Peripheral Arterial Disease: The Best (Zuzuki and Kawarada) explain the Worst (PAD) in Diabetic Foot Disease

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Peripheral arterial disease (PAD) can result in a range of serious complications and death. Accurate and timely diagnosis is important for wound healing and proper preoperative workup in foot and ankle surgery. Offering insights from the latest PAD guidelines and research, these authors offer a closer look at non-invasive diagnostic methods and a brief review of medical, endovascular and surgical treatment of PAD.

Peripheral arterial disease (PAD) affects approximately 8 million Americans who experience significant and costly morbidity such as leg amputation and death.¹ There is a 20 percent incidence of PAD in patients 75 years of age and older. Despite the prevalence of the disease and associated cardiovascular risk, only 25 percent of these patients undergo treatment.²
Early diagnosis and treatment of PAD not only improves quality of life, it saves lives. According to the REACH Registry, approximately 16 percent of patients with PAD have other atherosclerotic changes, such as cerebrovascular disease and/or coronary artery disease.² Consequently, patients with PAD have a mortality risk that is two to three times greater than patients who do not have PAD and patients with PAD reportedly die 10 years earlier on average than those without PAD.³ Remember that PAD is not just a “leg cramping problem” but an ominous sign of declining health that requires our close attention.
Diabetes is an independent and significant risk factor for developing PAD. Currently, there are approximately 25.8 million people with diabetes or approximately 8.3 percent of the population in the United States.⁴ The American Diabetes Association consensus statement presents clinical data that one in three patients with diabetes mellitus are known to have PAD.⁴ The statement urged clinicians to participate actively in the diagnosis and treatment of this disease.

Recognizing The Challenges Of Diagnosing PAD

Although we often associate PAD with intermittent claudication (calf pain caused by walking), this classic symptom is present in only 10 percent of patients with PAD. Surprisingly, 50 percent of people with PAD have no symptoms while 40 to 50 percent may present with atypical, non-specific leg complaints.⁵

Diagnosing PAD can be challenging visually and clinically. A recent systematic review of clinical studies on PAD found that a physical examination of the lower extremities (e.g., palpation of pulses and “classic findings” such as atrophic skin changes or lack of hair growth) alone is unreliable and “not independently sufficient to include or exclude the diagnosis of PAD.”⁶ The authors of the review strongly recommended the use of non-invasive vascular diagnostics to diagnose PAD.⁶

What You Should Know About Diagnosing Lower Extremity PAD

When it comes to diagnosing PAD, we follow a three-step checklist.
1. Obtain a full history and perform a physical exam to determine the pre-test probability of PAD.
2. For high-risk individuals, perform a non-invasive perfusion test.
3. After confirming a PAD diagnosis with non-invasive perfusion testing, notify the patient’s primary care physician or cardiologist. For evaluation and treatment of symptomatic PAD, the patient should get a referral to a vascular specialist (i.e. vascular surgeon, interventional cardiologist or interventional radiologist). This referral is more urgent for patients with severe ischemia.
Diagnosing lower extremity PAD starts with the patient history and physical exam. The American College of Cardiology Foundation/American Heart Association 2011 PAD guideline indicates that people 65 years of age and older are at risk for PAD. The 2005 PAD guideline noted that people 70 years of age and older were at risk for PAD.^5,7 Smokers and patients with diabetes 50 years of age and older are also at high risk for PAD.^5,7 A history of coronary artery disease, stroke or other types of PAD (carotid, renal and mesenteric) or claudication are also known risk factors. Finally, one should consider the presence of gangrenous wounds or chronic lower extremity wounds (non-healing over four weeks) as PAD risk factors.
The physical exam should include observation of the skin for any skin lesions, gangrenous wounds or abnormal coloration. Then palpate for abnormal skin texture and pulses (pedal, ankle, popliteal and femoral arteries) and check for the capillary refill of toes and feet.
This “pre-test” probability assessment dictates the necessity of non-invasive testing. Random screening of PAD with non-invasive testing methods is not recommended as it is a waste of resources and is not reimbursable.

A Closer Look At Non-Invasive Testing Methods For PAD

Peripheral arterial flow in the foot and ankle consists of two categories: macro- and microcirculation. Macrocirculation involves three major arteries (anterior tibial, posterior tibial and peroneal arteries) with diameters up to 3 mm. Microcirculation consists of non-pulsatile arterioles within the skin capillary bed with a diameter of approximately 0.012 mm. There are various non-invasive perfusion testing methods that are commercially available and in wide use. The macrocirculation tests include the ankle-brachial index (ABI), the toe-brachial index (TBI), pulse volume recording (PVR) and the handheld Doppler exam. The two microcirculation tests are transcutaneous oxygen monitoring (TCOM or TcPO₂) and skin perfusion pressure (SPP).
Ankle-brachial index. The “resting” ABI is the most well known, non-invasive vascular testing tool. Clinicians perform an ABI test with a handheld Doppler probe and a blood pressure cuff while a patient lies in a supine position. Calculate the ABI by dividing the ankle pressure by the brachial systolic pressure.

The ABI has a known sensitivity and specificity of over 90 percent. In terms of interpretation, an ABI below 0.9 is abnormal and diagnostic of PAD. However, non-compressible calcified leg arteries in patients with diabetes or those on dialysis may yield falsely elevated ABI results, sometimes over the non-physiological value (1.4+). Accordingly, this tool is highly unreliable in these populations. Simply put, a low ABI below 0.9 indicates PAD but seemingly “normal” ABI values may be misleading or unreliable in ruling out PAD, especially in those with diabetes and patients on dialysis.⁸
Toe-brachial index. The TBI is less influenced by calcification but is limited in application. Analogous to the ABI, the TBI is systolic blood pressure of the great toe divided by the systolic brachial blood pressure. Clinicians can measure toe pressure by placing a small toe cuff around the great toe and attaching a plethysmography probe at the toe tip.
The digital arteries in the great toe are less affected by arterial calcification. However, this test is limited if the great toe is wounded or previously amputated. Interpretation of toe pressure and TBI vary in the literature. In general, a toe pressure over 70 mmHg or TBI over 0.5 is normal, and anything below is diagnostic of PAD. In general, we consider toe pressure measurements to be limited in usefulness and the TBI diagnostic criteria for PAD is too vague to utilize in a clinical setting today.
Pulse volume recording. The PVR is a versatile macroperfusion test, even with arterial calcification. The PVR uses blood pressure cuffs (inflated to 65 mmHg) around the lower limbs. This effectively compresses limb veins while the transducer detects the pressures in pulsatile arterial flow. This facilitates documentation of the arterial waveform. Pulse volume recording has a major advantage of being unaffected by calcified arteries. This is a morphologic test without numerical values and interpretation is difficult. One should always pair PVR with other quantitative non-invasive vascular tests.
A normal PVR waveform shows a rapid rise and fall with sharp peaks — similar to what one might see with an EKG — while flatter, non-pulsatile flow may represent ischemia and diagnosis of PAD. The PVR waveforms can be triphasic, biphasic, monophasic or stenotic on the waveform shape, which one can interpret as normal (or minimal ischemia), mild, moderate and severe ischemia.
Handheld Doppler waveform test. This provides a quick macroperfusion analysis. When other diagnostic tools are unavailable or when the patient cannot be in a supine position (i.e. those with contracted limbs due to stroke, morbidly obese patients or those in wheelchairs), a handheld Doppler device may offer a quick method to assess the macroperfusion of the lower extremity. One can elicit Doppler waveforms by applying a Doppler probe at a right angle with conductive gel over the foot and ankle arteries. A clinician may assign normal or minimal ischemia, mild, moderate and severe ischemia based on the morphology of the Doppler waveforms.
Transcutaneous oxygen monitoring. This is a microperfusion test with many limitations. Transcutaneous oxygen monitoring, which was developed in the neonatal intensive care unit for the monitoring of newborns, measures tissue oxygenation or transcutaneous partial oxygen pressure (TcPO₂) in mmHg. The transcutaneous oxygen monitor uses Clarke electrode sensors to measure oxygen molecule permeation through the skin as heating elements warm the epidermis. One would place the sensors on the patient’s skin surface with adhesive plastic fixation rings.
Transcutaneous oxygen monitoring is a clinically validated tool that reveals a linear correlation between partial pressure oxygen readings and wound healing potential.8 In terms of interpretation of the test, normal values are > 50 mmHg, and wound healing potential drops as TcPO₂ values decline.⁸Traditionally, 30 mmHg correlates with a diagnosis of severe PAD or critical limb ischemia (CLI).
Unfortunately, there are many physical limitations to monitoring oxygen. One cannot place the sensor over the plantar foot as the plantar skin is too thick for oxygen permeation. Clinicians cannot monitor transcutaneous oxygen to measure edematous limbs or attach the sensor on dry and flaky skin without compromising the accuracy of the test. These factors eliminate many of our patients as proper study candidates. As the electrodes are highly sensitive to temperature and humidity changes, there is also a significant margin of error when assessing tissue oxygenation level in an exam room (as opposed to a temperature controlled vascular lab). The test is also time consuming. Skin preparation, calibration and the testing procedure have a cumulative duration of up to 45 minutes per patient.

Due to these limitations, we have abandoned transcutaneous oxygen monitoring testing and replaced it with SPP testing. Many recent comparative studies have suggested that SPP has higher accuracy than transcutaneous oxygen monitoring in assessing wound healing potential.^9-11
Skin perfusion pressure. Skin perfusion pressure is a newer alternative technology to transcutaneous oxygen montoring for assessing the skin capillary blood pressure. To measure SPP, one would ensure supine positioning of the patient and place a laser Doppler sensor over the specific skin site with a pressure cuff wrapped around the limb. The computer operates the laser Doppler and pressure cuff in combination with guidance through a gentle inflation/deflation process that detects sufficient arterial compression and identifies the point at which blood flow resumes. This provides SPP measurement in mmHg.
Skin perfusion pressure is a clinically validated tool with a strong correlation to wound healing potential even in patients with diabetes and this test is not affected by calcified leg arteries. Skin perfusion pressure has fewer physical limitations in comparison to transcutaneous oxygen monitoring and clinicians can measure SPP in plantar skin, edematous limbs or those with dry, flaky skin.^11-14Skin perfusion pressure testing is in wide use for the diagnosis of PAD/CLI as well as the assessment and validation of the lower extremity perfusion in catheter labs before and after endovascular intervention procedures.^15,16
Normal perfusion in lower extremities correlates with SPP values over 50 mmHg. A SPP measurement between 30 and 50 mmHg is diagnostic of PAD while a SPP measurement below 30 mmHg is diagnostic of severe PAD or CLI.¹³ Wound healing potential correlates with SPP in a sigmoid curve and wound healing potential drops dramatically when the SPP is below 40 mmHg.^13,14 We also confirmed this correlation with our own retrospective analysis. In the SPP measurement of 412 limbs and their wound closure time, we validated that SPP measurement over 40 mmHg is a reliable predictor of good wound healing potential.¹⁷

What The Authors Recommend For The Diagnostic Workup

In our wound care center, we use the SensiLase PAD-IQ System (Väsamed) for comprehensive non-invasive vascular testing of the lower extremities. The diagnostic device can measure SPP in mmHg (microcirculation test) and record PVR waveforms (macrocirculation test) with its laser Doppler sensor and the computer automated cuff.
We established that the combined use of SPP and PVR tests allows us to reserve ABI tests in our practice. The latest clinical study comparing various non-invasive perfusion tests to magnetic resonance angiography found SPP to be the most sensitive in the diagnosis of PAD with a sensitivity of 85 percent while ABI had a sensitivity of 30 percent.¹⁸ In this particular study, ABI failed to diagnose 70 percent of PAD patients tested due to calcified leg arteries. This illustrates the need to incorporate more sensitive testing methods such as SPP and PVR for the perfusion of patients with diabetes and patients on dialysis.
To illustrate the utility of SPP over ABI, we obtained SPP and ABI in supine and dependent positions on 29 patients (40 limbs) with critical limb ischemia.¹⁶ Patients with critical limb ischemia often sleep with their legs “dangling” or in a dependent position to increase blood flow to the legs and abate rest pain. Dramatic increases in SPP values occurred (over 30 mmHg increase) with postural change from supine to dependent. However, we observed only a slight increase in ABI.
In addition, a recent prospective trial observed the effect of oral cilostazol (Pletal^®) in 14 patients (20 limbs) with CLI and showed improved symptoms in the majority of cases with a significant increase in SPP values while no changes in ABI occurred.¹⁹

Understanding The Angiosome Concept In Regard To SPP Testing

Skin perfusion pressure can be a powerful diagnostic tool and wound healing predictor when one appropriately places laser Doppler sensors around the foot and ankle. This facilitates incorporation of the angiosome concept. The SPP has another distinct advantage over transcutaneous oxygen monitoring with the ability to measure plantar foot microcirculation.
 

Attinger further developed the “angiosome” concept, which Taylor introduced in 1982.^20,21 Angiosomes, three-dimensional blocks of tissue fed by source arteries, are somewhat analogous to the relationships between peripheral nerves and dermatomes. The human body consists of at least 40 angiosomes with three source arteries and six angiosomes feeding the foot and ankle.²¹
The angiosomes of the foot and ankle are composed as follows.
• The anterior tibial artery (and dorsalis pedis) angiosome supplies the anterior leg and the dorsum of the foot.
• Posterior tibial artery angiosomes supply the medial ankle and the plantar foot, including the heel.
• Peroneal artery angiosomes supply the lateral ankle and the lateral heel.
The heel is unique in that there is redundant supply from two arteries: the calcaneal branches of the posterior tibial artery and the peroneal artery. As Attinger and colleagues described, the knowledge of the angiosome concept can be helpful in choosing the best incision placement in foot and ankle surgery.²¹

Pertinent Insights On Medical Treatment, Prevention And Risk Reduction Of PAD

In the updated 2011 PAD guidelines, medical treatment of patients with PAD aims to optimize the medical status of each patient to prevent further atherosclerosis and/or atheroembolic processes.⁷Medical treatment of PAD should start with optimization of cholesterol (LDL below 100 mg/dL), blood pressure (140/90 mmHg), blood glucose (HbA1c below 7%) and weight (body mass index between 18.5 and 24.9 kg/m². Physicians should also encourage physical activity of at least 30 minutes for five to seven days per week.
The guidelines place a new emphasis on smoking cessation.⁷ One should ask smokers or former smokers about their tobacco use at every visit and give them assistance in the form of counseling, developing a plan to quit smoking, pharmacotherapy or referral to a smoking cessation program.
In regard to anti-platelet therapy, the guidelines recommend aspirin (daily dose of 75 mg to 325 mg) or clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals) (daily dose 75 mg) as safe and effective anti-platelet therapy to reduce the risk of myocardial infarction, stroke or vascular death in patients with symptomatic PAD.⁷ One should use statins, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and beta blockers in the absence of contraindications or documented adverse effects.⁷ If your patients with PAD are not on these medications, it is essential to refer them back to their internist or cardiologist to review their medications.

What The Literature Reveals About Revascularization And PAD

There is an ongoing debate over revascularization procedures for symptomatic patients with PAD. The treatment choices are divided into endovascular and surgical treatment. Generally speaking, endovascular therapy (angioplasty, atherectomy, thrombolysis and stenting, etc.) is less invasive and less traumatic for patients although application of these modalities may be limited to shorter lesions or incomplete occlusions of main leg arteries. Surgical treatment (leg bypass and endarterectomy) may be more versatile in treating long and complex lesions, and may create more durable results than endovascular treatments.
On the downside, the surgical procedure selection is limited to the availability of bypass target and conduit. Native veins are ideal while prosthetic polytetrafluoroethylene conduits are abysmal in patency and inferior to endovascular therapy.²² The surgery for leg bypass lasts many hours and prolonged recovery time may not be suitable for patients with advanced age, multiple comorbidities or dementia.²²
Although the above comparisons generally hold true, with the advancement of newer catheter and chronic total occlusion re-entry devices, endovascular therapy is certainly expanding beyond the conventional role. Indeed, many advanced institutions are now implementing an “endo-first” approach. In this approach, patients with PAD first go to a vascular interventionalist for an angiogram and endovascular therapy. They subsequently receive referrals if more perfusion is necessary or major leg amputation is required due to overwhelming ischemia and/or infection.
The BASIL study, comparing balloon angioplasty with leg bypass surgery for the treatment of severe limb ischemia, found that the two treatments achieved similar outcomes in amputation-free survival rate.^23,24 However, the study was flawed as it excluded 90 percent of the patients screened as high risk and only one-third of the patients underwent tibial revascularization.
Recently, we published a study that reflects a more realistic patient population. Our study showed “one straight line and more arterial flow to the foot” was essential for infrapopliteal intervention and we achieved a limb salvage rate of 92.4 percent at one year.²⁵ Our study suggests that pedal arch revascularization, the absence of diabetes and infected wounds are independent predictors of wound healing.²⁵
We believe that endovascular intervention can indeed be the first-line therapy for all patients with CLI, given the implementation of a multidisciplinary team approach — advocated by the 2007 TASC-II consensus panel — with sophisticated wound management by wound specialists and prudent intervention by vascular interventionalists.²²

In Summary

It is in our patients’ best interest to ensure that clinicians have a heightened awareness of PAD/CLI and the ability to diagnose these conditions with non-invasive tools. We have found that combining SPP with PVR is one of the most effective diagnostic tests in our practices to aid in limb preservation. Advances in wound management and endovascular therapy over the last several years have enabled us to preserve many at-risk ischemic limbs that previously would have faced amputation.
Dr. Suzuki is the Medical Director of the Tower Wound Care Center at the Cedars-Sinai Medical Towers in Los Angeles. He is also on the medical staff of the Cedars-Sinai Medical Center and is a Visiting Professor at the Tokyo Medical and Dental University in Tokyo.
Dr. Kawarada is affiliated with the Department of Cardiovascular Medicine at the National Cerebral and Cardiovascular Center in Osaka, Japan.
References
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