29] The recommended dose of cilostazol is 100mg orally twice a day.[23,26] Aspirin should be provided to all patients as an effective agent in diminishing the risk of fatal and nonfatal ischemic events in patients with peripheral arterial disease.[19]

There is no current pharmacologic therapy for patients with critical leg ischemia, the end stage of peripheral vascular disease. Studies have shown that revascularization procedures in patients with severe leg ischemia resulted in low patient mortality and excellent long-term limb salvage.[30] Evidence also points to thrombolytic therapy prior to any surgical revascularization as reducing the incidence of recurrent ischemia and enhancing limb salvage especially for patients with acute bypass graft occlusions.[31] Revascularization by angioplasty or bypass surgery is the standard intervention for patients with progressively worsening claudication in whom medical therapy has failed.[32]

Patient Management

The patient underwent an invasive procedure involving intravenous heparinization and left common femoral endarterectomy a few days after visiting our clinic. The patient tolerated the procedure well and has recovered adequate peripheral pulses of the left lower extremity. She will follow-up with the vascular surgeon within the next three months.

How to obtain educational credits by reading this article

Learning Assessment: Successful completion entails scoring at least 70 percent on the questions, printing off and completing the entire answer and evaluation form (found below), and sending it to the correct address listed below. Certificates will be mailed to those who successfully complete the learning assessment by May 10, 2004.

Fax the completed form to: (610) 560-0501 or mail the completed form to: Trish Levy, CME Director, HMP Communications, LLC, 83 General Warren Blvd., Suite 100, Malvern, PA 19355

Questions

1. What is the annual mortality rate of critical leg ischemia?
A. 90 percent
B. 10 percent
C. 1 percent
D. 25 percent

2. What are some risk factors for peripheral vascular disease?
A. Smoking history
B. Diabetes
C. History of cholecystitis
D. Prior cerebrovascular event
E. A and B

3. What is the current theory regarding the pathogenesis of peripheral vascular disease?
A. Endothelial dysfunction
B. Endothelial trauma
C. Obesity
D. Prolonged immobility

4. What is the most effective FDA-approved medications for patients with peripheral vascular disease?
A. Aspirin
B. Pentoxifylline
C. Cilostazol
D. COX-II inhibitors
E. Indomethacin

5. Which characteristic physical sign of the lower extremity is quite evident for patients with arterial disease?
A. Varicosities
B. Hyperpigmentation
C. Hypertrichosis
D. Dependent rubor
E. Relief with leg elevation

6. What is the standard therapy of patients with critical leg ischemia?
A. Pharmacologic therapy
B. Diet modification
C. Weight loss
D. Exercise program
E. Angioplasty or bypass surgery

7. Which of the noninvasive modalities has shown an association with cardiovascular complications?
A. X-ray digital subtraction angiography
B. Auscultation of bruits
C. Palpation of peripheral pulses
D. Ankle:brachial index

Critical Leg Ischemia Answer Form and Evaluation

Please print clearly:

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Organization/Institute Department

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Answers (Refer to questions above. Circle one letter for each answer):

1. A B C D
2. A B C D E
3. A B C D
4. A B C D E
5. A B C D E
6. A B C D E
7. A B C D

Evaluation (circle one): Excellent (4) Good (3) Satisfactory (2) Poor (1)

Accuracy and timeliness of content: 4 3 2 1
Relevance to your daily practice: 4 3 2 1
Impact on your professional effectiveness: 4 3 2 1
Relevance of the content to the learning objectives: 4 3 2 1
Effectiveness of the teaching/learning methods: 4 3 2 1
This activity avoided commercial bias or influence YES NO

Now that you have read this article, can you:

1. Discuss the general risk factors of peripheral vascular disease YES NO
2. Explain the urgency of critical leg ischemia YES NO
3. Describe FDA-approved medications for peripheral vascular disease YES NO
4. Describe the nonpharmacologic treatment role of peripheral vascular disease YES NO
5. Discuss the current pathophysiology of peripheral vascular disease YES NO
6. Describe the clinical signs of peripheral arterial disease. YES NO

What questions do you still have?_________________________________

How will you use what you have learned from this activity?______________

All tests must be received by 5/10/04.