Point-Counterpoint: Is Ischemia A Direct Risk Factor For Ulceration?

   Yes, these panelists say ischemia plays a significant role in chronic ulcerations and emphasize the importance of a thorough vascular workup in these patients. By Peter A. Blume, DPM, Kenneth L. Cornell, DPM, Bauer Sumpio, MD, and John Aruny, MD    Clinicians must consider numerous factors when evaluating and treating ulcerations of the foot. Ulceration in the foot most frequently occurs as a result of a combination of neuropathy, ischemia and trauma. Ulcerations that become chronic in nature frequently result in a lower extremity that is at an increased risk of major amputation. With these ulcerations, arterial insufficiency is a key component that one must identify and manage appropriately.    Atherosclerosis of lower extremity vessels has been identified as a causative factor in lower extremity ischemia. The comorbidities of diabetes mellitus, hypertension, hyperlipidemia and tobacco use are known to accelerate the progression of lower extremity atherosclerosis.1 Patients with lower extremity arterial insufficiency may be asymptomatic or present with intermittent claudication, ischemic rest pain or tissue necrosis (gangrene). Obtaining a detailed patient history, ensuring a proper vascular assessment and pursuing a consultation with a vascular surgeon for further assessment/treatment are essential in order to promote wound healing and prevent lower extremity amputation.    When patients have a history of diabetes, macrovascular and microvascular alterations contribute to arterial insufficiency. Atherosclerosis affects the larger peripheral arteries of the cerebral, coronary and lower extremity vasculature. It has been noted that the walls of the arteries affected by atherosclerosis exhibit endothelial cell and smooth muscle cell dysfunction. In patients with peripheral arterial disease (PAD), endothelial cells have a reduced ability to proliferate and migrate in the arterial wall. Conversely, vascular smooth muscle cells demonstrate increased migration, adhesion and proliferation that contribute to the development of atherosclerotic lesions in the arterial wall.2 These focal segmental lesions in the arterial wall result in stenosis of the arterial lumen and an increased resistance to normal blood flow in the artery. Inflammation has been established as a risk marker and a risk factor for atherothrombotic disease states, including PAD.    Researchers have identified elevated C-reactive protein (CRP) levels in patients with PAD and diabetes.3 C-reactive protein has been found to bind to endothelial cell receptors, promoting apoptosis. In addition, CRP stimulates endothelial production of procoagulant tissue factor, leukocyte adhesion molecules and chemotactic substances, and inhibits endothelial cell nitric oxide synthase, which results in abnormalities in the regulation of vascular tone. C-reactive protein increases the local production of compounds, impairing fibrinolysis and lending to thrombus formation on the arterial wall.    Nitric oxide is a potent stimulus for vasodilatation and inhibits inflammation by altering the leukocyte-vascular cell wall interface. In addition to limiting platelet activation, nitric oxide acts to inhibit vascular smooth muscle cell migration and proliferation. Therefore, disruption of nitric oxide homeostasis has a significant role in the formation of atherosclerotic plaque development.4 The formation of atherosclerotic plaques in the arterial cell wall can initiate the formation of a platelet-fibrin thrombus. If the platelet-fibrin thrombus is firmly attached to the cell wall, it can continue to increase in dimension until the lumen of the artery is completely obstructed. If the platelet-fibrin thrombus is loosely adhered to the arterial cell wall, the thrombus can be sheared loose by turbulent blood flow and travel to arterioles, causing complete occlusion of the vessel.5

Pertinent Points On Contributing Factors With Arterial Insufficiency

   There is continuing debate as to whether microvascular changes at the level of the capillaries directly contribute to arterial insufficiency. Studies have shown there is capillary basement membrane thickening in patients with diabetes. However, this does not inhibit the diffusion of oxygen to the surrounding tissue.    Inadequate glycemic control contributes to abnormal capillary blood and serum viscosity, resulting in abnormal flow of erythrocytes, leukocytes, platelets and plasma proteins. Glycosylation of the hemoglobin molecule results in an increased affinity for oxygen by hemoglobin, resulting in decreased oxygen diffusion.6 Ischemia due to vascular disease leads to a reduction in tissue oxygen, nutrients and soluble mediators. When adequate perfusion has been restored, one will see a noted correction of tissue hypoxia and improvement in cutaneous microcirculation.7

How To Assess Lower Extremity PAD

   In order to perform a thorough assessment of lower extremity PAD, one must ensure a detailed physical examination and vascular laboratory evaluation. Palpating the femoral, popliteal, posterior tibial and dorsalis pedal pulses can grossly determine the level of arterial obstruction. When observing the lower extremity and foot, keep in mind that signs of subcutaneous atrophy, decreased temperature, pallor, loss of pedal hair and brittle toenails are indicative of reduced perfusion to the lower extremity.    Elevating the foot above the central venous pressure promotes draining of pooled venous blood, allowing for the accurate evaluation of arterial perfusion to the foot. Pallor of the foot upon elevation is indicative of poor arterial perfusion. Placing the extremity in the dependent position will cause an intense ruborus change in the color of the foot. The time it takes for the return of blood to the dependent extremity is a useful indicator of the severity of arterial insufficiency.8    Performing a noninvasive vascular evaluation can help determine the location and severity of obstructive lesions in the lower extremity. One can assess arterial perfusion with the ankle-brachial index (ABI). The resulting ratio indicates the severity of occlusive disease throughout the entire extremity. The ABI should be roughly equal to 1 and any ratio <0.9 is considered abnormal. However, be aware that one may get a falsely elevated reading in patients with arteries that are not compressible due to calcification of the arterial wall.    Segmental limb pressures help to localize and quantify the severity of peripheral vascular disease. One would place serial blood pressure cuffs at the proximal and distal thigh, calf and ankle. A 20 mmHg or greater reduction in pressure between segments of the ipsilateral extremity or in comparison to the contralateral extremity along the same segment is considered clinically significant for vascular lesions that limit blood flow.    One may use pulse volume recordings as an adjunctive measure to identify the location of areas of reduced flow and establish the severity of disease. Clinicians can obtain toe pressures in a similar manner to ascertain perfusion at the level of the digit. Pressures >30mmHg in the digits are considered adequate for healing of ulcerations. Transcutaneous oxygen tension (TcPO2) can provide adjunctive information regarding local tissue perfusion and often assesses the healing potential of lower extremity ulcerations or amputation sites.8    Contrast angiography continues to be the gold standard in the radiographic anatomic imaging of blood vessels in the lower extremity. However, one should only restrict this imaging to individuals who do not have a contraindication to contrast dye administration and who are planning to undergo future surgical revascularization. One usually performs a complete study of the aorta, iliac, femoral, popliteal and pedal vessels on both extremities since atherosclerotic disease is usually bilateral and occurs at multiple levels. When patients cannot receive contrast dye due to allergy or impaired kidney function, magnetic resonance angiography (MRA) is becoming an increasing useful alternative to conventional contrast angiography.9

What About The Emerging Role Of Vascular Surgery Techniques?

   Identifying the location of arterial disease dictates the plan for surgical revascularization. Lower extremity arterial disease regularly requires a bypass procedure from an inflow vessel (femoral artery) to a distal outflow artery (tibial or peroneal artery).8 Symptoms of ischemia can present in patients with aortoiliac lesions or femoropopliteal lesions. Patients with a history of diabetes tend to have a higher incidence of peripheral arterial disease in the infrapopliteal vessels compared to non-diabetic patients.    However, the arteries to the foot are often spared the severe atherosclerotic disease and provide outflow target vessels for revascularization. Selecting pedal vessels as an outflow target in bypass grafting procedures aids in providing maximum perfusion to the foot. When patients have a history of diabetes and multiple levels of arterial stenosis or occlusion, they may need revascularization at each level to achieve wound healing and limb salvage.2    Endovascular techniques are playing an increasing role in the management of lower extremity arterial disease. Vascular surgeons are performing percutaneous transluminal angioplasty of iliac, femoral and popliteal lesions in an attempt to restore adequate perfusion to the foot to allow for healing of ulcerations. Complications associated with this procedure include a difficulty in maintaining long-term patency of the occluded vessel. With the emergence of percutaneous transluminal cryoablation therapy of arterial lesions, preliminary research has shown sustained patency of arterial vessels after the procedure.10

In Conclusion

   Numerous ulcers occur because of inadequate perfusion of skin and subcutaneous tissue at rest. Arterial occlusive disease, which is common among smokers, patients with diabetes and the elderly, can lead to claudication, rest pain and gangrene in addition to localized ulceration. Other processes, such as venous stasis, pressure, trauma and vasculitis, can also cause ischemia.    However, a thorough patient history and physical assessment can help discriminate between ischemic ulcers caused by arterial disease and other types of ulcers. The key to the diagnosis of arterial occlusive disease is the patient history. Pain while walking is the most common presenting complaint and can indicate intermittent claudication. The physical assessment should include a focused exam of the affected extremities and arterial pulses. Vascular laboratory findings can also help confirm a diagnosis of arterial ischemic ulceration.    The key to treatment is improving the vascular perfusion to the affected area. Surgical revascularization is the mainstay of treatment with some interventional procedures becoming accepted. In addition to correcting underlying medical problems, treatment options should facilitate good wound and supportive care. When an adequate blood supply has been re-established, most arterial ulcers will progress to healing unless there are complicating factors. References 1. Queral LA. Evaluation and treatment of vascular insufficiency. In Myerson MS: Foot and Ankle Disorders Volume 1. WB Saunders, Philadelphia, 2000. 2. Faries PL, et. al. The role of surgical revascularization in the management of diabetic foot wounds. Am J Surg 187:34S-37S, 2004. 3. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology and management, JAMA 15:2570-2581, 2002. 4. Veves A, Akbari CM, Primavera J, et. al. Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease and foot ulceration. Diabetes 47:457-463, 1998. 5. Ouriel K. Peripheral arterial disease. Lancet 358:1257-1264, 2001. 6. Hu MY, Allen BT. The role of vascular surgery in the diabetic patient. In Levin and O’Neal’s The Diabetic Foot, 6th Edition. Mosby, Inc., St. Louis, 2001. 7. Arora S, Pomposelli F, LoGerfo FW, Veves A. Cutaneous microcirculation in the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization. J Vasc Surg 35(3):501-505, 2002. 8. Sumpio, BE, Lee T, Blume PA. Vascular evaluation and arterial reconstruction of the diabetic foot. Clin Pod Med Surg 20: 689-708, 2003. 9. Halperin JL. Evaluation of patients with peripheral vascular disease. Thrombosis Research 106:V303-V311, 2002. 10. Fava M, et. al. Cryoplasty for femoropopliteal arterial disease: late angiographic results of initial human experience. J Vasc Interv Radiol 15:1239-1243, 2004. Dr. Blume (Left) is a Clinical Assistant Professor in the Department of Orthopaedics and Rehabilitation at the Yale University School of Medicine. He is Director of Limb Preservation at Yale New Haven Hospital in New Haven, Conn. Dr. Cornell (Right) is a second-year resident within the Yale/VA Connecticut Healthcare System Podiatric Surgical Residency. Dr. Sumpio is the Chief of the Section of Vascular Surgery at the Yale University School of Medicine. Dr. Aruny is an Assistant Professor and Co-Chief of Vascular and Interventional Radiology at the Yale University School of Medicine.    No, this author says PAOD is more of an associative risk factor for ulceration but is a leading contributing factor to amputation in patients with diabetes. By Mardon R. Day, DPM    There have been several multivariate studies in the past few years that have elevated peripheral arterial occlusive disease (PAOD) from an associative risk factor to a direct risk factor for diabetic foot ulceration. I would agree that tissue ischemia impairs healing but also impacts the resiliency of skin to a variable extent. Whether or not this rises to the level of a direct risk factor for ulcerations is questionable.    This debate can often be polarizing in an academic discussion. To my knowledge, there has not been a published article that has identified PAOD as the sole etiology of diabetic foot ulceration. To be clear, there should be a clear delineation between frank ischemic gangrene and diabetic foot ulcerations. One should assume the common understanding of the latter of these two when considering this side of the debate.    For foundation purposes, it is prudent to review what is accepted as the causal pathway to diabetic foot ulceration. In 1999, Reiber, et. al., published a study in Diabetes Care that identified pathways leading to diabetic foot ulceration as well as their “component causes.”1 The researchers identified 32 unique pathways in 146 patients. Each clinical component is generally not enough by itself to cause ulceration. Rather, it is the cumulative effects of multiple, coexisting components that create the “sufficient cause” or pivotal event leading to ulceration. Within the 32 pathways, the researchers identified the three most common component risks, which were neuropathy, deformity and minor trauma.    It is the issue of commonality that, in part, fuels the debate. Is PAOD a common risk factor leading to diabetic foot ulceration? Many researchers have alleged an under-appreciation of its importance. Neuropathy is widely accepted as the “permissive” risk factor leading to ulceration. Neuropathic ulcerations comprise up to 60 percent of all diabetic foot wounds and we all understand that neuropathy alone does not cause ulceration.

Can PAOD Be A Risk Factor That Leads To An Ulceration?

   More recent studies have tried to put a finer point on what we identify as risk factors. The Seattle Diabetic Foot Study, published in 1999, evaluated 749 patients over a period of 3.7 years.2 The authors of the study identified 32 risk factors and found that nine of them were significant. They found that low TcPO2 had the lowest relative risk compared to the other eight risk factors, which consisted of loss of protective sensation (LOPS), previous ulcer, history of amputation, insulin use, increased weight, higher ankle-arm index, Charcot, impaired vision and orthostatic hypotension. The North-West Diabetes Foot Care Study, which was published in 2002, also identified nine significant risks for diabetic foot ulceration. The authors of this study identified PAOD as one of the risk factors but noted that it carried an equal relative risk for ulceration as LOPS.3

Is It More Appropriate To Call PAOD An ‘Associative’ Risk Factor?

   Many practitioners and academics would agree that PAOD is a risk factor for ulceration. However, to what degree of relative risk to severity does PAOD, in and of itself, impart?    In 1998, Abbott, et. al., used the Michigan Diabetic Peripheral Neuropathy (DPN) score and Vibratory Perceptive Threshold (VPT) as baseline comparators to evaluate 1,035 diabetic patients over a two-year period. They found that each one unit increase in VPT translated into a 5.6 percent increase in the risk of ulceration or a 28 percent average increase in the risk of ulceration for every five unit increase in VPT. For each one unit increase in the Michigan DPN score, there was a 5 percent increased risk of ulceration.4    There has not been a published study that has quantified the patient risk relative to the severity of PAOD. Aside from ischemic gangrene, how does PAOD cause an ulcer to develop independent of any other identifiable risk? With these questions in mind, I still believe PAOD is an important “associative” risk factor or component cause but it is not an independent direct risk factor for diabetic foot ulceration.

Why PAOD Is A Leading Risk Factor For Amputation

   However, PAOD in the diabetic population is unquestionably significant as a leading risk factor for amputation. Despite the best efforts of any physician treating a diabetic ulceration, if there is not adequate tissue perfusion for healing, wounds fail to heal.    In the study by Pecoraro, et. al., regarding pathways leading to amputations, the researchers identified faulty healing as one of the major component causes leading to amputation.5 The distressing effects that large vessel and small vessel disease can have on the tissue of a diabetic limb are potent impediments to healing.    As a former Diabetic Foot Fellow at the University of Texas Health Science Center at San Antonio, I had the privilege of working with Mellick Sykes, MD, an outstanding vascular surgeon. He would often describe the tissue ischemia as a drought-ridden forest that had been ignited. The water-deprived trees will be consumed until either rain or artificial fire suppressants halt the spread. This analogy applies to tissue hypoxia. Once the skin is damaged in a vascularly compromised limb, the poorly perfused skin will begin to fail and necrose.    The progression of tissue death or gangrene will continue until physicians can improve the tissue perfusion via some endovascular procedure or a level of relatively stable tissue oxygenation is reached. As anyone who encounters wounds complicated by tissue hypoxia and gangrene knows, skin becomes a needed commodity to facilitate limb salvage. Stopping the domino-like effect of skin loss is vital to that end.    Unlike any of the other factors that have been identified as risk factors for either ulceration or amputation, vascularity dictates the ability to preserve limbs in the diabetic population. References 1. Reiber GE, Vileikyte L, Boyko EJ, del Aguila M, Smith DG, Lavery LA and Boulton AJ. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care 1999 22:157-162. 2. Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Davignon DR and Smith DG. A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study. Diabetes Care 22(7):1036-1042. 3. Abbott CA, Carrington AL, Ashe H, Bath S, Every LC, Griffiths J, Hahn AW, Hussein A, Jackson N, Johnson KE, Ryder CH, Torkington R, Van Ross ERE, Whalley AM, Widdows P, Williamson S, Boulton AJM. Diabetic Medicine 2002 19:377-384. 4. Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJM. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 1998 7:1071-1075. 5. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputations: Basis for prevention. Diabetes Care 1990 13:513-521. Dr. Day is in private practice in Nashville, Tn. He is a former Diabetic Foot Fellow at the University of Texas Health Science Center at San Antonio. Dr. Day is also a member of the American Diabetes Association. For related articles, check out the archives at www.podiatrytoday.com.