Emerging Vascular Interventions In The Diabetic Foot
Ensuring adequate vascularity can be critical to facilitating the healing of diabetic foot ulcerations. Accordingly, these authors discuss current mainstay approaches in vascular surgery as well as emerging techniques that could make a difference in the future for limb salvage in patients with diabetes and chronic wounds.
Despite its primary classification as an endocrine disease, diabetes mellitus manifests with wide-ranging secondary effects on multiple organ systems, including the cardiac, vascular, nervous and renal systems. With almost 18 million Americans diagnosed with diabetes mellitus in 2007 and an expected increasing prevalence, the burden of the complications of the disease on the medical system is best represented in its economic cost. The American Diabetes Association estimates $116 billion in excess medical expenditures and another $58 billion in lost productivity from the affected patients.1
The particular challenges diabetes mellitus presents to the practicing podiatrist often manifests in the architectural sequelae of the secondary effects of diabetes, mainly in the predilection toward ulcer formation and subsequent infection, as well as the contribution of long-standing diabetes toward poor wound healing and chronic limb ischemia. However, the seemingly inevitable progression of the diabetic foot toward the feared complication of amputation is no stranger to the medical practitioners who treat these patients.
Indeed, researchers have estimated that diabetes mellitus, worldwide, is associated with 25 to 90 percent of all amputations.2 Diabetes mellitus and its secondary complications, when considered as a single disease entity, are the leading cause of lower extremity amputations not due to trauma in the United States.3 A 2002 analysis of patients discharged from U.S. hospitals demonstrated that vascular disease, including diabetic complications, was the underlying pathology leading to amputations in 82 percent of cases.4
The impact of increasing numbers of revascularization procedures on the rate of amputation in patients with vascular disease remains a current source of continuing debate. In the 2007 update to the Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Artery Disease (TASC II), the authors noted that older U.S. studies had shown no reduction on amputation rates with the increase of revascularization procedures.5
Nonetheless, more recent data from Sweden, Denmark and Finland reflected a significant decrease in amputations with the increased availability and use of both endovascular interventions and surgical revascularization.5 United Kingdom data demonstrated a plateau in major amputations that may reflect increasingly successful limb salvage.5 Recent studies of Medicare B claims between 1996 to 2006 confirmed trends similar to the European studies, namely a clear decrease in total lower extremity amputations with increasing numbers of vascular interventions.6 The advent of emerging interventions in vascular surgery may hold promise in reducing amputations and increasing limb salvage for those with diabetic feet.
Understanding The Pathophysiology Of The Diabetic Foot
Before delving into the details of what vascular surgery has to offer, a brief review of diabetic foot disorders is beneficial. The diabetic foot arises from the combined effects of hyperglycemia on the vascular, immune and nervous systems of the affected patient, projecting subsequent sequelae on the musculoskeletal architecture of the foot.
Sensory neuropathy results in neglect of minor traumatic events that trigger ulcer formation. Motor neuropathy contributes to clawing of the metatarsophalangeal joints, altered weight distribution and repeated painless fractures that create the Charcot foot deformity. The altered weight load on the foot, in addition to the peripheral vascular disease and microcirculation disorders associated with long-standing diabetes, contribute to further pressure ulceration and delayed healing. A predilection to infection results from the poor circulation in combination with the inhibitory effects of hyperglycemia on the immune system.7-9
Ultimately, the combined effect of these physiological disturbances underlie the propensity of the diabetic foot toward slow healing plantar ulcers that may penetrate to underlying tissues and consequent infectious complications, such as osteomyelitis and abscess formation.8
It is well established that a multidisciplinary team is essential for optimal management of the diabetic foot. This multidisciplinary team would include (among others): primary care physicians to manage the effects of diabetes and provide continuing surveillance of complications; podiatrists to manage local ulcerations; and prosthetists to balance the needs of the structurally altered foot.9-25 While one cannot reverse the complications of neuropathy, the greatest benefit a vascular surgeon can give to a patient with diabetes in this multidisciplinary scheme is the ability to reperfuse an ischemic foot. This allows the surgeon to limit tissue loss and improve healing capacity.
A Closer Look At Mainstay Techniques In Vascular Surgery
Limb salvage in patients with peripheral vascular disease has been greatly aided by the advancement of modern vascular surgical reconstruction strategies and improvements in endovascular techniques. Primary amputation, amputation prior to revascularization attempts, has fallen to the wayside in favor of revascularization in the treatment of limb ischemia. This now accounts for less than a quarter of initial treatments on the first diagnosis of peripheral vascular insufficiency.10
The long-held gold standard in vascular surgery for lower extremity revascularization procedures is the performance of an arterial bypass with autologous saphenous vein graft. A 20-year review of infrainguinal revascularization procedures published in 2011 reaffirmed the superiority of saphenous vein as the bypass material of choice in all positions over time, regardless of the inflow or outflow vessel.11 The five- and 10-year patency rates for femoropopliteal bypass, the most common procedure, were 83 percent and 63 percent respectively with an associated limb salvage rate of 89 percent over the same period.
A recent trend that emerged over the study period was the increased use of polytetrafluoroethylene as the conduit material. The five- and 10-year patency rates (62 percent and 24 percent) and limb salvage rates (71 percent and 68 percent) were inferior to those of saphenous vein.11 However, this synthetic material allowed the expanded availability of bypass surgery to patients who previously had no surgical option due to inadequate vein for harvest, less than optimal pre-surgical conditions, or earlier use of saphenous vein for coronary artery bypass, all of which are common comorbidities in patients with diabetes.
While the most durable and effective revascularization procedure is surgical bypass, endovascular angioplasty stenting provides a less invasive alternative in properly selected patients. Specifically, patients with short-segment disease in proximal locations, such as isolated iliac artery stenosis, are prime candidates for angioplasty and endovascular stent placement.12
While many trials have shown poorer long-term patency rates with more frequent interventions when researchers compare endovascular interventions to open surgery, the large multicenter BASIL trial from the U.K., found that limb salvage rates were similar between balloon angioplasty and bypass surgery.13 Unfortunately, angioplasty has been disappointing in dealing with complex infrainguinal disease.13
What The Literature Reveals About Emerging Vascular Interventions
When considering amputation for severe vascular disease, the current indications at the time of writing are limited to the clinical situations in which vascular reconstruction is contraindicated. For example, patients who would not be ideal candidates for limb salvage include: those whose anatomy does not allow for surgical bypass (i.e. such as having no distal target for outflow); those who have prohibitive baseline comorbidities like end-stage congestive heart failure; or those whose limbs are compromised to such a degree by their disease burden that one could not establish a useful extremity even if revascularization were successful.
However, technologies have emerged in the field of vascular surgery over the last decade to increase the patient population in whom we can offer a chance at revascularization and, as such, a chance to avoid amputation.
Though it was first described in the 1990s, the endovascular technique of subintimal angioplasty has become established recently in the treatment of lower extremity arterial occlusions. Conceptually similar to an endovascular bypass procedure, the procedure consists of creating a dissection in the subintimal plane to cross an occluded arterial segment and then re-enter the patent distal true arterial lumen. One would expand this dissection plane with an angioplasty balloon, thus creating a non-anatomic bypass canal free of atheromatous plaque.14
Meta-analyses on subintimal angioplasty outcomes have shown results at the 12-month timeframe of a primary patency of 55.8 percent, clinical success rates of 50 to 70 percent and an associated limb salvage rate of 80 to 90 percent. However, researchers noted that limb salvage rates at four years were as low as 34 percent.15,16 The adoption of this technique has been able to expand the scope of therapy to those with complex infrapopliteal occlusions, and those patients considered to have a high cardiac risk who are otherwise unsuited for open surgical repair.
Another emerging technological advancement in interventional therapy has been the addition of endovascular atherectomy to the vascular surgeon’s arsenal. The method by which one undertakes atherectomy — the removal of atherosclerotic lesions from the artery — is based highly on the system the surgeon uses. Options include ablative lasers and excisional modalities. Ablative lasers can be associated with thermal damage complications. Vascular surgeons use excisional modalities to strip or grind the atherosclerotic plaque from the arterial walls, but these modalities have the potential to create embolic complications downstream from the affected area.17
The theoretical advantages of atherectomy over traditional angioplasty and stenting are in lesion debulking and minimizing barotrauma to the artery. Eliminating this stretch injury on the arterial walls has the potential to reduce the rate of restenosis by minimizing a known stimulant for neointimal hyperplasia.18
While atherectomy is not a novel recent technique, the introduction of new technology has generated renewed interest in interventional circles.17 The rapid evolution of this technology can be reflected in the fact that the FDA has approved four new atherectomy devices for the treatment of peripheral arterial disease over the last decade.19 Previous iterations of these devices, however, have not demonstrated any significant long-term benefit over angioplasty. It remains to be seen whether the new generation of devices will show additional clinical benefit.
Other Modalities On The Horizon
While technological improvements have brought new solutions to the operating room, basic scientists are seeking to bring further innovations to the forefront in the laboratory. Experimentation relevant to vascular surgery that holds promise in wider adoption toward wider clinical usage includes: the creation of artificial biological blood vessels; and adopting signaling manipulations in ischemic limbs to increase collateralization and possibly instigate new blood vessel formation.
Over the last 20 years, we have seen a wide expansion in the use of artificial and non-human biologic materials in vascular grafting for the purposes of repair and revascularization. Advances in this technology are leading toward the creation of synthetic bypass conduits utilizing autologous cells and tissues from the affected patient. Christopher Breuer, MD, and Toshiharu Shin’oka, MD, who are affiliated with the Yale University Interdepartmental Program in Vascular Biology and Therapeutics, have developed a tissue engineered vascular graft that utilizes cells derived directly from the designated host. This graft has entered clinical trials and may signal the next generation of technology to enter the vascular operating theater.20
Efforts to increase limb salvage in patients who are otherwise unfit for intervention have led to the concept of increasing the body’s native adaptation to ischemia: collateralization. Experimental ischemia models in animals have demonstrated that direct injection of growth factors, bone marrow derived stem cells, or progenitor cells into affected limbs have promoted angiogenesis.21,22
From this base, human trials of stem cell injections into patients with critical limb ischemia have started with promising early results. To date, the interventions to induce therapeutic angiogenesis show more efficacy in improving subjective measures, such as relief of calf pain, than in objective end points such as ulcer healing or limb salvage. However, researchers have noted trends toward significance in these aspects in some studies.23,24
Key Considerations With Amputation And Limb Salvage
The desire for limb salvage has an understandable psychological weight. When considering the impact on overall health that is associated with amputations, limb salvage takes on an additional importance. However, in the interests of the patient for the best clinical outcome, physicians must be sensitive to the need for secondary amputation in the face of repeated treatment failure. The most common causes of secondary amputation are unreconstructable vascular disease and persistent infection despite aggressive vascular reconstruction.5 Carrying a diagnosis of diabetes mellitus is an independent risk factor associated with amputation.6
Compared to a patient in whom limb salvage is attainable, an amputee faces increased difficulties in terms of daily energy expenditure and post-operative mobility. These challenges are directly related to the degree of amputation. Highly conservative approaches are favored, especially in consideration of preservation of the knee joint.
Despite the most ambitious rehabilitation protocols, amputees who have experienced a below-the-knee amputation achieve post-surgical ambulation rates up to 80 percent.25 (See “What One Study Reveals About Energy Expenditure And Ambulation Rates As A Function Of Amputation Level” at left.)
In contrast, those who have above-the-knee amputation achieve bipedal ambulation only 38 to 50 percent of the time. These results drop dramatically when there is bilateral amputation. All amputees experience a greater energy expenditure when walking in comparison to non-amputated controls. However, amputees with a preserved knee joint have a 10 to 40 percent increase in exertion whereas those with an above-the-knee amputation face at least a 60 percent elevation.25
The human cost of major limb amputation in terms of morbidity and mortality is heavy. In one series of 954 amputations, researchers reported a median survival of 20 months after above-knee amputations and 52 months after below-knee amputations. Having diabetes mellitus as a comorbidity contributed to a 50 percent decline in survival at 60 months in this population.26 However, these deaths within the first decade after amputation are usually due to preexisting medical conditions. Major causes of death include congestive heart failure, myocardial infarction, respiratory failure, disseminated cancer, stroke and renal failure.27
Care for the diabetic foot represents an opportunity for a multidisciplinary team consisting of health practitioners from the fields of primary care, podiatry, vascular surgery, and rehabilitation medicine to make a palpable impact on a patient’s life through a natural spectrum of disease.
While surgical arterial bypass with saphenous vein remains the mainstay and gold standard for therapy in patients with peripheral vascular compromise, the advent of endovascular therapies has allowed for increasing rates of limb salvage in patients in whom surgery would not be feasible. As our endovascular technologies advance through techniques such as subintimal angioplasty and excisional atherectomy, we are able to expand our interventions to populations who would have otherwise been relegated to primary amputation and its attendant difficulties.
Similarly, the utilization of synthetic grafts has made it possible to expand the pool of patients amenable to open surgical procedures. In the future, we may see a revolution in graft technology engineered from patient-derived tissues, possibly allowing for superior graft patency and limb salvage rates, as well as new modalities for treating limb ischemia that rely on increasing blood flow without the need for surgical or endovascular intervention.
We must keep in mind, however, that we may improve clinical outcomes in many patients by performing a limited amputation rather than having them undergo a futile attempt at limb salvage through repeated failed interventions.
Ultimately, as members of the healthcare team, we must emphasize the significant role of prevention through glycemic control, careful and vigilant surveillance, and the maintenance of overall well-being.
Dr. Ziegler is a surgical resident physician in the Department of Surgery at the Yale University School of Medicine.
Dr. Blume is an Assistant Clinical Professor of Surgery in the Department of Orthopaedics and Rehabilitation at the Yale University School of Medicine. He is the Director of Limb Preservation at the Yale New Haven Hospital in New Haven, Conn. Dr. Blume is a Fellow of the American College of Foot and Ankle Surgeons.
Dr. Sumpio is the Chief of the Section of Vascular Surgery at the Yale University School of Medicine.
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12. Muhs BE, Gagne P, Sheehan P. Peripheral arterial disease: clinical assessment and indications for revascularization in the patient with diabetes. Curr Diab Rep. 2005;5(1): 24-29.
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20. Hibino N, Villalona G, Pietris N, Duncan DR, Schoffner A, Roh JD, Yi T, Dobrucki LW, Mejias D, Sawh-Martinez R, Harrington JK, Sinusas A, Krause DS, Kyriakides T, Saltzman WM, Pober JS, Shin’oka T, Breuer CK. Tissue-engineered vascular grafts form neovessels that arise from regeneration of the adjacent blood vessel. FASEB Journal. 2011;25(8):2731-9.
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23. De Haro J, Acin F, Lopez-Quintana A, Florez A, Martinez-Aguilar E, Varela C. Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. Heart Vessels. 2009;24(5):321-328.
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For further reading, see “A Guide To New Advances In Vascular Imaging” in the June 2009 issue of Podiatry Today, “Vascular Intervention In Difficult Wounds” in the July 2002 issue or “How To Perform A Thorough Vascular Exam” in the July 2007 issue.